72 results on '"Wierońska JM"'
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2. The GABA B receptor agonist CGP44532 and the positive modulator GS39783 reverse some behavioural changes related to positive syndromes of psychosis in mice.
- Author
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Wierońska, JM, Kusek, M, Tokarski, K, Wabno, J, Froestl, W, Pilc, A, and Wierońska, J M
- Subjects
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GABA receptors , *NEURAL transmission , *AMPHETAMINES , *PSYCHIATRIC treatment , *PSYCHOSES , *SYNDROMES , *DRUG administration , *LABORATORY mice - Abstract
Background and Purpose: An important role of GABAergic neurotransmission in schizophrenia was proposed a long time ago, but there is limited data to support this hypothesis. In the present study we decided to investigate GABA(B) receptor ligands in animal models predictive for the antipsychotic activity of drugs. The GABA(B) receptor antagonists CGP51176 and CGP36742, agonist CGP44532 and positive allosteric modulator GS39783 were studied.Experimental Approach: The effects of all ligands were investigated in MK-801- and amphetamine-induced hyperactivity tests. The anti-hallucinogenic-like effect of the compounds was screened in the model of head twitches induced by (±)1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Furthermore, the effect of GS39783 and CGP44532 on DOI-induced frequency of spontaneous excitatory postsynaptic currents (EPSCs) in slices from mouse brain frontal cortices was investigated. The anti-cataleptic properties of the compounds were also assessed.Key Results: The GABA(B) receptor activators CGP44532 and GS39783 exhibited antipsychotic-like effects both in the MK-801- and amphetamine-induced hyperactivity tests, as well as in the head-twitch model in mice. Such effects were not observed for the GABA(B) receptor antagonists. DOI-induced increased frequency of spontaneous EPSCs was also decreased by the compounds. Moreover, CGP44532 and GS39783 inhibited haloperidol-induced catalepsy and EPSCs.Conclusion and Implications: These data suggest that selective GABA(B) receptor activators may be useful in the treatment of psychosis. [ABSTRACT FROM AUTHOR]- Published
- 2011
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3. Prevention of MK-801-induced amnestic effect with combined activation of 5-HT 1A and muscarinic receptors in mice.
- Author
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Cieślik P, Rafało-Ulińska A, and Wierońska JM
- Subjects
- Mice, Animals, Receptors, Muscarinic, Brain, Cholinergic Agents pharmacology, Receptor, Serotonin, 5-HT1A, Dizocilpine Maleate pharmacology, Serotonin
- Abstract
Background: Muscarinic or 5-HT
1A receptors are crucial in learning and memory processes, and their expression is evident in the brain areas involved in cognition. The administration of the activators of these receptors prevents the development of cognitive dysfunctions in animal models of schizophrenia induced by MK-801 (N-methyl-d-aspartate receptor antagonist) administration. GABAergic dysfunction is considered as one of the most important causes of MK-801-induced spatial learning deficits., Methods: Novel object recognition (NOR) and Morris water maze (MWM) tests were used to study the anti-amnestic effect of the biased 5-HT1A receptor agonist (F15599) alone or in combinations with VU0357017 (M1 receptor allosteric agonist), VU0152100 (M4 receptor positive allosteric modulator), and VU0238429 (M5 receptor positive allosteric modulator) on MK-801-induced dysfunctions. The compounds were administered for 5 consecutive days. Animals tested with the MWM underwent 5-day training. Western blotting was used to study the expressions of 5-HT1A receptors and the level of GAD65 in the frontal cortices (FCs) and hippocampi of the animals., Results: F15599 prevented the amnestic effect induced by MK-801 in the MWM at a dose of 0.1 mg/kg. The co-administration of the compound with muscarinic receptors activators had no synergistic effect. The additive effect of the combinations was evident in the prevention of declarative memory dysfunctions investigated in NOR. The administration of MK-801 impaired 5-HT1A expression in the hippocampi and decreased GAD65 levels in both the FCs and hippocampi. The administration of muscarinic ligands prevented these MK-801-induced deficits only in the hippocampi of MWM-trained animals. No effects of the compounds were observed in untrained mice., Conclusion: Our results indicate that F15599 prevents schizophrenia-related spatial learning deficits in the MWM; however, the activity of the compound is not intensified with muscarinic receptors activators. In contrast, the combined administration of the ligands is effective in the NOR model of declarative memory. The muscarinic receptors activators reversed MK-801-induced 5-HT1A and GAD65 dysfunctions in the hippocampi of MWM-trained mice, but not in untrained mice., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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4. The Impact of LY487379 or CDPPB on eNOS Expression in the Mouse Brain and the Effect of Joint Administration of Compounds with NO • Releasers on MK-801- or Scopolamine-Driven Cognitive Dysfunction in Mice.
- Author
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Płoska A, Siekierzycka A, Cieślik P, Dobrucki LW, Kalinowski L, and Wierońska JM
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- Mice, Animals, Nitric Oxide pharmacology, Scopolamine pharmacology, Nitric Oxide Synthase Type III, Brain, Allosteric Regulation, Dizocilpine Maleate pharmacology, Cognitive Dysfunction drug therapy, Nitroso Compounds, Pyrazoles, Benzamides, Sulfonamides, Pyridines
- Abstract
The role of endothelial nitric oxide synthase (eNOS) in the regulation of a variety of biological processes is well established, and its dysfunction contributes to brain pathologies, including schizophrenia or Alzheimer's disease (AD). Positive allosteric modulators (PAMs) of metabotropic glutamate (mGlu) receptors were shown to be effective procognitive compounds, but little is known about their impact on eNOS expression and stability. Here, we investigated the influence of the acute and chronic administration of LY487379 or CDPPB (mGlu2 and mGlu5 PAMs), on eNOS expression in the mouse brain and the effect of the joint administration of the ligands with nitric oxide (NO) releasers, spermineNONOate or DETANONOate, in different combinations of doses, on MK-801- or scopolamine-induced amnesia in the novel object recognition (NOR) test. Our results indicate that both compounds provoked eNOS monomer formation, and CDPPB at a dose of 5 mg/kg exaggerated the effect of MK-801 or scopolamine. The coadministration of spermineNONOate or DETANONOate enhanced the antiamnesic effect of CDPPB or LY487379. The best activity was observed for ineffective or moderate dose combinations. The results indicate that treatment with mGluR2 and mGluR5 PAMs may be burdened with the risk of promoting eNOS uncoupling through the induction of dimer dissociation. Administration of the lowest possible doses of the compounds with NO
• donors, which themselves have procognitive efficacy, may be proposed for the treatment of schizophrenia or AD.- Published
- 2024
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5. Prenatal stress aggravates age-dependent cognitive decline, insulin signaling dysfunction, and the pro-inflammatory response in the APP NL-F/NL-F mouse model of Alzheimer's disease.
- Author
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Trojan E, Curzytek K, Cieślik P, Wierońska JM, Graff J, Lasoń W, Saito T, Saido TC, and Basta-Kaim A
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- Female, Pregnancy, Male, Mice, Animals, Amyloid beta-Peptides metabolism, Insulin, Mice, Transgenic, Mice, Inbred C57BL, Disease Models, Animal, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Alzheimer Disease metabolism, Cognitive Dysfunction etiology, Cognitive Dysfunction pathology
- Abstract
Accumulating evidence indicates that early adverse life experiences may be involved in the pathogenesis of Alzheimer's disease (AD). Prenatal stress (PS) can affect brain maturation and neuroimmune and metabolic interactions, leading to age-dependent cognitive deficits in offspring. However, a multi-faceted cause-and-effect impact of PS on the development of cognitive deficits in the process of physiological ageing and in the APP
NL-F/NL-F mouse model of Alzheimer's disease has not yet been evaluated. We have identified age-dependent cognitive learning and memory deficits using male C57BL/6 J (wild type, WT) and the knock-in APPNL-F/NL-F (KI) aged 12, 15, and 18 months. An increase in the Aβ42/Aβ40 ratio and mouse ApoE levels in the hippocampus and frontal cortex preceded the onset of cognitive deficits in the KI mice. Moreover, dysfunction in insulin signaling, including increased IRS-1 serine phosphorylation in both brain areas and the tyrosine phosphorylation deficit in the frontal cortex, suggested age-dependent insulin/IGF-1 resistance. Resistance was reflected by disturbances in mTOR or ERK1/2 kinase phosphorylation and excessive pro-inflammatory (TNF-α, IL-6, and IL-23) status in the KI mice. Importantly, our study has provided insights into the higher vulnerability to PS-induced exacerbation of age-dependent cognitive deficits and biochemical dysfunction in KI mice than in WT animals. We anticipate our study will lead to future investigation of a multi-faceted cause-and-effect relationship between stress during neurodevelopment and the onset of AD pathology, distinguishing it from changes in the course of dementia during normal ageing., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (Copyright © 2023. Published by Elsevier Inc.)- Published
- 2023
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6. Activation of Metabotropic Glutamate Receptor (mGlu 2 ) and Muscarinic Receptors (M 1 , M 4 , and M 5 ), Alone or in Combination, and Its Impact on the Acquisition and Retention of Learning in the Morris Water Maze, NMDA Expression and cGMP Synthesis.
- Author
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Wierońska JM, Cieślik P, Burnat G, and Kalinowski L
- Subjects
- Animals, Glutamic Acid, N-Methylaspartate, Morris Water Maze Test, Receptors, Muscarinic, Dizocilpine Maleate pharmacology, Receptors, Metabotropic Glutamate metabolism
- Abstract
The Morris water maze (MWM) is regarded as one of the most popular tests for detecting spatial memory in rodents. Long-term potentiation and cGMP synthesis seem to be among the crucial factors involved in this type of learning. Muscarinic (M
1 , M4 , and M5 receptors) and metabotropic glutamate (mGlu) receptors are important targets in the search for antipsychotic drugs with the potency to treat cognitive disabilities associated with the disorder. Here, we show that muscarinic receptor activators (VU0357017, VU0152100, and VU0238429) and an mGlu2 receptor activator, LY487379, dose-dependently prevented the development of cognitive disorders as a result of MK-801 administration in the MWM. The dose-ranges of the compounds were as follows: VU0357017, 0.25, 0.5, and 1 mg/kg; VU0152100, 0.05, 0.25, and 1 mg/kg; VU0238429, 1, 5, and 20 mg/kg; and LY487379, 0.5, 3, and 5 mg/kg. The co-administration of LY487379 with each of the individual muscarinic receptor ligands showed no synergistic effect, which contradicts the results obtained earlier in the novel object recognition (NOR) test. MWM learning resulted in increased cGMP synthesis, both in the cortex and hippocampi, when compared to that in intact animals, which was prevented by MK-801 administration. The investigated compounds at the highest doses reversed this MK-801-induced effect. Neither the procedure nor the treatment resulted in changes in GluN2B-NMDA expression.- Published
- 2023
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7. Endothelial dysfunction due to eNOS uncoupling: molecular mechanisms as potential therapeutic targets.
- Author
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Janaszak-Jasiecka A, Płoska A, Wierońska JM, Dobrucki LW, and Kalinowski L
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- Humans, Endothelial Cells metabolism, Superoxides, Oxidative Stress, Nitric Oxide Synthase Type III metabolism, Vascular Diseases
- Abstract
Nitric oxide (NO) is one of the most important molecules released by endothelial cells, and its antiatherogenic properties support cardiovascular homeostasis. Diminished NO bioavailability is a common hallmark of endothelial dysfunction underlying the pathogenesis of the cardiovascular disease. Vascular NO is synthesized by endothelial nitric oxide synthase (eNOS) from the substrate L-arginine (L-Arg), with tetrahydrobiopterin (BH
4 ) as an essential cofactor. Cardiovascular risk factors such as diabetes, dyslipidemia, hypertension, aging, or smoking increase vascular oxidative stress that strongly affects eNOS activity and leads to eNOS uncoupling. Uncoupled eNOS produces superoxide anion (O2 - ) instead of NO, thus becoming a source of harmful free radicals exacerbating the oxidative stress further. eNOS uncoupling is thought to be one of the major underlying causes of endothelial dysfunction observed in the pathogenesis of vascular diseases. Here, we discuss the main mechanisms of eNOS uncoupling, including oxidative depletion of the critical eNOS cofactor BH4 , deficiency of eNOS substrate L-Arg, or accumulation of its analog asymmetrical dimethylarginine (ADMA), and eNOS S-glutathionylation. Moreover, potential therapeutic approaches that prevent eNOS uncoupling by improving cofactor availability, restoration of L-Arg/ADMA ratio, or modulation of eNOS S-glutathionylation are briefly outlined., (© 2023. The Author(s).)- Published
- 2023
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8. A Comparative Study of the Impact of NO-Related Agents on MK-801- or Scopolamine-Induced Cognitive Impairments in the Morris Water Maze.
- Author
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Cieślik P, Borska M, and Wierońska JM
- Abstract
Learning and memory deficits accompany numerous brain dysfunctions, including schizophrenia and Alzheimer's disease (AD), and many studies point to the role of nitric oxide (NO) in these processes. The present investigations constitute the follow-up of our previous research, in which we investigated the activity of NO releasers and a selective inhibitor of neuronal NO synthase (nNOS) to prevent short-term memory deficits in novel object recognition and T-maze. Here, the ability of the compounds to prevent the induction of long-term memory deficits by MK-801 or scopolamine administration was investigated. The Morris Water Maze test, a reliable and valid test of spatial learning and memory, was used, in which escape latency in the acquisition phase and nine different parameters in the retention phase were measured. A fast NO releaser (spermine NONOate), a slow NO releaser (DETA NONOate), and a nNOS inhibitor, N(ω)-propyl-L-arginine (NPLA), were used. The compounds were administered i.p. at a dose range of 0.05-0.5 mg/kg. All compounds prevented learning deficits in the acquisition phase and reversed reference memory deficits in the retention phase of the scopolamine-treated mice. Spermine NONOate was the least effective. In contrast, the drugs poorly antagonised MK-801-induced deficits, and only the administration of DETA NONOate induced some improvements in the retention trial.
