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Progress in the understanding of the receptor GPR39 is held up by inconsistent pharmacological data. First, the endogenous ligand(s) remain(s) contentious. Data pointing to zinc ions (Zn 2+ ) and/or eicosanoids as endogenous ligands are a matter of debate. Second, there are uncertainties in the specificity of the widely used synthetic ligand (agonist) TC-G 1008. Third, activation of GPR39 has been often proposed as a novel treatment strategy, but new data also support that inhibition might be beneficial in certain disease contexts. Constitutive activity/promiscuous signaling suggests the need for antagonists/inverse agonists in addition to (biased) agonists. Here, we scrutinize data on the signaling and functions of GPR39 and critically assess factors that might have contributed to divergent outcomes and interpretations of investigations on this important receptor., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The cryptoglandular perianal fistula is a common benign anorectal disorder that is managed mainly with surgery and in some cases may be an extremely challenging condition. Perianal fistulas are often characterized by significantly decreased patient quality of life. Lack of fully recognized pathogenesis of this disease makes it difficult to treat it properly. Recently, adipose tissue hormones have been proposed to play a role in the genesis of cryptoglandular anal fistulas. The expression of adipose tissue hormones and epithelial-to-mesenchymal transition (EMT) factors were characterized based on 30 samples from simple fistulas and 30 samples from complex cryptoglandular perianal fistulas harvested during surgery. Tissue levels of leptin, resistin, MMP2, and MMP9 were significantly elevated in patients who underwent operations due to complex cryptoglandular perianal fistulas compared to patients with simple fistulas. Adiponectin and E-cadherin were significantly lowered in samples from complex perianal fistulas in comparison to simple fistulas. A negative correlation between leptin and E-cadherin levels was observed. Resistin and MMP2 levels, as well as adiponectin and E-cadherin levels, were positively correlated. Complex perianal cryptoglandular fistulas have a reduced level of the anti-inflammatory adipokine adiponectin and have an increase in the levels of proinflammatory resistin and leptin. Abnormal secretion of these adipokines may affect the integrity of the EMT in the fistula tract. E-cadherin, MMP2, and MMP9 expression levels were shifted in patients with more advanced and complex perianal fistulas. Our results supporting the idea of using mesenchymal stem cells in the treatment of cryptoglandular perianal fistulas seem reasonable, but further studies are warranted.

The pharmacological activation of the GPR39 receptor has been proposed as a novel strategy for treating seizures; however, this hypothesis has not been verified experimentally. TC-G 1008 is a small molecule agonist increasingly used to study GPR39 receptor function but has not been validated using gene knockout. Our aim was to assess whether TC-G 1008 produces anti-seizure/anti-epileptogenic effects in vivo and whether the effects are mediated by GPR39. To obtain this goal we utilized various animal models of seizures/epileptogenesis and GPR39 knockout mice model. Generally, TC-G 1008 exacerbated behavioral seizures. Furthermore, it increased the mean duration of local field potential recordings in response to pentylenetetrazole (PTZ) in zebrafish larvae. It facilitated the development of epileptogenesis in the PTZ-induced kindling model of epilepsy in mice. We demonstrated that TC-G 1008 aggravated PTZ-epileptogenesis by selectively acting at GPR39. However, a concomitant analysis of the downstream effects on the cyclic-AMP-response element binding protein in the hippocampus of GPR39 knockout mice suggested that the molecule also acts via other targets. Our data argue against GPR39 activation being a viable therapeutic strategy for treating epilepsy and suggest investigating whether TC-G 1008 is a selective agonist of the GPR39 receptor., (© 2023. The Author(s).)

The G-protein coupled receptor 39 (GPR39) is gaining increasing attention as a target for future drugs, yet there are gaps in the understanding of its pharmacology. Zinc is an endogenous agonist or an allosteric modulator, while TC-G 1008 is a synthetic, small molecule agonist. Zinc is also a positive allosteric modulator for the activity of TC-G 1008 at GPR39. Activation of GPR39 by TC-G 1008 facilitated the development of epileptogenesis in the pentylenetetrazole (PTZ)-induced kindling model of epilepsy. Congruently, TC-G 1008 decreased the seizure threshold in the maximal electroshock seizure threshold (MEST) test. Here, we investigated the effects of TC-G 1008 under the condition of zinc deficiency. Mice were fed a zinc-adequate diet (ZnA, 50 mg Zn/kg) or a zinc-deficient diet (ZnD, 3 mg Zn/kg) for 4 weeks. Following 4 weeks of dietary zinc restriction, TC-G 1008 was administered as a single dose and the MEST test was performed. Additional groups of mice began the PTZ-kindling model during which TC-G 1008 was administered repeatedly and the diet was continued. TC-G 1008 administered acutely decreased the seizure threshold in the MEST test in mice fed the ZnD diet but not in mice fed the ZnA diet. TC-G 1008 administered chronically increased the maximal seizure severity and the percentage of fully kindled mice in those fed the ZnA diet, but not in mice fed the ZnD diet. Our data showed that the amount of zinc in a diet is a factor contributing to the effects of TC-G 1008 in vivo.