- Published
- 2023
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9. Design and Synthesis of New Quinazolin-4-one Derivatives with Negative mGlu 7 Receptor Modulation Activity and Antipsychotic-Like Properties.
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Kaczorowska K, Stankiewicz A, Bugno R, Paluchowska MH, Burnat G, Brański P, Cieślik P, Wierońska JM, Milik M, Nowak M, Przybyłowicz A, Kozioł A, Hogendorf A, Hogendorf AS, Kalinowska-Tłuścik J, Duszyńska B, Pilc A, and Bojarski AJ
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- Animals, Humans, Dizocilpine Maleate, Drug Design, Antipsychotic Agents pharmacology, Antipsychotic Agents therapeutic use, Quinazolinones pharmacology, Quinazolinones therapeutic use, Receptors, Metabotropic Glutamate drug effects, Receptors, Metabotropic Glutamate metabolism, Schizophrenia drug therapy, Schizophrenia metabolism
- Abstract
Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu
7 NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu7 activity in the T-REx 293 cell line expressing a recombinant human mGlu7 receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3 H )-one ( A9-7 , ALX-171 , mGlu7 IC50 = 6.14 µM) was selective over other group III mGlu receptors (mGlu4 and mGlu8 ), exhibited satisfactory drug-like properties in preliminary DMPK profiling, and was further tested in animal models of antipsychotic-like activity, assessing the positive, negative, and cognitive symptoms. ALX-171 reversed DOI-induced head twitches and MK-801-induced disruptions of social interactions or cognition in the novel object recognition test and spatial delayed alternation test. On the other hand, the efficacy of the compound was not observed in the MK-801-induced hyperactivity test or prepulse inhibition. In summary, the observed antipsychotic activity profile of ALX-171 justifies the further development of the group of quinazolin-4-one derivatives in the search for a new drug candidate for schizophrenia treatment.- Published
- 2023
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10. New 1,2,4-oxadiazole derivatives with positive mGlu 4 receptor modulation activity and antipsychotic-like properties.
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Stankiewicz A, Kaczorowska K, Bugno R, Kozioł A, Paluchowska MH, Burnat G, Chruścicka B, Chorobik P, Brański P, Wierońska JM, Duszyńska B, Pilc A, and Bojarski AJ
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- Allosteric Regulation drug effects, Animals, Antipsychotic Agents chemical synthesis, Antipsychotic Agents chemistry, Dose-Response Relationship, Drug, Mice, Molecular Structure, Oxadiazoles chemical synthesis, Oxadiazoles chemistry, Structure-Activity Relationship, Antipsychotic Agents pharmacology, Oxadiazoles pharmacology, Receptors, Metabotropic Glutamate metabolism
- Abstract
Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu
4 receptor positive allosteric modulatory activity (EC50 = 282-656 nM). Selectivity screening revealed that they were devoid of activity at mGlu1 , mGlu2 and mGlu5 receptors, but modulated mGlu7 and mGlu8 receptors, thus were classified as group III-preferring mGlu receptor agents. None of the compounds was active towards hERG channels or in the mini-AMES test. The most potent in vitro mGlu4 PAM derivative 52 (N-(3-chloro-4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)picolinamide) was readily absorbed after i.p. administration (male Albino Swiss mice) and reached a maximum brain concentration of 949.76 ng/mL. Five modulators ( 34 , 37 , 52 , 60 and 62 ) demonstrated significant anxiolytic- and antipsychotic-like properties in the SIH and DOI-induced head twitch test, respectively. Promising data were obtained, especially for N-(4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)picolinamide ( 62 ), whose effects in the DOI-induced head twitch test were comparable to those of clozapine and better than those reported for the selective mGlu4 PAM ADX88178.- Published
- 2022
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11. The mGlu 7 receptor in schizophrenia - An update and future perspectives.
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Cieślik P and Wierońska JM
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- Animals, Glutamic Acid, Ligands, Male, Mice, Antipsychotic Agents pharmacology, Antipsychotic Agents therapeutic use, Receptors, Metabotropic Glutamate metabolism, Schizophrenia drug therapy, Schizophrenia metabolism
- Abstract
The mGlu
7 receptor belongs to the III group of metabotropic glutamatergic (mGlu) receptors and physiologically serves as an "emergency" receptor that is activated by high, almost pathological, glutamate concentrations. Of all mGlu receptors, this receptor is most highly expressed in the brain. Additionally, relatively intense expression of the receptor was found at the periphery, for example in the bowels or in the reproductive system of male mice, but this review will be focused predominantly on its role in the brain. In the CNS, the receptor is expressed presynaptically, in the center of the synaptic cleft, at the terminals of both excitatory glutamatergic and inhibitory GABAergic neurons. Thus, it may regulate the release of both glutamate and GABA. Schizophrenia is thought to develop as a consequence of a disturbed glutamatergic-GABAergic balance in different parts of the brain. Thus, the mGlu7 receptor may be involved in the pathophysiology of schizophrenia and consequently constitute the target for antipsychotic drug discovery. In this review, we summarize the available data about mGlu7 receptor ligands and their activity in animal models of schizophrenia. At present, only a few ligands are available, and negative allosteric modulators (NAMs) appear to exert antipsychotic-like efficacy, indicating that the inhibition of the receptor could constitute a promising target in the search for novel drugs. Additionally, the data concerning the expression of the receptor in the CNS and putative mechanisms by which its inhibition may contribute to the treatment of schizophrenia will be discussed. Finally, the polymorphisms of genes encoding the receptor in schizophrenic patients will also be provided., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2022
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12. Procognitive activity of nitric oxide inhibitors and donors in animal models.
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Cieślik P, Kalinowski L, and Wierońska JM
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- Alzheimer Disease chemically induced, Animals, Arginine analogs & derivatives, Arginine therapeutic use, Cognitive Dysfunction chemically induced, Dizocilpine Maleate, Enzyme Inhibitors therapeutic use, Male, Mice, Nitric Oxide antagonists & inhibitors, Nitric Oxide Synthase Type I antagonists & inhibitors, Nitroso Compounds therapeutic use, Open Field Test drug effects, Rotarod Performance Test, Schizophrenia chemically induced, Scopolamine, Spermine analogs & derivatives, Spermine therapeutic use, Alzheimer Disease drug therapy, Cognitive Dysfunction drug therapy, Nitric Oxide metabolism, Nitric Oxide Donors therapeutic use, Nootropic Agents therapeutic use, Schizophrenia drug therapy
- Abstract
Nitric oxide is a small gaseous molecule that plays important roles in the majority of biological functions. Impairments of NO-related pathways contribute to the majority of neurological disorders, such as Alzheimer's disease (AD), and mental disorders, such as schizophrenia. Cognitive decline is one of the most serious impairments accompanying both AD and schizophrenia. In the present study, the activities of NO donors, slow (spermine NONOate) or fast (DETANONOate) releasers, and selective inhibitor of neuronal nitric oxide synthase N(ω)-propyl-l-arginine (NPLA) were investigated in pharmacological models of schizophrenia and AD. Cognitive impairments were induced by administration of MK-801 or scopolamine and were measured in novel object recognition (NOR) and Y-maze tests. The compounds were investigated at doses of 0.05-0.5 mg/kg. The dose-dependent effectiveness of all the compounds was observed in the NOR test, while only the highest doses of spermine NONOate and NPLA were active in the Y-maze test. DETANONOate was not active in the Y-maze test. The impact of the investigated compounds on motor coordination was tested at doses of 0.5 and 1 mg/kg. Only NPLA at a dose of 1 mg/kg slightly disturbed motor coordination in animals., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2022
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13. Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies.
- Author
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Cieślik P, Siekierzycka A, Radulska A, Płoska A, Burnat G, Brański P, Kalinowski L, and Wierońska JM
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- Animals, Dizocilpine Maleate pharmacology, Excitatory Amino Acid Antagonists pharmacology, Male, Maze Learning drug effects, Mice, Scopolamine pharmacology, Cerebral Cortex metabolism, Dizocilpine Maleate adverse effects, Excitatory Amino Acid Antagonists adverse effects, Hippocampus metabolism, Memory Disorders chemically induced, Memory Disorders metabolism, Nitric Oxide metabolism, Scopolamine adverse effects
- Abstract
MK-801, an NMDA receptor antagonist, and scopolamine, a cholinergic receptor blocker, are widely used as tool compounds to induce learning and memory deficits in animal models to study schizophrenia or Alzheimer-type dementia (AD), respectively. Memory impairments are observed after either acute or chronic administration of either compound. The present experiments were performed to study the nitric oxide (NO)-related mechanisms underlying memory dysfunction induced by acute or chronic (14 days) administration of MK-801 (0.3 mg/kg, i.p.) or scopolamine (1 mg/kg, i.p.). The levels of L-arginine and its derivatives, L-citrulline, L-glutamate, L-glutamine and L-ornithine, were measured. The expression of constitutive nitric oxide synthases (cNOS), dimethylaminohydrolase (DDAH1) and protein arginine N-methyltransferases (PMRTs) 1 and 5 was evaluated, and the impact of the studied tool compounds on cGMP production and NMDA receptors was measured. The studies were performed in both the cortex and hippocampus of mice. S-nitrosylation of selected proteins, such as GLT-1, APP and tau, was also investigated. Our results indicate that the availability of L-arginine decreased after chronic administration of MK-801 or scopolamine, as both the amino acid itself as well as its level in proportion to its derivatives (SDMA and NMMA) were decreased. Additionally, among all three methylamines, SDMA was the most abundant in the brain (~70%). Administration of either compound impaired eNOS-derived NO production, increasing the monomer levels, and had no significant impact on nNOS. Both compounds elevated DDAH1 expression, and slight decreases in PMRT1 and PMRT5 in the cortex after scopolamine (acute) and MK-801 (chronic) administration were observed in the PFC, respectively. Administration of MK-801 induced a decrease in the cGMP level in the hippocampus, accompanied by decreased NMDA expression, while increased cGMP production and decreased NMDA receptor expression were observed after scopolamine administration. Chronic MK-801 and scopolamine administration affected S-nitrosylation of GLT-1 transport protein. Our results indicate that the analyzed tool compounds used in pharmacological models of schizophrenia or AD induce changes in NO-related pathways in the brain structures involved in cognition. To some extent, the changes resemble those observed in human samples.
- Published
- 2021
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14. Neurochemical changes underlying cognitive impairment in olfactory bulbectomized rats and the impact of the mGlu 5 -positive allosteric modulator CDPPB.
- Author
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Płoska A, Cieślik P, Siekierzycka A, Kalinowski L, and Wierońska JM
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- Alzheimer Disease physiopathology, Amidohydrolases metabolism, Animals, Antidepressive Agents metabolism, Benzamides pharmacology, Brain metabolism, Cognitive Dysfunction physiopathology, Disease Models, Animal, Hippocampus metabolism, Male, Nervous System chemistry, Nitric Oxide Synthase metabolism, Olfactory Bulb physiology, Prefrontal Cortex metabolism, Pyrazoles pharmacology, Rats, Rats, Sprague-Dawley, Receptor for Advanced Glycation End Products metabolism, Receptor, Metabotropic Glutamate 5 drug effects, Cognitive Dysfunction metabolism, Receptor, Metabotropic Glutamate 5 metabolism
- Abstract
The olfactory bulbectomized (OBX) rat model is a well-established model of depression in which antidepressant drugs reverse deficits in the passive avoidance test 14 days after administration. Recently, the olfactory bulbectomized rat model has been proposed to be a model of Alzheimer's disease (AD), and the available data indicate similarities between the changes that typically occur in AD and those observed in OBX animals. In the present study, the occurrence of neurochemical impairments related to AD were investigated 8 months after OB ablation. The expression of the nitric oxide synthases eNOS and nNOS, receptor for advanced glycation endproducts (RAGEs) and dimethylarginine dimethylaminohydrolase (DDAH1) in the prefrontal cortices (PFCs), hippocampi and striata of olfactory bulbectomized and sham-operated rats was evaluated. Subsequently, the impact of the administration of a positive allosteric modulator of the mGlu
5 receptor, CDPPB (14 days, 2.5 or 5 mg/kg), on OBX-related changes was assessed. OB ablation induced typical deficits in passive avoidance. Significant aberrations in the expression of both isoforms of NOS were observed in the hippocampus and striatum, and the expression of DDAH1 was increased in the PFCs of OBX animals. CDPPB at a dose of 5 mg/kg ameliorated cognitive impairment in the passive avoidance test and partially reversed the changes in eNOS and nNOS expression induced by the lesion. The results of this study confirm that some of the neurochemical changes observed in OBX animals may resemble those associated with AD pathology and that activation of the mGlu5 receptor may partially counteract these pathological alterations., (Copyright © 2021 Elsevier B.V. All rights reserved.)- Published
- 2021
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15. Serotonergic-Muscarinic Interaction within the Prefrontal Cortex as a Novel Target to Reverse Schizophrenia-Related Cognitive Symptoms.