Several ligands have been proposed for the GPR39 receptor, including the element zinc. The relationship between GPR39 and magnesium homeostasis has not yet been examined, nor has such a relationship in the context of seizures/epilepsy. We used samples from mice that were treated with an agonist of the GPR39 receptor (TC-G 1008) and underwent acute seizures (maximal electroshock (MES)- or 6-hertz-induced seizures) or a chronic, pentylenetetrazole (PTZ)-induced kindling model of epilepsy. MES seizures and PTZ kindling, unlike 6 Hz seizures, increased serum magnesium concentration. In turn, Gpr39 -KO mice that underwent PTZ kindling displayed decreased concentrations of this element in serum, compared to WT mice subjected to this procedure. However, the levels of expression of TRPM7 and SlC41A1 proteins-which are responsible for magnesium transport into and out of cells, respectively-did not differ in the hippocampus between Gpr39 -KO and WT mice. Furthermore, laser ablation inductively coupled plasma mass spectrometry applied to hippocampal slices did not reveal differences in magnesium levels between the groups. These data show the relationship between magnesium homeostasis and certain types of acute or chronic seizures (MES seizures or PTZ kindling, respectively), but do not explicitly support the role of GPR39 in mediating magnesium balance in the hippocampus in the latter model. However, decreased expression of TRPM7 and increased expression of SLC41A1-which were observed in the hippocampi of Gpr39 -KO mice treated with TC-G 1008, in comparison to WT mice that received the same treatment-implicitly support the link between GPR39 and hippocampal magnesium homeostasis.

Emerging evidence indicates that the gut microbiota play a crucial role in the bidirectional communication between the gut and the brain suggesting that the gut microbes may shape neural development, modulate neurotransmission and affect behavior, and thereby contribute to the pathogenesis and/or progression of many neurodevelopmental, neuropsychiatric, and neurological conditions. This review summarizes recent data on the role of microbiota-gut-brain axis in the pathophysiology of neuropsychiatric and neurological disorders including depression, anxiety, schizophrenia, autism spectrum disorders, Parkinson's disease, migraine, and epilepsy. Also, the involvement of microbiota in gut disorders co-existing with neuropsychiatric conditions is highlighted. We discuss data from both in vivo preclinical experiments and clinical reports including: (1) studies in germ-free animals, (2) studies exploring the gut microbiota composition in animal models of diseases or in humans, (3) studies evaluating the effects of probiotic, prebiotic or antibiotic treatment as well as (4) the effects of fecal microbiota transplantation., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Several studies with larvae and adult zebrafish have shown that old and new antiseizure drugs (ASDs) produce discrepant results in seizure tests, locomotor activity or anxiety models. In this study, the pentylenetetrazole seizure test (PTZ) was performed to assess the effectiveness of four new ASDs: lamotrigine (LTG), topiramate (TPM), felbamate (FBM), and levetiracetam (LEV) in the subsequent stages of seizures in adult fish. All ASDs were administered intraperitoneally (i.p.). The time of maximal anticonvulsant effect and the dose-response relationship of the drugs were assessed. The effects of studied ASDs on the locomotor activity and the anxiety-like behavior in the color preference test were also investigated. Furthermore, drug concentrations in zebrafish homogenates were determined. LTG, TPM, and LEV significantly increased the seizure latency at three subsequent stages of seizures (SI-SIII), while FBM was effective only at SI. Locomotor activity decreased after TPM treatment. TPM and FBM exhibited a strong anxiolytic-like effect in the color preference test. LEV at the highest dose tested had a weak anxiolytic-like effect. The HPLC analysis showed average concentrations of the studied ASDs in the fish body during their maximum anticonvulsant activity. The present study shows that FBM cannot inhibit all subsequent PTZ seizure stages in the adult fish. Except for LTG, the studied drugs affected the anxiety-like behavior of treated animals. Furthermore, only TPM significantly changed locomotion parameters. Our findings support the need to accurately characterize the efficacy of new ASDs at different stages of the PTZ-induced seizures in adult zebrafish., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