- Author
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Cieślik P, Radulska A, Burnat G, Kalinowski L, and Wierońska JM
- Subjects
- Animals, Benzamides pharmacokinetics, Benzamides pharmacology, Benzamides therapeutic use, Blood-Brain Barrier metabolism, Cholinergic Agents pharmacokinetics, Cholinergic Agents therapeutic use, Cognitive Dysfunction etiology, Dizocilpine Maleate toxicity, Male, Maze Learning, Mice, Piperidines pharmacokinetics, Piperidines pharmacology, Piperidines therapeutic use, Prefrontal Cortex metabolism, Pyridines pharmacokinetics, Pyridines pharmacology, Pyridines therapeutic use, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Pyrimidines therapeutic use, Receptors, Muscarinic metabolism, Receptors, Serotonin metabolism, Schizophrenia complications, Serotonin Receptor Agonists pharmacokinetics, Serotonin Receptor Agonists therapeutic use, Thiophenes pharmacokinetics, Thiophenes pharmacology, Thiophenes therapeutic use, Cholinergic Agents pharmacology, Cognitive Dysfunction drug therapy, Prefrontal Cortex drug effects, Schizophrenia drug therapy, Serotonin Receptor Agonists pharmacology
- Abstract
Recent studies revealed that the activation of serotonergic 5-HT
1A and muscarinic M1 , M4 , or M5 receptors prevent MK-801-induced cognitive impairments in animal models. In the present study, the effectiveness of the simultaneous activation of 5-HT1A and muscarinic receptors at preventing MK-801-induced cognitive deficits in novel object recognition (NOR) or Y-maze tests was investigated. Activators of 5-HT1A (F15599), M1 (VU0357017), M4 (VU0152100), or M5 (VU0238429) receptors administered at top doses for seven days reversed MK-801-induced deficits in the NOR test, similar to the simultaneous administration of subeffective doses of F15599 (0.05 mg/kg) with VU0357017 (0.15 mg/kg), VU0152100 (0.05 mg/kg), or VU0238429 (1 mg/kg). The compounds did not prevent the MK-801-induced impairment when administered acutely. Their activity was less evident in the Y-maze. Pharmacokinetic studies revealed high brain penetration of F15599 (brain/plasma ratio 620%), which was detected in the frontal cortex (FC) up to 2 h after administration. Decreases in the brain penetration properties of the compounds were observed after acute administration of the combinations, which might have influenced behavioral responses. This negative effect on brain penetration was not observed when the compounds were administered repeatedly. Based on our results, prolonged administration of a 5-HT1A activator with muscarinic receptor ligands may be effective at reversing cognitive decline related to schizophrenia, and the FC may play a critical role in this interaction.- Published
- 2021
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16. Nitric Oxide-Dependent Pathways as Critical Factors in the Consequences and Recovery after Brain Ischemic Hypoxia.
- Author
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Wierońska JM, Cieślik P, and Kalinowski L
- Subjects
- Animals, Apoptosis, Disease Progression, Free Radical Scavengers, Humans, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Inflammation, Ischemia, Lymphocytes metabolism, Necrosis, Neurons metabolism, Nitric Oxide Synthase metabolism, Nitric Oxide Synthase Type II metabolism, Oxidative Stress, Reactive Nitrogen Species, Reactive Oxygen Species, Brain Ischemia pathology, Hypoxia, Brain pathology, Nitric Oxide metabolism
- Abstract
Brain ischemia is one of the leading causes of disability and mortality worldwide. Nitric oxide (NO
• ), a molecule that is involved in the regulation of proper blood flow, vasodilation, neuronal and glial activity constitutes the crucial factor that contributes to the development of pathological changes after stroke. One of the early consequences of a sudden interruption in the cerebral blood flow is the massive production of reactive oxygen and nitrogen species (ROS/RNS) in neurons due to NO• synthase uncoupling, which leads to neurotoxicity. Progression of apoptotic or necrotic neuronal damage activates reactive astrocytes and attracts microglia or lymphocytes to migrate to place of inflammation. Those inflammatory cells start to produce large amounts of inflammatory proteins, including pathological, inducible form of NOS (iNOS), which generates nitrosative stress that further contributes to brain tissue damage, forming vicious circle of detrimental processes in the late stage of ischemia. S-nitrosylation, hypoxia-inducible factor 1α (HIF-1α) and HIF-1α-dependent genes activated in reactive astrocytes play essential roles in this process. The review summarizes the roles of NO• -dependent pathways in the early and late aftermath of stroke and treatments based on the stimulation or inhibition of particular NO• synthases and the stabilization of HIF-1α activity.- Published
- 2021
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17. The Trace Kynurenine, Cinnabarinic Acid, Displays Potent Antipsychotic-Like Activity in Mice and Its Levels Are Reduced in the Prefrontal Cortex of Individuals Affected by Schizophrenia.
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Ulivieri M, Wierońska JM, Lionetto L, Martinello K, Cieslik P, Chocyk A, Curto M, Di Menna L, Iacovelli L, Traficante A, Liberatore F, Mascio G, Antenucci N, Giannino G, Vergassola M, Pittaluga A, Bruno V, Battaglia G, Fucile S, Simmaco M, Nicoletti F, Pilc A, and Fazio F
- Subjects
- Adult, Animals, Antipsychotic Agents administration & dosage, Cells, Cultured, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Oxazines administration & dosage, Rats, Rats, Wistar, Tissue Banks, Antipsychotic Agents pharmacology, Behavior, Animal drug effects, Electrophysiological Phenomena drug effects, Kynurenine metabolism, Oxazines metabolism, Oxazines pharmacology, Prefrontal Cortex metabolism, Receptors, Metabotropic Glutamate deficiency, Schizophrenia drug therapy, Schizophrenia metabolism
- Abstract
Cinnabarinic acid (CA) is a kynurenine metabolite that activates mGlu4 metabotropic glutamate receptors. Using a highly sensitive ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS-MS) method, we found that CA is present in trace amounts in human brain tissue. CA levels were largely reduced in the prefrontal cortex (PFC) of individuals affected by schizophrenia. This reduction did not correlate with age, sex, duration of the disease, and duration and type of antipsychotic medication and might, therefore, represent a trait of schizophrenia. Interestingly, systemic treatment with low doses of CA (<1 mg/kg, i.p.) showed robust efficacy in several behavioral tests useful to study antipsychotic-like activity in mice and rats and attenuated MK-801-evoked glutamate release. CA failed to display antipsychotic-like activity and inhibit excitatory synaptic transmission in mice lacking mGlu4 receptors. These findings suggest that CA is a potent endogenous antipsychotic-like molecule and reduced CA levels in the PFC might contribute to the pathophysiology of schizophrenia., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
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18. Regulation of Glutamatergic Activity via Bidirectional Activation of Two Select Receptors as a Novel Approach in Antipsychotic Drug Discovery.
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Cieślik P and Wierońska JM
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- Animals, Brain drug effects, Brain metabolism, Brain pathology, Disease Models, Animal, Drug Combinations, Drug Discovery, Humans, Receptors, Metabotropic Glutamate metabolism, Antipsychotic Agents therapeutic use, Muscarinic Antagonists therapeutic use, Receptors, Metabotropic Glutamate antagonists & inhibitors, Receptors, Muscarinic metabolism, Schizophrenia drug therapy
- Abstract
Schizophrenia is a mental disorder that affects approximately 1-2% of the population and develops in early adulthood. The disease is characterized by positive, negative, and cognitive symptoms. A large percentage of patients with schizophrenia have a treatment-resistant disease, and the risk of developing adverse effects is high. Many researchers have attempted to introduce new antipsychotic drugs to the clinic, but most of these treatments failed, and the diversity of schizophrenic symptoms is one of the causes of disappointing results. The present review summarizes the results of our latest papers, showing that the simultaneous activation of two receptors with sub-effective doses of their ligands induces similar effects as the highest dose of each compound alone. The treatments were focused on inhibiting the increased glutamate release responsible for schizophrenia arousal, without interacting with dopamine (D
2 ) receptors. Ligands activating metabotropic receptors for glutamate, GABAB or muscarinic receptors were used, and the compounds were administered in several different combinations. Some combinations reversed all schizophrenia-related deficits in animal models, but others were active only in select models of schizophrenia symptoms (i.e., cognitive or negative symptoms).- Published
- 2020
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19. Simultaneous activation of mGlu 2 and muscarinic receptors reverses MK-801-induced cognitive decline in rodents.
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Cieślik P, Domin H, Chocyk A, Gruca P, Litwa E, Płoska A, Radulska A, Pelikant-Małecka I, Brański P, Kalinowski L, and Wierońska JM
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- Animals, Dose-Response Relationship, Drug, Excitatory Amino Acid Antagonists toxicity, Male, Mice, Pyridines pharmacology, Rats, Rats, Wistar, Receptor, Muscarinic M1 agonists, Receptor, Muscarinic M5 agonists, Receptors, Metabotropic Glutamate agonists, Sulfonamides pharmacology, Cognitive Dysfunction drug therapy, Cognitive Dysfunction metabolism, Dizocilpine Maleate toxicity, Receptor, Muscarinic M1 metabolism, Receptor, Muscarinic M5 metabolism, Receptors, Metabotropic Glutamate metabolism
- Abstract
The activity of an allosteric agonist of muscarinic M
1 receptor, VU0357017, and a positive allosteric modulator (PAM) of M5 receptor, VU0238429, were investigated alone or in combination with the mGlu2 receptor PAM, LY487379 using the following behavioural tests: prepulse inhibition (PPI), novel object recognition (NOR), and spatial delayed alternation (SDA). VU0357017 (10 and 20 mg/kg) and VU0238429 (5 and 10 mg/kg) reversed deficits in PPI while VU0238429 (2.5 and 5 mg/kg) was effective in SDA. The simultaneous administration of subeffective doses of M1 or M5 activators (5, 1, or 0.25 mg/kg) with LY487379 (0.5 mg/kg) induced the same effect as that observed for the active dose of each compound. Selective M1 or M5 receptor blockers antagonized the effect exerted by these combinations, and pharmacokinetic studies confirmed independent transport through the blood-brain barrier. The expression of both receptors (M1 and M5 ) was established in brain structures involved in cognition (neocortex, hippocampus, and entorhinal cortex) in both the rat and the mouse brains by immunofluorescence staining. Specifically, double neuronal staining of mGlu2 -M1 and mGlu2 -M5 receptors was observed in many areas of the rat brain, while the number of double-stained mGlu2 -M1 receptors was moderate in the mouse brain with no mGlu2 -M5 colocalization. Finally, the combined administration of subeffective doses of the compounds did not alter prolactin levels or motor coordination, in contrast to the compounds given alone at the highest dose or in combination with standard neuroleptics., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2020
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20. Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice.
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Cieślik P, Radulska A, Pelikant-Małecka I, Płoska A, Kalinowski L, and Wierońska JM
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- Animals, Antipsychotic Agents administration & dosage, Antipsychotic Agents pharmacology, Benzamides administration & dosage, Benzamides pharmacology, Dizocilpine Maleate toxicity, Drug Therapy, Combination, Excitatory Amino Acid Agonists administration & dosage, Excitatory Amino Acid Agonists pharmacology, Excitatory Amino Acid Agonists therapeutic use, Excitatory Amino Acid Antagonists toxicity, Male, Mice, Pyrazoles administration & dosage, Pyrazoles pharmacology, Pyridines administration & dosage, Pyridines pharmacology, Receptor, Muscarinic M4 drug effects, Receptors, Glutamate, Schizophrenia etiology, Sulfonamides administration & dosage, Sulfonamides pharmacology, Antipsychotic Agents therapeutic use, Benzamides therapeutic use, Memory, Short-Term drug effects, Pyrazoles therapeutic use, Pyridines therapeutic use, Schizophrenia drug therapy, Social Behavior, Sulfonamides therapeutic use
- Abstract
Negative and cognitive symptoms of schizophrenia contribute to an impaired social and professional life for schizophrenic patients, and in most cases, these symptoms are treatment resistant. Therefore, identification of new treatment strategies is sorely needed. Metabotropic glutamate receptors (mGlu) and muscarinic (M) receptors for acetylcholine have been considered promising targets for novel antipsychotics. Among them, mGlu
2 and M4 subtypes seem to be of particular importance. In the present study, the effect of mutual activation of mGlu2 and M4 receptors was assessed in MK-801-based animal models of negative and cognitive symptoms of schizophrenia, that is, social interaction and novel object recognition tests. Low sub-effective doses of LY487379 (0.5 mg/kg), a positive allosteric activator of the mGlu2 receptor, and VU152100 (0.25-0.5 mg/kg), a positive allosteric modulator of the M4 receptor, were simultaneously administered in the aforementioned tests. Combined administration of these compounds prevented MK-801-induced disturbances in social interactions and object recognition when acutely administered 30 min before MK-801. Prolonged (7 days) administration of these compounds resulted in the loss of effectiveness in preventing MK-801-induced disruptions in the novel object recognition test but not in the social interaction test. In the next set of experiments, MK-801 (0.3 mg/kg) was administered for seven consecutive days, and the activity of the compounds was investigated on day eight, during which time MK-801 was not administered. In this model, based on prolonged MK-801 administration, the effectiveness of the compounds to treat MK-801-induced disruptions was evident at low doses which were ineffective in preventing the behavioural disturbances induced by an acute MK-801 injection. Combined administration of the compounds did not exert better efficacy than each compound given alone. Pharmacokinetic analysis confirmed a lack of possible drug-drug interactions after combined administration of LY487379 and VU152100. Our data show that modulation of M4 and mGlu2 receptors may potentially be beneficial in the treatment of negative and cognitive symptoms of schizophrenia.- Published
- 2019
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21. Simultaneous activation of muscarinic and GABA B receptors as a bidirectional target for novel antipsychotics.
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Cieślik P, Woźniak M, Tokarski K, Kusek M, Pilc A, Płoska A, Radulska A, Pelikant-Małecka I, Żołnowska B, Sławiński J, Kalinowski L, and Wierońska JM
- Subjects
- Allosteric Regulation, Animals, Antipsychotic Agents pharmacokinetics, Benzamides pharmacokinetics, Benzamides pharmacology, Brain drug effects, Brain metabolism, Cyclopentanes pharmacokinetics, Cyclopentanes pharmacology, Disease Models, Animal, Drug Therapy, Combination, Excitatory Postsynaptic Potentials drug effects, Excitatory Postsynaptic Potentials physiology, Indoles pharmacokinetics, Indoles pharmacology, Male, Mice, Neurotransmitter Agents pharmacokinetics, Pyridines pharmacokinetics, Pyridines pharmacology, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Schizophrenia metabolism, Thiophenes pharmacokinetics, Thiophenes pharmacology, Antipsychotic Agents pharmacology, Neurotransmitter Agents pharmacology, Receptors, GABA-B metabolism, Receptors, Muscarinic metabolism, Schizophrenia drug therapy
- Abstract
Recent preclinical studies point to muscarinic and GABA
B receptors as novel therapeutic targets for the treatment of schizophrenia. This study was aimed to assess the role of muscarinic and GABAB receptor interactions in animal models of schizophrenia, using positive allosteric modulators (PAMs) of GABAB receptor (GS39783), muscarinic M4 (VU0152100) and M5 (VU0238429) receptor, and partial allosteric agonist of M1 receptor (VU0357017). DOI-induced head twitches, social interaction and novel object recognition tests were used as the models of schizophrenia. Analyses of DOI-induced increases in sEPSCs (spontaneous excitatory postsynaptic currents) were performed as complementary experiments to the DOI-induced head twitch studies. Haloperidol-induced catalepsy and the rotarod test were used to examine the adverse effects of the drugs. All three activators of muscarinic receptors were active in DOI-induced head twitches. When administered together with GS39783 in subeffective doses, only the co-administration of VU0152100 and GS39783 was effective. The combination also reduced the frequency but not the amplitude of DOI-induced sEPSCs. Neither VU0357017 nor VU0238429 were active in social interaction test when given alone, and also the combination of VU0152100 and GS39783 failed to reverse MK-801-induced deficits observed in this test. All muscarinic activators when administered alone or in combination with GS39783 reversed the MK-801-induced disruption of memory in the novel object recognition test, and their actions were blocked by specific antagonists. None of the tested compounds or their combinations influenced the motor coordination of the animals. The compounds had no effect on haloperidol-induced catalepsy and did not induce catalepsy when administered alone. Pharmacokinetic analysis confirmed lack of possible drug-drug interactions after combined administration of GS39783 with VU0357017 or VU0152100; however, when the drug was co-administered with VU0238429 its ability to pass the blood-brain barrier slightly decreased, suggesting potential drug-drug interactions. Our data show that modulation of cholinergic and GABAergic systems can potentially be beneficial in the treatment of the positive and cognitive symptoms of schizophrenia without inducing the adverse effects typical for presently used antipsychotics., (Copyright © 2018 Elsevier B.V. All rights reserved.)- Published
- 2019
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22. Depression and schizophrenia viewed from the perspective of amino acidergic neurotransmission: Antipodes of psychiatric disorders.
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Wierońska JM and Pilc A
- Subjects
- Animals, Antipsychotic Agents pharmacology, Depression metabolism, Humans, Receptors, GABA metabolism, Receptors, Ionotropic Glutamate metabolism, Receptors, Metabotropic Glutamate metabolism, Schizophrenia metabolism, Synaptic Transmission, Antipsychotic Agents therapeutic use, Depression drug therapy, Glutamic Acid metabolism, Schizophrenia drug therapy, gamma-Aminobutyric Acid metabolism
- Abstract
Depression and schizophrenia are burdensome, costly serious and disabling mental disorders. Moreover the existing treatments are not satisfactory. As amino-acidergic (AA) neurotransmitters built a vast majority of brain neurons, in this article we plan to focus on drugs influencing AA neurotransmission in both diseases: we will discuss several facts concerning glutamatergic and GABA-ergic neurotransmission in these diseases, based mainly on preclinical experiments that used stimulators and/or blockers of both neurotransmitter systems. In general a picture emerges showing, that treatments that increase excitatory effects (with either antagonists or agonists) tend to evoke antidepressant effects, while treatments that increase inhibitory effects tend to display antipsychotic properties. Moreover, it seems that the antidepressant activity of a given compound excludes it as a potential antipsychotic and vice versa., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
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23. Mutual activation of glutamatergic mGlu 4 and muscarinic M 4 receptors reverses schizophrenia-related changes in rodents.
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Cieślik P, Woźniak M, Rook JM, Tantawy MN, Conn PJ, Acher F, Tokarski K, Kusek M, Pilc A, and Wierońska JM
- Subjects
- Amphetamine toxicity, Animals, Antipsychotic Agents pharmacology, Disease Models, Animal, Dizocilpine Maleate toxicity, Dose-Response Relationship, Drug, Excitatory Amino Acid Agonists pharmacology, Excitatory Amino Acid Agonists therapeutic use, Male, Mice, Motor Activity drug effects, Motor Activity physiology, Phosphinic Acids pharmacology, Phosphinic Acids therapeutic use, Receptor, Muscarinic M4 agonists, Receptors, Metabotropic Glutamate agonists, Rodentia, Schizophrenia chemically induced, Antipsychotic Agents therapeutic use, Receptor, Muscarinic M4 metabolism, Receptors, Metabotropic Glutamate metabolism, Schizophrenia drug therapy, Schizophrenia metabolism
- Abstract
Rationale: Metabotropic glutamate receptors and muscarinic M
4 receptors have been proposed as novel targets for various brain disorders, including schizophrenia. Both receptors are coupled to Go/i proteins and are expressed in brain circuits that are important in schizophrenia. Therefore, their mutual activation may be an effective treatment and allow minimizing the doses of ligands required for optimal activity., Objectives: In the present studies, subactive doses of mGlu4 and M4 activators (LSP4-2022 and VU152100, respectively) were administered to investigate the mutual interaction between mGlu4 and M4 receptors in animal models of schizophrenia., Methods: The behavioral tests used were MK-801-induced hyperactivity, (±)-2.5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced head twitches, the modified forced swim test, and MK-801-induced disruptions of social interactions and novel object recognition. DOI-induced spontaneous excitatory postsynaptic currents (sEPSCs) in brain slices and positron emission tomography (PET) in were used to establish the ability of these compounds to modulate the glutamatergic and dopaminergic systems. Rotarod was used to assess putative adverse effects., Results: The mutual administration of subactive doses of LSP4-2022 and VU152100 exerted similar antipsychotic-like efficacy in animals as observed for active doses of both compounds, indicating their additive actions. VU152100 inhibited the DOI-induced frequency (but not amplitude) of sEPSCs in the frontal cortex, confirming presynaptic regulation of glutamate release. Both compounds reversed amphetamine-induced decrease in D2 receptor levels in the striatum, as measured with [18 F]fallypride. The compounds did not induce any motor impartments when measured in rotarod test., Conclusions: Based on our results, the simultaneous activation of M4 and mGlu4 receptors is beneficial in reversing MK-801- and amphetamine-induced schizophrenia-related changes in animals.- Published
- 2018
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24. Search for a 5-CT alternative. In vitro and in vivo evaluation of novel pharmacological tools: 3-(1-alkyl-1 H -imidazol-5-yl)-1 H -indole-5-carboxamides, low-basicity 5-HT 7 receptor agonists.
- Author
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Latacz G, Hogendorf AS, Hogendorf A, Lubelska A, Wierońska JM, Woźniak M, Cieślik P, Kieć-Kononowicz K, Handzlik J, and Bojarski AJ
- Abstract
Close structural analogues of 5-carboxamidotryptamine (5-CT) based on the newly discovered indole-imidazole scaffold were synthesized and evaluated to search for a 5-HT
7 receptor agonist of higher selectivity. In vitro drug-likeness studies and in vivo pharmacological evaluation of potent and selective low-basicity 5-HT7 receptor agonists, previously published 7 (3-(1-ethyl-1 H -imidazol-5-yl)-1 H -indole-5-carboxamide, AH-494) and 13 (3-(1-methyl-1 H -imidazol-5-yl)-1 H -indole-5-carboxamide), have supported their usefulness as pharmacological tools. Comprehensive in vitro comparison studies between 7 , 13 and the commonly used 5-CT showed their very similar ADMET properties. Compound 7 at 1 mg kg-1 reversed MK-801-induced disruption in novel object recognition in mice and alleviated stress-induced hyperthermia (SIH) at high doses. Taking into account both in vitro and in vivo data, 7 and 13 may be considered as alternatives to 5-CT as pharmacological tools with important additional benefit associated with their low-basicity: high selectivity over 5-HT1A R.- Published
- 2018
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25. Vascular Cognitive Impairment Linked to Brain Endothelium Inflammation in Early Stages of Heart Failure in Mice.
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Adamski MG, Sternak M, Mohaissen T, Kaczor D, Wierońska JM, Malinowska M, Czaban I, Byk K, Lyngsø KS, Przyborowski K, Hansen PBL, Wilczyński G, and Chlopicki S
- Subjects
- Amyloid beta-Peptides metabolism, Animals, Blood Platelets metabolism, Blood-Brain Barrier metabolism, Blood-Brain Barrier physiopathology, Capillary Permeability, Cerebral Arteries metabolism, Cerebrovascular Circulation, Cognition, Cognition Disorders metabolism, Cognition Disorders physiopathology, Cognition Disorders psychology, Dementia, Vascular metabolism, Dementia, Vascular physiopathology, Dementia, Vascular psychology, Disease Models, Animal, Disease Progression, Encephalitis metabolism, Encephalitis pathology, Encephalitis physiopathology, Endothelium, Vascular metabolism, Female, GTP-Binding Protein alpha Subunits, Gq-G11 genetics, Genetic Predisposition to Disease, Heart Failure genetics, Heart Failure metabolism, Heart Failure physiopathology, Mice, Transgenic, Myocytes, Cardiac metabolism, Peptide Fragments metabolism, Phenotype, Time Factors, Ventricular Dysfunction, Left etiology, Ventricular Dysfunction, Left physiopathology, Ventricular Function, Left, Behavior, Animal, Brain blood supply, Cerebral Arteries physiopathology, Cognition Disorders etiology, Dementia, Vascular etiology, Encephalitis etiology, Endothelium, Vascular physiopathology, Heart Failure complications
- Abstract
Background: Although advanced heart failure (HF) is a clinically documented risk factor for vascular cognitive impairment, the occurrence and pathomechanisms of vascular cognitive impairment in early stages of HF are equivocal. Here, we characterize vascular cognitive impairment in the early stages of HF development and assess whether cerebral hypoperfusion or prothrombotic conditions are involved., Methods and Results: Tgαq*44 mice with slowly developing isolated HF triggered by cardiomyocyte-specific overexpression of G-αq*44 protein were studied before the end-stage HF, at the ages of 3, 6, and 10 months: before left ventricle dysfunction; at the stage of early left ventricle diastolic dysfunction (with preserved ejection fraction); and left ventricle diastolic/systolic dysfunction, respectively. In 6- to 10-month-old but not in 3-month-old Tgαq*44 mice, behavioral and cognitive impairment was identified with compromised blood-brain barrier permeability, most significantly in brain cortex, that was associated with myelin sheet loss and changes in astrocytes and microglia. Brain endothelial cells displayed increased E-selectin immunoreactivity, which was accompanied by increased amyloid-β
1-42 accumulation in piriform cortex and increased cortical oxidative stress (8-OHdG immunoreactivity). Resting cerebral blood flow measured by magnetic resonance imaging in vivo was preserved, but ex vivo NO-dependent cortical arteriole flow regulation was impaired. Platelet hyperreactivity was present in 3- to 10-month-old Tgαq*44 mice, but it was not associated with increased platelet-dependent thrombogenicity., Conclusions: We report for the first time that vascular cognitive impairment is already present in the early stage of HF development, even before left ventricle systolic dysfunction. The underlying pathomechanism, independent of brain hypoperfusion, involves preceding platelet hyperreactivity and brain endothelium inflammatory activation., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)- Published
- 2018
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26. Low-basicity 5-HT 7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol.
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Hogendorf AS, Hogendorf A, Kurczab R, Satała G, Lenda T, Walczak M, Latacz G, Handzlik J, Kieć-Kononowicz K, Wierońska JM, Woźniak M, Cieślik P, Bugno R, Staroń J, and Bojarski AJ
- Subjects
- Blood-Brain Barrier metabolism, Brain Chemistry, Drug Design, HEK293 Cells, Hep G2 Cells, Humans, Models, Molecular, Protein Binding, Recognition, Psychology drug effects, Structure-Activity Relationship, Imidazoles chemical synthesis, Imidazoles pharmacology, Receptors, Serotonin metabolism, Serotonin Receptor Agonists chemical synthesis, Serotonin Receptor Agonists pharmacology
- Abstract
A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT
7 receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-1H-indole (AGH-107, 1o, Ki 5-HT7 = 6 nM, EC50 = 19 nM, 176-fold selectivity over 5-HT1A R) and 1e (5-methoxy analogue, Ki 5-HT7 = 30 nM, EC50 = 60 nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain (Cmax = 2723 ng/g) were found for 1o after i.p. (5 mg/kg) administration in mice. The compound was found active in novel object recognition test in mice, at 0.5, 1 and 5 mg/kg. Docking to 5-HT7 R homology models indicated a plausible binding mode which explain the unusually high selectivity over the related CNS targets. Halogen bond formation between the most potent derivatives and the receptor is consistent with both the docking results and SAR. 5-Chlorine, bromine and iodine substitution resulted in a 13, 27 and 89-fold increase in binding affinities, respectively, and in enhanced 5-HT1A R selectivity.- Published
- 2017
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27. Neurochemical and behavioral studies on the 5-HT 1A -dependent antipsychotic action of the mGlu 4 receptor agonist LSP4-2022.
- Author
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Woźniak M, Gołembiowska K, Noworyta-Sokołowska K, Acher F, Cieślik P, Kusek M, Tokarski K, Pilc A, and Wierońska JM
- Subjects
- Animals, Dizocilpine Maleate pharmacology, Dose-Response Relationship, Drug, Excitatory Amino Acid Agonists pharmacology, Interpersonal Relations, Locomotion drug effects, Male, Mice, Piperazines pharmacology, Pyridines pharmacology, Rats, Rats, Wistar, Serotonin Antagonists pharmacology, Antipsychotic Agents pharmacology, Locomotion physiology, Phosphinic Acids pharmacology, Receptor, Serotonin, 5-HT1A physiology, Receptors, Metabotropic Glutamate agonists, Receptors, Metabotropic Glutamate physiology
- Abstract
LSP4-2022 is a novel, orthosteric agonist of mGlu
4 receptor that induces antipsychotic-like activity in animal studies. In the present study, the involvement of 5-HT1A receptors in LSP4-2022-induced antipsychotic actions and the neurochemical background of that interaction were investigated. In several behavioral tests the actions of effective doses of the compound (0.5-2 mg/kg) were antagonized via the administration of the 5-HT1A antagonist WAY100635 (0.1 mg/kg). The co-administration of sub-effective dose of the 5-HT1A agonist (R)-(S)-8-OH-DPAT (0.01 mg/kg) intensified the activity of ineffective doses of LSP4-2022, having no influence on the efficacy of the active doses. The co-administration of effective doses of both compounds did not intensify each other's action. In the microdialysis in vivo tests, MK-801 (0.6 mg/kg) induced an enhancement of the release of dopamine, serotonin, glutamate and GABA in the prefrontal cortex. Administration of LSP4-2022 (2 mg/kg) abolished this MK-801-induced effect on neurotransmitter release. Co-administration with WAY100635 (0.1 mg/kg), a 5-HT1A antagonist, completely (dopamine, serotonin) or partially (glutamate, GABA) counteracted this LSP4-2022-induced effect. Subsequently, the patch-clamp recordings of spontaneous EPSCs were performed. sEPSCs were evoked in slices from the mouse prefrontal cortex by DOI (10 μM). LSP4-2022 (2.5; 5 and 10 μm) reversed DOI-induced changes in both the frequency and amplitude of the sEPSCs, but the more robust effect on the frequency was observed. The administration of WAY100635 had no effect on the LSP4-2022-induced effects on sEPSCs, indicating that the mGlu4 -5-HT1A interaction does not occur via single-neuron signaling but involves neuronal circuits that regulate neurotransmitter release. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'., (Copyright © 2016 Elsevier Ltd. All rights reserved.)- Published
- 2017
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28. Involvement of GABAB Receptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu4 Receptor, LSP4-2022.
- Author
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Woźniak M, Acher F, Marciniak M, Lasoń-Tyburkiewicz M, Gruca P, Papp M, Pilc A, and Wierońska JM
- Subjects
- Amphetamine, Animals, Cyclopentanes pharmacology, Disease Models, Animal, Dizocilpine Maleate, Dose-Response Relationship, Drug, Dyskinesia, Drug-Induced drug therapy, Dyskinesia, Drug-Induced metabolism, GABA Agents pharmacology, Male, Mice, Knockout, Motor Activity drug effects, Motor Activity physiology, Pyrimidines pharmacology, Receptors, Metabotropic Glutamate genetics, Receptors, Metabotropic Glutamate metabolism, Recognition, Psychology drug effects, Recognition, Psychology physiology, Schizophrenia, Social Behavior, Antipsychotic Agents pharmacology, Excitatory Amino Acid Agonists pharmacology, Phosphinic Acids pharmacology, Receptors, GABA-B metabolism, Receptors, Metabotropic Glutamate agonists
- Abstract
Considering that ligands of metabotropic glutamate and GABA receptors may exert beneficial effects on schizophrenia, we assessed the actions of the first mGlu>4-selective orthosteric agonist, LSP4-2022, in several tests reflecting positive, negative, and cognitive symptoms of schizophrenia. Moreover, we investigated the possible involvement of GABAB receptors in LSP4-2022-induced actions. Hyperactivity induced by MK-801 or amphetamine and DOI-induced head twitches in mice were used as the models of positive symptoms. The social interaction test, modified forced swim test (FST), and novel object recognition (NOR) test were used as the models of negative and cognitive symptoms of schizophrenia. LSP4-2022 inhibited hyperactivity (in a dose-dependent manner, 0.5-2 mg/kg) induced by MK-801 or amphetamine and DOI-induced head twitches. In mGlu4 receptor knockout mice, LSP4-2022 was not effective. However, it reversed MK-801-induced impairment in the social interaction test and the MK-801-induced increase of immobility in the modified FST. In the NOR test, LSP4-2022 was active at a dose of 2 mg/kg. GABAB receptor antagonist, CGP55845 (10 mg/kg), reversed LSP4-2022-induced effects in hyperactivity and head twitch tests. At the same time, the simultaneous administration of subeffective doses of LSP4-2022 (0.1 mg/kg) and a positive allosteric modulator of GABAB receptor PAM, GS39783 (0.1 mg/kg), induced clear antipsychotic-like effects in those two tests. Such an interaction between mGlu4 and GABAB receptors was not observed in the social interaction and NOR tests. Therefore, we suggest that the activation of the mGlu
4 receptor is a promising approach facilitating the discovery of novel antipsychotic drugs, and that the interplay between mGlu4 and GABAB receptors may become the basis for a novel therapy for schizophrenic patients with predomination of positive symptoms.- Published
- 2016
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29. Metabotropic glutamate receptors as targets for new antipsychotic drugs: Historical perspective and critical comparative assessment.
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Wierońska JM, Zorn SH, Doller D, and Pilc A
- Subjects
- Animals, Humans, Ligands, Schizophrenia metabolism, Antipsychotic Agents therapeutic use, Receptors, Metabotropic Glutamate metabolism, Schizophrenia drug therapy
- Abstract
In this review, we aim to present, discuss and clarify our current understanding regarding the prediction of possible antipsychotic effects of metabotropic glutamate (mGlu) receptor ligands. The number of preclinical trials clearly indicates, that this group of compounds constitutes an excellent alternative to presently used antipsychotic therapy, being effective not only to positive, but also negative and cognitive symptoms of schizophrenia. Although the results of clinical trials that were performed for the group of mGlu2/3 agonists were not so enthusiastic as in animal studies, they still showed that mGlu ligands do not induced variety of side effects typical for presently used antipsychotics, and were generally well tolerated. The lack of satisfactory effectiveness towards schizophrenia symptoms of mGlu2/3 activators in humans could be a result of variety of uncontrolled factors and unidentified biomarkers different for each schizophrenia patient, that should be taken into consideration in the future set of clinical trials. The subject is still open for further research, and the novel classes of mGlu5 or mGlu2/3 agonists/PAMs were recently introduced, including the large group of compounds from the third group of mGlu receptors, especially of mGlu4 subtype. Finally, more precise treatment based on simultaneous administration of minimal doses of the ligands for two or more receptors, seems to be promising in the context of symptoms-specific schizophrenia treatment., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2016
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30. mGlu₅-GABAB interplay in animal models of positive, negative and cognitive symptoms of schizophrenia.
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Wierońska JM, Kłeczek N, Woźniak M, Gruca P, Łasoń-Tyburkiewicz M, Papp M, Brański P, Burnat G, and Pilc A
- Subjects
- Animals, Antipsychotic Agents pharmacology, Antipsychotic Agents therapeutic use, Cognition Disorders drug therapy, Excitatory Amino Acid Agonists pharmacology, Excitatory Amino Acid Agonists therapeutic use, GABA-B Receptor Agonists pharmacology, GABA-B Receptor Agonists therapeutic use, Interpersonal Relations, Male, Mice, Motor Activity physiology, Rats, Rats, Wistar, Receptor, Metabotropic Glutamate 5 agonists, Schizophrenia drug therapy, Cognition Disorders metabolism, Disease Models, Animal, Receptor, Metabotropic Glutamate 5 metabolism, Receptors, GABA-B metabolism, Schizophrenia metabolism
- Abstract
Diverse preclinical studies exploiting the modulation of the GABAergic and/or glutamatergic system in brain via metabotropic receptors suggest their potential therapeutic utility. GS39783 and CDPPB, positive allosteric modulators of GABAB and mGlu5 receptors, were previously shown to reverse behavioral phenotypes in animal models to mimic selected (predominantly positive) symptoms of schizophrenia. In the present study we investigated the activity of selected GABAB (GS39783 and CGP7930) and mGlu5 (CDPPB) positive allosteric modulators. We focused mainly on the aspects of their efficacy in the models of negative and cognitive symptoms of schizophrenia. We used modified swim test, social interactions (models of negative symptoms) and novel object recognition (model of cognitive disturbances). The activity of the compounds was also tested in haloperidol-induced catalepsy test. The mutual interaction between GABAB/mGlu5 ligands was investigated as well. In the second part of the study, DHPG-induced PI hydrolysis in the presence of GABAB receptor antagonist (SKF97541), and SKF97541-induced inhibition of cAMP formation in the presence of DHPG, was performed. Both mGlu5 and GABAB receptor modulators effectively reversed MK-801-induced deficits in behavioral models of schizophrenia. Moreover, the concomitant administration of sub-effective doses of CDPPB and GS39783 induced a clear antipsychotic-like effect in all the procedures used, except DOI-induced head twitches. The concomitant administration of group I mGlu and GABAB agonists did not displayed any synergistic effects in vitro. Summing up, an activation of both types of receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative and cognitive symptoms., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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31. The antipsychotic-like effects in rodents of the positive allosteric modulator Lu AF21934 involve 5-HT1A receptor signaling: mechanistic studies.
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Wierońska JM, Sławińska A, Łasoń-Tyburkiewicz M, Gruca P, Papp M, Zorn SH, Doller D, Kłeczek N, Noworyta-Sokołowska K, Gołembiowska K, and Pilc A
- Subjects
- Allosteric Regulation drug effects, Allosteric Regulation physiology, Animals, Dizocilpine Maleate pharmacology, Male, Mice, Motor Activity drug effects, Motor Activity physiology, Rats, Rats, Wistar, Receptors, Metabotropic Glutamate agonists, Receptors, Metabotropic Glutamate physiology, Anilides pharmacology, Antipsychotic Agents pharmacology, Cyclohexanecarboxylic Acids pharmacology, Receptor, Serotonin, 5-HT1A physiology, Signal Transduction drug effects, Signal Transduction physiology
- Abstract
Rationale: Diverse preclinical studies suggest the potential therapeutic utility of the modulation of the glutamatergic system in brain via metabotropic glutamate (mGlu) receptors. Lu AF21934, a positive allosteric modulator of the mGlu4 receptor, was previously shown to reverse behavioral phenotypes in animal models thought to mimic positive, negative, and cognitive symptoms of schizophrenia., Objectives: To begin elucidating the brain circuitry involved in mGlu4 receptor pharmacology and add mechanistic support to Lu AF21934-induced phenotypic responses, the potential involvement of 5-HT1A receptors in these antipsychotic-like effects was explored. The tests used were the following: MK-801-induced hyperactivity and 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitches in mice, for positive symptoms; MK-801-induced disruptions of social interactions for negative symptoms; and novel object recognition and spatial delayed alteration test for cognitive symptoms. The microdialysis studies in which the effect of Lu AF21934 on MK-801-induced dopamine and serotonin release was investigated., Results: The effects caused by Lu AF2193 were inhibited by administration of the selective 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg). That inhibition was observed across all models used. Moreover, the concomitant administration of sub-effective doses of Lu AF21934 and a sub-effective dose of the selective 5-HT1A receptor agonist tool compound (R)-(+)-8-hydroxy-DPAT hydrobromide (0.01 mg/kg) induced a clear antipsychotic-like effect in all the procedures used. Lu AF21934 (5 mg/kg) also inhibited MK-801-induced increase in dopamine and 5-HT release., Conclusions: The actions of Lu AF21934 are 5-HT1A receptor-dependent. Activation of the mGlu4 receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative, and cognitive symptoms.
- Published
- 2015
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32. The antidepressant-like action of mGlu5 receptor antagonist, MTEP, in the tail suspension test in mice is serotonin dependent.
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Pałucha-Poniewiera A, Brański P, Wierońska JM, Stachowicz K, Sławińska A, and Pilc A
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- Animals, Citalopram pharmacology, Diet, Fenclonine pharmacology, Fluoxetine pharmacology, Male, Mice, Mice, Inbred C57BL, Motor Activity drug effects, Serotonin Antagonists pharmacology, Selective Serotonin Reuptake Inhibitors pharmacology, Tryptophan deficiency, Antidepressive Agents, Excitatory Amino Acid Antagonists pharmacology, Hindlimb Suspension psychology, Piperidines pharmacology, Receptors, Kainic Acid antagonists & inhibitors, Serotonin physiology, Thiazoles pharmacology
- Abstract
Rationale: Numerous studies indicate the potential antidepressant actions of several mGlu5 receptor antagonists, including 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP). The explanation for the mechanism of these effects might be a key step in finding new antidepressant drugs (AD)., Objectives: The aim of the present study was to investigate the possible role of the serotonergic system in the antidepressant-like activity of MTEP in the tail suspension test (TST) in C57BL/6J mice, using selected antagonists of serotonergic receptors and by applying two different methods of serotonin (5-HT) depletion., Results: The results of our studies showed that the mGlu5 receptor antagonist, MTEP, similar to the fluoxetine used as reference AD, did not induce antidepressant-like effects in mice pretreated with tryptophan hydroxylase inhibitor, parachlorophenylalanine. On the other hand, MTEP worked as a potential AD in the TST in mice fed on a tryptophan-free (TRP-free) diet for 3 weeks. However, fluoxetine, which was used as a reference control was also active in this experiment, suggesting that a TRP-free diet was not sufficiently effective in reducing the 5-HT level. Furthermore, we showed that the 5HT2A/2C antagonist, ritanserin, yet not the 5-HT1A antagonist, WAY100635, 5HT1B antagonist, SB224289 or 5HT4 antagonist, GR125487, reversed the antidepressant-like effects of MTEP in the TST. Finally, a sub-effective dose ofMTEP coadministered with a sub-effective dose of citalopram induced an antidepressant-like effect in the TST in mice., Conclusion: The results of our studies suggest the involvement of serotonergic system activation in the antidepressant-like effects of the mGlu5 antagonist, MTEP, in the TST in mice.
- Published
- 2014
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33. The reversal of cognitive, but not negative or positive symptoms of schizophrenia, by the mGlu₂/₃ receptor agonist, LY379268, is 5-HT₁A dependent.
- Author
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Wierońska JM, Sławińska A, Stachowicz K, Łasoń-Tyburkiewicz M, Gruca P, Papp M, and Pilc A
- Subjects
- Animals, Cognition physiology, Dose-Response Relationship, Drug, Male, Mice, Motor Activity drug effects, Motor Activity physiology, Neuropsychological Tests, Piperazines pharmacology, Pyridines pharmacology, Rats, Wistar, Receptors, Metabotropic Glutamate agonists, Receptors, Metabotropic Glutamate metabolism, Recognition, Psychology drug effects, Recognition, Psychology physiology, Schizophrenia physiopathology, Serotonin 5-HT1 Receptor Agonists pharmacology, Serotonin 5-HT1 Receptor Antagonists pharmacology, Social Behavior, Amino Acids pharmacology, Antipsychotic Agents pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Cognition drug effects, Receptor, Serotonin, 5-HT1A metabolism, Schizophrenia drug therapy, Schizophrenic Psychology
- Abstract
mGlu(2/3) receptor agonists were shown to possess an antipsychotic-like potential in animal studies. Recent clinical investigations revealed that their antipsychotic potential might also manifest in humans. LY379268, the group II mGlu receptor orthosteric agonist, was previously shown to exhibit antipsychotic-like action in animal models of schizophrenia. However, the mechanism of its action is not fully recognized. Here, we decided to investigate the involvement of 5-HT1A receptors in the LY379268-induced antipsychotic effects. We used models of positive, negative and cognitive symptoms of schizophrenia, such as MK-801- and amphetamine-induced hyperactivity tests, DOI-induced head twitches, social interaction and novel object recognition. LY379268 was active in a wide range of doses (0.5-5 mg/kg), depending on the paradigm. The effects of the drug were not antagonized by 5-HT(1A) antagonist, WAY100635 (0.1 mg/kg) in the models of positive and negative symptoms. Conversely, in the novel object recognition test, which exerts cognitive disturbances, the action of LY379268 was antagonized by WAY100635. Concomitantly, the action of a sub-effective dose of the drug was enhanced by the administration of a sub-effective dose of 5-HT(1A) agonist, (R)-(+)-8-Hydroxy-DPAT. Altogether, we propose that the antipsychotic-like action of group II mGlu receptors' agonist is 5-HT(1A) independent in context of positive and negative symptoms, while the action toward cognitive disturbances seems to be 5-HT(1A) dependent., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
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34. Glutamate-based anxiolytic ligands in clinical trials.
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Wierońska JM and Pilc A
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- Animals, Anxiety metabolism, Anxiety physiopathology, Glutamic Acid physiology, Humans, Ion Channels physiology, Ligands, Synapses physiology, Anti-Anxiety Agents therapeutic use, Anxiety drug therapy, Excitatory Amino Acid Agents therapeutic use
- Abstract
Introduction: With regard to anxiety, the role of the balance between glutamatergic and GABAergic systems was pursued for many years. The majority of drugs used presently as effective anxiolytics enhance the GABAergic system activity, thus increasing inhibition within the central nervous system (CNS). On the other hand, decreasing the activity of glutamatergic neurotransmission may attenuate excitation in the CNS, thus resulting in anxiolysis., Areas Covered: The present review focuses on clinical data of well-known and recently discovered glutamatergic and, to a lesser extent, GABAergic agents, which reached at least the Phase II criteria., Expert Opinion: A variety of glutamatergic agents active at both N-acetylo-D-asparaginian and metabotropic glutamate (mGlu) receptors have been tested in humans to examine their potential anxiolytic activity. Many compounds acting on the glutamatergic system and approved for the treatment of other disorders than anxiety were shown to exert anxiolytic effects in clinical trials. Those are mainly voltage-dependent ion channel ligands as well as d-cycloserin and memantine. Also, ligands active at mGlu receptors, such as fenobam and LY354740, exhibited activity in controlled clinical trials. However, relatively few trials are found on the agents that are focused on GABAergic neurotransmission. Therefore, it seems that glutamatergic system may become a novel target for modern and effective anxiolytics.
- Published
- 2013
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35. The antipsychotic-like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents.
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Sławińska A, Wierońska JM, Stachowicz K, Marciniak M, Lasoń-Tyburkiewicz M, Gruca P, Papp M, Kusek M, Tokarski K, Doller D, and Pilc A
- Subjects
- Allosteric Regulation, Amphetamine, Animals, Disease Models, Animal, Dizocilpine Maleate, Dose-Response Relationship, Drug, Excitatory Postsynaptic Potentials drug effects, Hyperkinesis drug therapy, Male, Mice, Motor Activity drug effects, Rats, Schizophrenia chemically induced, Anilides pharmacology, Antipsychotic Agents pharmacology, Cyclohexanecarboxylic Acids pharmacology, Receptors, Metabotropic Glutamate drug effects, Schizophrenia drug therapy
- Abstract
Background and Purpose: Because agonists at metabotropic glutamate receptors exert beneficial effects in schizophrenia, we have assessed the actions of Lu AF21934 and Lu AF32615, two chemically distinct, selective and brain-penetrant positive allosteric modulators (PAMs) of the mGlu4 receptor, in several tests reflecting positive, negative and cognitive symptoms of schizophrenia in rodents., Experimental Approach: Hyperactivity induced by MK-801 or amphetamine and head twitches induced by 2,5-dimethoxy-4-iodoamphetamine (DOI) in mice were used as models for positive symptoms. Disruption of social interaction and spatial delayed alternation tests induced by MK-801 in rats were used as models for negative and cognitive symptoms of schizophrenia, respectively., Key Results: Lu AF21934 (0.1-5 mg·kg(-1) ) and Lu AF32615 (2-10 mg·kg(-1) ) dose-dependently inhibited hyperactivity induced by MK-801 or amphetamine. They also antagonized head twitches and increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) in brain slices, induced by DOI. In mice lacking the mGlu4 receptor (mGlu4 (-/-) ) mice, Lu AF21934 did not antagonize DOI-induced head twitches. MK-801-induced disruption in the social interaction test was decreased by Lu AF21934 at 0.5 mg·kg(-1) and by Lu AF32615 at 10 mg·kg(-1) . In the delayed spatial alternation test, Lu AF21934 was active at 1 and 2 mg·kg(-1) , while Lu AF32615 was active at 10 mg·kg(-1) ., Conclusions and Implications: We propose that activation by PAMs of the mGlu4 receptor is a promising approach to the discovery of novel antipsychotic drugs., (© 2013 The British Pharmacological Society.)
- Published
- 2013
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36. Glutamate-based antidepressants: preclinical psychopharmacology.
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Pilc A, Wierońska JM, and Skolnick P
- Subjects
- Animals, Antidepressive Agents pharmacology, Excitatory Amino Acid Antagonists pharmacology, Excitatory Amino Acid Antagonists therapeutic use, Glutamic Acid metabolism, Humans, Antidepressive Agents therapeutic use, Depressive Disorder drug therapy, Drug Evaluation, Preclinical, Psychopharmacology
- Abstract
Over the past 20 years, converging lines of evidence have both linked glutamatergic dysfunction to the pathophysiology of depression and demonstrated that the glutamatergic synapse presents multiple targets for developing novel antidepressants. The robust antidepressant effects of the N-methyl-D-aspartate receptor antagonists ketamine and traxoprodil provide target validation for this family of ionotropic glutamate receptors. This article reviews the preclinical evidence that it may be possible to develop glutamate-based antidepressants by not only modulating ionotropic (N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) and metabotropic glutamate (mGlu) receptors, including mGlu2/3, mGLu5 and mGlu7 receptors, but also by altering synaptic concentrations of glutamate via specialized transporters such as glial glutamate transporter 1 (excitatory amino-acid transporter 2)., (Copyright © 2013 Society of Biological Psychiatry. All rights reserved.)
- Published
- 2013
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37. The antipsychotic-like effects of the mGlu group III orthosteric agonist, LSP1-2111, involves 5-HT₁A signalling.
- Author
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Wierońska JM, Acher FC, Sławińska A, Gruca P, Lasoń-Tyburkiewicz M, Papp M, and Pilc A
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Aminobutyrates administration & dosage, Amphetamines pharmacology, Animals, Antipsychotic Agents administration & dosage, Cyclohexanes pharmacology, Dextroamphetamine pharmacology, Disease Models, Animal, Dizocilpine Maleate toxicity, Dose-Response Relationship, Drug, Male, Mice, Phosphinic Acids administration & dosage, Piperazines pharmacology, Rats, Rats, Wistar, Receptors, Metabotropic Glutamate agonists, Signal Transduction, Aminobutyrates pharmacology, Antipsychotic Agents pharmacology, Phosphinic Acids pharmacology, Psychotic Disorders drug therapy, Receptor, Serotonin, 5-HT1A metabolism
- Abstract
Rationale: Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new way to achieve antipsychotic-like activity. LSP1-2111, the group III mGlu receptor orthosteric agonist, with a high affinity towards mGlu4 receptors, was previously shown to exhibit antipsychotic-like action in animal models displaying positive symptoms of schizophrenia., Objectives: Here, we decided to investigate the possible role of LSP1-2111 in models of negative (social interaction) and cognitive (NOR) symptoms of psychosis. We also investigated the involvement of 5-HT1A receptors in the LSP1-2111-induced antipsychotic effects. Apart from the above-mentioned models of negative and cognitive symptoms, MK-801 and amphetamine-induced hyperactivity tests, plus the DOI-induced head twitches in mice as models for positive symptoms of psychosis, were used in this part of the investigations., Results: LSP1-2111 (0.5, 2, and 5 mg/ kg) dose-dependently inhibited MK-801-induced deficits in social interaction and NOR tests. The effects of the drug were antagonized by 5-HT1A antagonist, WAY100635 (0.1 mg/kg). A similar inhibition of LSP1-2111-induced effects was observed in models of positive symptoms of schizophrenia. Moreover, the concomitant administration of subeffective doses of LSP1-2111 (0.3-0.5 mg/kg) with a subeffective dose of 5-HT1A agonist, (R)-(+)-8-Hydroxy-DPAT (0.01 mg/kg), induced a clear antipsychotic-like effect in all of the procedures used., Conclusions: Altogether, we propose that the activation of group III mGlu receptors may be a promising target for the development of novel antipsychotic drugs, towards not only positive but also negative and cognitive symptoms. The action of the compound is 5-HT1A-dependent.
- Published
- 2013
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38. Anxiolytic- but not antidepressant-like activity of Lu AF21934, a novel, selective positive allosteric modulator of the mGlu₄ receptor.
- Author
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Sławińska A, Wierońska JM, Stachowicz K, Pałucha-Poniewiera A, Uberti MA, Bacolod MA, Doller D, and Pilc A
- Subjects
- Animals, Behavior, Animal drug effects, Brain drug effects, Brain metabolism, Dose-Response Relationship, Drug, Flumazenil pharmacology, GABA-A Receptor Antagonists pharmacology, Male, Mice, Mice, Inbred C57BL, Motor Activity drug effects, Piperazines pharmacology, Pyridines pharmacology, Rats, Rats, Wistar, Receptors, Metabotropic Glutamate agonists, Ritanserin pharmacology, Serotonin metabolism, Serotonin Antagonists pharmacology, Allosteric Regulation physiology, Anilides pharmacology, Anti-Anxiety Agents pharmacology, Antidepressive Agents pharmacology, Cyclohexanecarboxylic Acids pharmacology, Receptors, Metabotropic Glutamate physiology
- Abstract
Previous studies demonstrated that the Group III mGlu receptor-selective orthosteric agonist, LSP1-2111 produced anxiolytic- but not antidepressant-like effects upon peripheral administration. Herein, we report the pharmacological actions of Lu AF21934, a novel, selective, and brain-penetrant positive allosteric modulator (PAM) of the mGlu(4) receptor in the stress-induced hyperthermia (SIH), four-plate, marble-burying and Vogel's conflict tests. In all models, except Vogel's conflict test, a dose-dependent anxiolytic-like effect was seen. The anti-hyperthermic effect of Lu AF21934 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (10 mg/kg) and was not serotonin-dependent, as it persisted in serotonin-deficient mice and upon blockade of either 5-HT(1A) receptors by WAY100635, or 5-HT(2A/2C) receptors by ritanserin. These results suggest that the GABAergic system, but not the serotonergic system, is involved in the mechanism of the anxiolytic-like phenotype of Lu AF21934 in rodents. Lu AF21934 did not produce antidepressant-like effects in the tail suspension test (TST) in mice; however, it decreased the basal locomotor activity of mice that were not habituated to activity cages. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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39. Is the mGlu5 receptor a possible target for new antidepressant drugs?
- Author
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Pałucha-Poniewiera A, Wierońska JM, Brański P, Burnat G, Chruścicka B, and Pilc A
- Subjects
- Animals, Humans, Antidepressive Agents pharmacology, Antidepressive Agents therapeutic use, Depression drug therapy, Depression metabolism, Receptor, Metabotropic Glutamate 5 antagonists & inhibitors, Receptor, Metabotropic Glutamate 5 metabolism
- Abstract
The current treatment of depression, based on conventional antidepressant drugs that influence monoaminergic systems, is not satisfactory, and innovative antidepressant drugs are still needed. The next generation of treatments needs to be more effective, faster-acting and better tolerated than currently used antidepressants. A growing body of evidence indicates that compounds that modulate the glutamatergic system may be a group of novel and mechanistically distinct agents for the treatment of depression. Both preclinical and clinical data show strong, rapid and sustained effects of the NMDA receptor antagonist ketamine in treatment-resistant depression. However, ketamine cannot be considered as a novel antidepressant drug because of its side-effects and abuse potential. Because glutamatergic transmission is controlled not only by ionotropic but also by metabotropic glutamate receptors, their involvement in the etiology and the therapy of depression has also been postulated. Here, we review data supporting the potential antidepressant activity of mGlu5 receptor antagonists as well as the involvement of mGlu5 receptors in the pathophysiology of depression.
- Published
- 2013
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40. Opposing efficacy of group III mGlu receptor activators, LSP1-2111 and AMN082, in animal models of positive symptoms of schizophrenia.
- Author
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Wierońska JM, Stachowicz K, Acher F, Lech T, and Pilc A
- Subjects
- Aminobutyrates administration & dosage, Amphetamines toxicity, Animals, Antipsychotic Agents administration & dosage, Antipsychotic Agents pharmacology, Benzhydryl Compounds administration & dosage, Dextroamphetamine toxicity, Disease Models, Animal, Dizocilpine Maleate toxicity, Dose-Response Relationship, Drug, Drug Delivery Systems, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphinic Acids administration & dosage, Receptors, Metabotropic Glutamate genetics, Receptors, Metabotropic Glutamate metabolism, Schizophrenia physiopathology, Aminobutyrates pharmacology, Benzhydryl Compounds pharmacology, Phosphinic Acids pharmacology, Receptors, Metabotropic Glutamate agonists, Schizophrenia drug therapy
- Abstract
Rationale: Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new and efficient way to achieve antipsychotic-like activity., Objectives: Here, we decided to investigate the possible role of the group III mGlu receptor ligands, LSP1-2111, the group III mGlu receptor orthosteric agonist, preferentially stimulating mGlu4 receptors especially in low doses, and AMN082, the mGlu7 receptor positive modulator. We used MK-801- and amphetamine-induced hyperactivity tests, as well as DOI-induced head twitches in mice as models for positive symptoms of psychosis. The C57Bl/6J mGlu7 receptor knockout mice were used to confirm that AMN082-induced effect was receptor specific. A non-selective antagonist of the group II/III mGlu receptors, LY341495, was used to block LSP1-2111-induced effects., Results: LSP1-2111 (1, 2, and 5 mg kg(-1)) dose dependently inhibited both MK-801- and amphetamine-induced hyperactivities. Moreover, the drug antagonized DOI-induced head twitches. The effects of the drug were antagonized by LY341495 administration (1.5 mg kg(-1), i.p.). In contrast, AMN082 (3 and 6 mg kg(-1)) had no effect on amphetamine-induced hyperactivity but induced an enhancement of MK-801-induced hyperactivity and DOI-induced head twitches in mice. In C57Bl/6J mGlu7 receptor knockout animals (KO), those effects of AMN082 were not observed. Moreover, mGlu7 KO animals were less sensitive for DOI-induced effect than their wild type littermates., Conclusions: Altogether, we propose that among group III mGlu receptors, mGlu4 receptor may be a promising target for the development of novel antipsychotic drugs.
- Published
- 2012
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41. On the mechanism of anti-hyperthermic effects of LY379268 and LY487379, group II mGlu receptors activators, in the stress-induced hyperthermia in singly housed mice.
- Author
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Wierońska JM, Stachowicz K, Brański P, Pałucha-Poniewiera A, and Pilc A
- Subjects
- Analysis of Variance, Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Interactions, Fever etiology, Flumazenil therapeutic use, GABA Antagonists therapeutic use, GABA Modulators therapeutic use, Male, Mice, Phosphinic Acids therapeutic use, Piperazines therapeutic use, Propanolamines therapeutic use, Ritanserin therapeutic use, Serotonin Antagonists therapeutic use, Social Isolation, Stress, Psychological complications, Amino Acids therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Excitatory Amino Acid Agonists therapeutic use, Fever drug therapy, Pyridines therapeutic use, Receptors, AMPA metabolism, Sulfonamides therapeutic use
- Abstract
Earlier studies have demonstrated that the agonists of the mGlu(2/3) receptors produced anxiolytic actions after peripheral administration. However, the mechanism of their action is still not clear. Therefore the aim of the present study was to specify the role of the GABAergic and serotonergic system in the mechanism of the anxiolytic activity of group II mGlu receptor activators by using the stress induced hyperthermia test (SIH) in singly housed mice. We used an orthosteric mGlu(2/3) receptor agonist, LY379268, which induced anti-hyperthermic efficacy in the doses of 1-5mg/kg (73% of inhibition after a highest dose). The effect of the second ligand used, a mGlu(2) receptor positive modulator (PAM), LY487379, was observed in a dose range of 0.5-5mg/kg and reached 53% of the inhibition. The blockade of GABAergic system by GABA(A) receptor antagonist flumazenil (10mg/kg) or GABA(B) receptor antagonist CGP55845 (10mg/kg), and the blockade of serotonergic system by 5-HT(1A) receptor antagonist WAY100635 (0.1 and 1mg/kg) or 5-HT(2A/2C) receptor antagonist ritanserin (0.5mg/kg) had no influence on the anti-hyperthermic effect induced by effective dose of LY379268. However, the action of the effective dose of LY487379 was enhanced when co-administered with flumazenil, WAY100635 (0.1mg/kg) and ritanserin. Similar results were observed for the subeffective dose of LY379268 (0.5mg/kg). WAY100635 in a dose of 1mg/kg did not induce any enhancing effect on the activity of compounds. Therefore, it seems that the antagonism towards GABA(A) receptors, presynaptic 5-HT(1A) and postsynaptic 5-HT(2A/2C) receptors is responsible for the phenomenon. This article is part of a Special Issue entitled 'Anxiety and Depression'., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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42. Metabotropic glutamate receptor 4 novel agonist LSP1-2111 with anxiolytic, but not antidepressant-like activity, mediated by serotonergic and GABAergic systems.
- Author
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Wierońska JM, Stachowicz K, Pałucha-Poniewiera A, Acher F, Brański P, and Pilc A
- Subjects
- Animals, Diazepam pharmacology, Fever drug therapy, Fever etiology, Flumazenil pharmacology, GABA-A Receptor Antagonists pharmacology, Maze Learning drug effects, Mice, Piperazines pharmacology, Pyridines pharmacology, Receptor, Serotonin, 5-HT1A physiology, Receptor, Serotonin, 5-HT2A physiology, Receptors, GABA-A physiology, Ritanserin pharmacology, Serotonin 5-HT1 Receptor Antagonists pharmacology, Serotonin 5-HT2 Receptor Agonists pharmacology, Stress, Psychological complications, Aminobutyrates pharmacology, Anti-Anxiety Agents pharmacology, Antidepressive Agents pharmacology, Phosphinic Acids pharmacology, Receptors, Metabotropic Glutamate agonists, Serotonin physiology, gamma-Aminobutyric Acid physiology
- Abstract
Our earlier studies have demonstrated that the non-selective group III mGlu receptor agonist, ACPT-I, produced anxiolytic rather than antidepressant-like actions after its peripheral administration. Here, we describe the effects of LSP1-2111 ((2S)-2-amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitro-phenyl)methyl]phosphoryl]butanoic acid), a novel orthosteric, preferential agonist of the mGlu4 receptor, a member of the group III mGlu receptors family, in the stress-induced hyperthermia (SIH) and elevated plus-maze (EPM) tests in mice. In both tests an anxiolytic-like effect was clearly seen in doses of 2 and 5 mg/kg, i.p. The compound did not produce antidepressant-like effects in the tail suspension test (TST) or in the forced swim test (FST) in mice. The potential anxiolytic effect of LSP1-2111 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (given i.p., 10 mg/kg), and by a 5-HT(1A) receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl)cyclohexane-carboxamide (WAY100635) (0.1 mg/kg, s.c.). At the same time, ritanserin (0.5 mg/kg i.p.), the 5-HT(2A/C) receptor antagonist, did not change the anxiolytic-like effects of LSP1-2111. Moreover, the compound was not effective in 5-HT depleted animals. The results of these studies indicate that the GABAergic and serotonergic systems are involved in the potential anxiolytic action of LSP1-2111., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
43. On the mechanism of the antidepressant-like action of group II mGlu receptor antagonist, MGS0039.
- Author
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Pałucha-Poniewiera A, Wierońska JM, Brański P, Stachowicz K, Chaki S, and Pilc A
- Subjects
- Animals, Avoidance Learning drug effects, Depression metabolism, Depression psychology, Disease Models, Animal, Hindlimb Suspension, Male, Mice, Mice, Inbred C57BL, Motor Activity drug effects, Olfactory Bulb surgery, Rats, Rats, Sprague-Dawley, Receptors, AMPA antagonists & inhibitors, Receptors, AMPA metabolism, Receptors, Metabotropic Glutamate metabolism, Serotonin deficiency, Serotonin Antagonists pharmacology, Antidepressive Agents pharmacology, Behavior, Animal drug effects, Bridged Bicyclo Compounds pharmacology, Depression drug therapy, Dicarboxylic Acids pharmacology, Excitatory Amino Acid Antagonists pharmacology, Receptors, Metabotropic Glutamate antagonists & inhibitors
- Abstract
Rationale: Several studies have suggested that modulation of the glutamatergic system could be a new, efficient way to achieve antidepressant activity. Behavioral data showed that group II mGlu receptor antagonists (i.e., (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039) and (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xan th-9-yl) propanoic acid (LY341495)) elicited antidepressant activity in several animal models of depression in rats and/or mice. Although the antidepressant-like activity of MGS0039 and LY341495 is well documented, the mechanism of the antidepressant action of these compounds is still not clear., Objectives: The aim of the present study was to specify the role of the serotonergic system in the mechanism of the antidepressant-like activity of group II mGlu receptor ligands by using the tail suspension test (TST) in mice; the role of AMPA receptors was also investigated. Furthermore, the possible antidepressant-like action of MGS0039 using the olfactory bulbectomy (OB) model of depression in rats was investigated., Results: The results of the TST studies showed that antidepressant-like action of group II mGlu receptor antagonists does not depend on serotonergic system activation. However, the AMPA receptor seems to play a key role in the antidepressant-like action of these compounds. Moreover, we have shown that repeated administration of MGS0039 attenuated OB-related deficits, confirming antidepressant-like activity of the tested compound., Conclusions: The results suggest that the blockade of group II mGlu receptors may be effective in the treatment of depression. Moreover, we have found that the mechanism of action of group II mGlu receptor antagonists differs from that of typical antidepressants, such as SSRIs.
- Published
- 2010
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44. GABAergic dysfunction in mGlu7 receptor-deficient mice as reflected by decreased levels of glutamic acid decarboxylase 65 and 67kDa and increased reelin proteins in the hippocampus.
- Author
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Wierońska JM, Brański P, Siwek A, Dybala M, Nowak G, and Pilc A
- Subjects
- Analysis of Variance, Animals, Cell Adhesion Molecules, Neuronal genetics, Extracellular Matrix Proteins genetics, GABA Antagonists pharmacokinetics, Glutamate Decarboxylase genetics, Hippocampus cytology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Tissue Proteins genetics, Neurons metabolism, Organophosphorus Compounds pharmacokinetics, Protein Binding drug effects, Protein Binding genetics, RNA, Messenger metabolism, Reelin Protein, Serine Endopeptidases genetics, Tritium pharmacokinetics, gamma-Aminobutyric Acid metabolism, Cell Adhesion Molecules, Neuronal metabolism, Extracellular Matrix Proteins metabolism, Gene Expression Regulation genetics, Glutamate Decarboxylase metabolism, Hippocampus metabolism, Nerve Tissue Proteins metabolism, Receptors, Metabotropic Glutamate deficiency, Serine Endopeptidases metabolism
- Abstract
Glutamate is the main excitatory neurotransmitter in the brain, while gamma-aminobutyric acid (GABA) is a primary inhibitory neuromodulator. Both amino acids act through ionotropic and metabotropic receptors that are widely distributed in the central nervous system. There are at least eight subtypes of metabotropic glutamate receptors (mGlu), which have been divided into three groups (mGlu I, II, and III). The mGlu7 receptor subtype, which belongs to the mGlu III group, seems to play a special role, as it is abundant in brain structures that are known to be responsible for antidepressant and/or anxiolytic activity of drugs. In GABAergic neurons, GABA is synthesised from glutamate by the pyridoxal phosphate (PLP)-dependent enzyme glutamic acid decarboxylase (GAD). It is expressed as two major isoforms, GAD65 and GAD67, responsible for the synthesis of the vesicular and cytoplasmic pool of neurotransmitter, respectively. Moreover, GABAergic neurons express a variety of proteins such as reelin, involved in synaptic transmission and plasticity. The aim of our study was to investigate the regulation of GABA synthesis and the level of modulatory receptor for GABA in mice lacking mGlu7 receptor for glutamate. The levels of GAD mRNA, GADs, and reelin proteins in the hippocampi of mGlu7-/- and mGlu7-/+ mice were measured using in situ hybridisation, immunohistochemistry, and Western blotting (WB). GAD mRNAs in the CA and DG regions of the hippocampus were measured separately. The levels of GAD65, GAD67, and reelin proteins were determined in the homogenates using WB, and the number of stained neurons was estimated using a stereological method of counting. GABA(B) receptor level was measured using a radioligand binding assay. Our results show that the mRNA and protein levels of both GADs were decreased in the hippocampi of animals lacking the mGlu7 receptor. Decreased levels of GAD67 mRNA were found in both the CA and DG regions, while the decrease in GAD65 mRNA was observed mainly in the CA region of the hippocampus. The protein levels of GAD65 was lowered in mGlu7-/- animals only, while GAD67 and GABA(B) receptor number were decreased in both mGlu7+/- and mGlu7-/- mice when measured in the whole hippocampus. In contrast, reelin was shown to be increased both in mGlu7-/+ and mGlu7-/- mice. The results suggest that mGlu7 receptor is involved in the regulation of GABAergic system activity at the level of GABA synthesised enzymes, specific proteins expressed by GABAergic neurons and metabotropic receptor for GABA., (Copyright 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
- Full Text
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45. Metabotropic glutamate receptors in the tripartite synapse as a target for new psychotropic drugs.
- Author
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Wierońska JM and Pilc A
- Subjects
- Animals, Anxiety drug therapy, Depressive Disorder drug therapy, Glutamic Acid physiology, Humans, Neuroglia drug effects, Neurotransmitter Agents physiology, Schizophrenia drug therapy, Mental Disorders drug therapy, Psychotropic Drugs pharmacology, Psychotropic Drugs therapeutic use, Receptors, Metabotropic Glutamate drug effects, Synapses drug effects
- Abstract
Mental disorders, such as depression, anxiety and schizophrenia, has become a large medical and social problem recently. Studies performed in animal tests and early clinical investigations brought a new insight in the pharmacotherapy of these disorders. Latest investigations are focused mainly on the glutamatergic system, a main excitatory amino acid neurotransmitter in the brain. Evidence indicates that metabotropic glutamate receptors ligands have excellent antidepressant, anxiolytic and antipsychotic effects. Metabotopic glutamate receptors (mGlu) divaded into three groups (group I, II and III) are localized on nerve terminals, postsynaptic sites and glial cells and thus they can influence and modulate the action of glutamate on different levels in the synapse. Recent advances in the identification of selective and specific compounds (both ortho- and allosteric ligands), and the generation of transgenic animals enabled to have new insight into the pathophysiology and therapy of mood disorders. At present, the most potent seem to be negative allosteric modulators of the first group (mGlu1 and mGlu5), and positive allosteric modulators of the second (mGlu2 and mGlu3) and third (mGlu4/7/8) group of mGlu receptors.
- Published
- 2009
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46. Olfactory bulbectomy and amitriptyline treatment influences mGlu receptors expression in the mouse brain hippocampus.
- Author
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Wierońska JM, Legutko B, Dudys D, and Pilc A
- Subjects
- Animals, Blotting, Western, Depression drug therapy, Hippocampus chemistry, Immunohistochemistry, Male, Mice, Amitriptyline pharmacology, Antidepressive Agents, Tricyclic pharmacology, Depression metabolism, Disease Models, Animal, Hippocampus drug effects, Olfactory Bulb surgery, Receptors, Metabotropic Glutamate analysis
- Abstract
Olfactory bulbectomy (OB) is an established animal model of depression that has been investigated mostly in rats. As in human major depression, OB induces behavioral alterations that can be ameliorated by chronic antidepressant treatment. Furthermore, it was shown that OB induces changes of various protein receptor levels in brain areas that are important in antidepressant therapy. In the present study, we investigated the effects of OB and amitriptyline (AMI) treatment on the expression of metabotropic glutamate receptors (mGluR) in the mouse hippocampus using the western blot method. AMI was given for 14 days, in a dose of 10 mg/kg, intraperitoneally. The levels of most subtypes of mGlu receptors, e.g., mGlu1a (mGluR group I), mGlu2/3 (mGluR group II), mGlu4, and mGlu7 (mGluR group III) receptors, were measured. Additionally, immunohistochemical stainings were made in slices of the mouse hippocampus. It was found that OB induced an increase in mGluR1a-immunoreactivity (IR), which was abolished by AMI treatment in the hippocampus. The removal of the olfactory bulbs caused a decrease in the level of mGlu2/3 receptors in the hippocampus, which was reversed after AMI administration. MGluR4-IR was decreased in the hippocampus in all the groups studied. A decrease of mGluR7-IR was observed in the OB group, and the effect was abolished by the administration of AMI. However, decreases in the level of mGlu2/3 and mGlu7 receptors were observed after AMI administration. The results obtained indicate an influence of OB on mGlu receptors levels in the hippocampus, and the OB-induced effect can be reversed by chronic AMI treatment in the case of mGlu1a, mGlu2/3 and mGlu7 receptors.
- Published
- 2008
47. The behavioural and electrophysiological effects of CRF in rat frontal cortex.
- Author
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Zieba B, Grzegorzewska M, Brański P, Domin H, Wierońska JM, Hess G, and Smiałowska M
- Subjects
- Animals, Anti-Anxiety Agents pharmacology, Electrophysiology, Frontal Lobe physiology, Male, Maze Learning drug effects, Rats, Rats, Wistar, Receptors, Corticotropin-Releasing Hormone agonists, Receptors, Corticotropin-Releasing Hormone antagonists & inhibitors, Receptors, Corticotropin-Releasing Hormone metabolism, Behavior, Animal drug effects, Corticotropin-Releasing Hormone pharmacology, Frontal Lobe drug effects, Motor Activity drug effects
- Abstract
Corticotropin releasing factor (CRF) is a neuropeptide widely distributed in the brain. The role of CRF in the behavioural activity and modulation of anxiety states in several brain structures has been well documented, but its function in the cerebral cortex still remains unknown. The aim of our study was to investigate the effect of CRF injected bilaterally into rat frontal cortex on the locomotor and exploratory activity and anxiety of rats. We also examined the effect of CRF on extracellularly recorded field potentials in rat frontal cortical slices in vitro. Behavioural experiments showed that CRF in doses of 0.05, 0.1, 0.2 microg/1 microl/site decreased locomotor and exploratory activity during a 40-min session in the open field test. In the elevated plus-maze test, CRF in a dose of 0.2 microg/1 microl/site produced a significant anxiolytic-like effect, which was prevented by CRF receptor antagonists (alpha-helicalCRF(9-41) and NBI 27914). Electrophysiological experiments showed that CRF-induced a transient depression of field potentials in slices partly disinhibited by GABA(A) and GABA(B) receptors antagonists. The blockade of NMDA receptors prevented the occurrence of that effect. The obtained results suggest that CRF may have anxiolytic-like effects in the frontal cortex. Moreover, the peptide inhibits locomotor and exploratory activity and depresses excitatory synaptic transmission in a NMDA receptor-dependent manner.
- Published
- 2008
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48. Antidepressant-like activity of 8-Br-cAMP, a PKA activator, in the forced swim test.
- Author
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Brański P, Palucha A, Szewczyk B, Wierońska JM, Pilc A, and Nowak G
- Subjects
- Animals, Brain enzymology, Brain physiopathology, Cyclic AMP analogs & derivatives, Cyclic AMP pharmacology, Cyclic AMP-Dependent Protein Kinases drug effects, Depressive Disorder enzymology, Depressive Disorder physiopathology, Dose-Response Relationship, Drug, Enzyme Activation drug effects, Enzyme Inhibitors pharmacology, Motor Activity drug effects, Phosphorylation drug effects, Rats, Reaction Time drug effects, Stress, Psychological enzymology, Stress, Psychological physiopathology, Swimming, Thionucleotides pharmacology, 8-Bromo Cyclic Adenosine Monophosphate pharmacology, Antidepressive Agents pharmacology, Brain drug effects, Cyclic AMP-Dependent Protein Kinases metabolism, Depressive Disorder drug therapy, Stress, Psychological drug therapy
- Abstract
The PKA activator, 8-Br-cAMP, dose-dependently reduced the immobility time in the forced swim test in rats. This effect was antagonized by co-treatment with selective PKA inhibitor Rp-cAMPS. This is the first demonstration of the antidepressant-like activity of the PKA activator.
- Published
- 2008
- Full Text
- View/download PDF
49. Citalopram influences mGlu7, but not mGlu4 receptors' expression in the rat brain hippocampus and cortex.
- Author
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Wierońska JM, Kłak K, Pałucha A, Brański P, and Pilc A
- Subjects
- Analysis of Variance, Animals, Antidepressive Agents, Tricyclic pharmacology, Colforsin pharmacology, Cyclic AMP metabolism, Cyclopentanes pharmacology, Dose-Response Relationship, Drug, Imipramine pharmacology, Male, Rats, Tricarboxylic Acids pharmacology, Antidepressive Agents, Second-Generation pharmacology, Cerebral Cortex drug effects, Citalopram pharmacology, Gene Expression Regulation drug effects, Hippocampus drug effects, Receptors, Metabotropic Glutamate metabolism
- Abstract
Earlier studies showed that chronic electroconvulsive shock (ECS) or imipramine treatment induced a sub-sensitivity of group I metabotropic glutamate receptors (mGluRs) in the hippocampus as well as an increase in the receptor protein level in this structure. In the present study, the effects of chronic imipramine (10 mg/kg, 21 days) or citalopram (10 mg/kg, 21 days) treatment on the mGlu4 or mGlu7 receptors' protein levels in the frontal cortex and hippocampus of the rat brain were examined using the Western blot analysis. We also examined the influence of these drugs' administration on forskolin-stimulated cAMP formation. A non-selective agonist of all receptors belonging to the III group of mGluRs, ACPT-1, was used to establish their effects on the cAMP production. It was found that mGluR7-immunoreactivity both in the hippocampus and in the cerebral cortex was decreased after citalopram, but not imipramine treatment. No changes were observed in the mGluR4-immunoreactivity. Prolonged treatment with these two drugs failed to change the action of group III mGluR agonist, ACPT-1, on the forskolin-stimulated cAMP accumulation. Our results suggest that the mGluR7 receptor is influenced by prolonged treatment of the antidepressant drug citalopram in the brain regions that are considered to be implicated in the clinical response to antidepressant therapy whilst the mGlu4 receptor is not.
- Published
- 2007
- Full Text
- View/download PDF
50. Effects of GABAB receptor ligands in rodent tests of anxiety-like behavior.
- Author
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Partyka A, Kłodzińska A, Szewczyk B, Wierońska JM, Chojnacka-Wójcik E, Librowski T, Filipek B, Nowak G, and Pilc A
- Subjects
- Animals, Anxiety drug therapy, Anxiety psychology, Behavior, Animal drug effects, Dose-Response Relationship, Drug, Drinking drug effects, Electroshock, Exploratory Behavior drug effects, GABA-B Receptor Agonists, GABA-B Receptor Antagonists, Ligands, Male, Maze Learning drug effects, Mice, Motor Activity drug effects, Phosphinic Acids antagonists & inhibitors, Phosphinic Acids metabolism, Rats, Rats, Wistar, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid metabolism, Anti-Anxiety Agents pharmacology, Organophosphorus Compounds pharmacology, Phosphinic Acids pharmacology
- Abstract
GABAergic hypothesis of anxiety was introduced many years ago, however, a limited number of supporting data were accumulated so far and the role of GABA(B) receptors in behavioral processes related to the anxiety disorders has not been resolved. In the present study, we examined anxiolytic activity of CGP 36742, a potent and selective GABA(B) receptor antagonist, in rodent tests/models. We have demonstrated that CGP 36742 (30 mg/kg) is active in several animal tests detecting anxiolytic activity (the elevated plus-maze, conflict drinking test and four-plate test). Moreover, we examined the effects of another antagonist--CGP51176 and agonist--CGP 44532 of GABA(B) receptor in the four-plate test in mice. CGP 51176 (5 or 8 mg/kg) was inactive, while CGP 44532 (0.125 mg/kg) exhibited anxiogenic-like effect. These preclinical data further implicate GABA(B) receptor function in anxiety, and support the GABAergic hypothesis of this disorder.
- Published
- 2007
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