At present most of the evidence for the relevance of oligomerization for the pharmacology of depression comes from in vitro studies which identified oligomers, and from neuropsychopharmacological studies of receptors which participate in oligomerization. For example, behavioural and biochemical studies in knockout animals suggest that GPR39 may mediate the antidepressant action of monoaminergic antidepressants. We have recently found long-lasting antidepressant-like effects of GPR39 agonist, thus suggesting GPR39 as a target for the development of novel antidepressant drugs. In vitro studies have shown that GPR39 oligomerizes with other GPCRs. Oligomerization of GPR39 should thus be considered in relation to the development of new antidepressants targeting this receptor as well as antidepressants targeting other receptors that may form complexes with GPR39. Here, we summarize recent data suggestive of the importance of oligomerization for the pharmacology of depression and discuss approaches for validation of this phenomenon., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purinergic signaling involves the actions of purine nucleotides and nucleosides (such as adenosine) at P1 (adenosine), P2X, and P2Y receptors. Here, we present recent data contributing to a comprehensive overview of the association between purinergic signaling and depression. We start with background information on adenosine production and metabolism, followed by a detailed characterization of P1 and P2 receptors, with an emphasis on their expression and function in the brain as well as on their ligands. We provide data suggestive of altered metabolism of adenosine in depressed patients, which might be regarded as a disease biomarker. We then turn to considerable amount of preclinical/behavioral data obtained with the aid of the forced swim test, tail suspension test, learned helplessness model, or unpredictable chronic mild stress model and genetic activation/inactivation of P1 or P2 receptors as well as nonselective or selective ligands of P1 or P2 receptors. We also aimed to discuss the reason underlying discrepancies observed in such studies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The zebrafish is extensively used as a model organism for studying several disorders of the central nervous system (CNS), including epilepsy. Some antiseizure drugs (ASDs) have been shown to produce discrepant results in larvae and adults zebrafish, therefore, their anticonvulsant efficacy in subsequent stages of the pentylenetetrazole (PTZ)-induced seizures should be more precisely characterized. The purpose of this study was to investigate behavioral effects of five classic ASDs: valproate (VPA), phenytoin (PHT), carbamazepine (CBZ), diazepam (DZP), and phenobarbital (PB) administered intraperitoneally (i.p.) in the PTZ-induced seizure test in adult zebrafish. We determined the time of maximal effect and the dose-response relationship of the studied ASDs. Furthermore, we assessed changes in the locomotor activity and the anxiety-like behavior in the color preference test. Moreover, drug concentrations in zebrafish homogenates were examined. VPA, DZP, and PB significantly increased the seizure latency at three subsequent stages of seizures (SI-SIII). PHT produced the anticonvulsant-like effect at SI and SII, while CBZ was effective at SII and SIII. Only DZP decreased zebrafish locomotor activity. A strong anxiolytic-like effect was observed after administration of PHT and PB. A weak anxiolytic-like effect occurred after treatment with VPA and DZP. The HPLC analysis showed the average concentrations of the studied ASDs in the fish body during the maximum anticonvulsant activity of each drug. Our results confirm the advantages of using zebrafish with the mature CNS over larval models and its utility to investigate some neuropharmacological properties of the tested drugs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Though there are several classes of antidepressant drugs available on the pharmaceutical market, depression that affects globally over 320 million people is still undertreated. Scientists have made attempts to develop novel therapeutical strategies to maximize effectiveness of therapy and minimize undesired reactions. One of the ideas is use of either dual-action agents or combined administration of two substances that affect diverse neurotransmissions. Thus, we investigated whether the selected CB receptor ligands (oleamide, AM251, JWH133, and AM630) can have an impact on the activity of bupropion and moclobemide. Bupropion belongs to the dual acting drugs, whereas moclobemide is an inhibitor of monoamine oxidase., Methods: The mice forced swim test and the tail suspension test were applied in order to determine the potential antidepressant-like activity, whereas the HPLC method was used in order to assess the brain concentrations of the tested antidepressants., Results: An intraperitoneal injection of sub-effective doses of oleamide (5 mg/kg), AM251 (0.25 mg/kg), and AM630 (0.25 mg/kg) increased activity of bupropion (10 mg/kg) in both behavioural tests. Effects of moclobemide (1.5 mg/kg) were potentiated only by AM251. These results were not influenced by the hypo- or hyperlocomotion of animals., Conclusion: The outcomes of the present study revealed that particularly activation or inhibition of the CB 1 receptor function may augment the antidepressant activity of bupropion, whereas only inhibition of the CB 1 receptor function manages to increase activity of moclobemide. Most probably, an interplay between CB receptor ligands and bupropion or moclobemide takes place at the cellular level.

Several lines of evidence support a link between the essential element zinc and the coronavirus disease 2019 (COVID-19). An important fact is that zinc is present in proteins of humans and of viruses. Some zinc sites in viral enzymes may serve as drug targets and may liberate zinc ions, thus leading to changes in intracellular concentration of zinc ions, while increased intracellular zinc may induce biological effects in both the host and the virus. Drugs such as chloroquine may contribute to increased intracellular zinc. Moreover, clinical trials on the use of zinc alone or in addition to other drugs in the prophylaxis/treatment of COVID-19 are ongoing. Thereby, we aim to discuss the rationale for targeting zinc metalloenzymes as a new strategy for the treatment of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc., (© 2020 The British Pharmacological Society.)

The κ-opioid receptor has recently gained attention as a new molecular target in the treatment of many psychiatric and neurological disorders including epilepsy. Salvinorin A is a potent plant-derived hallucinogen that acts as a highly selective κ-opioid receptor agonist. It has unique structure and pharmacological properties, but its influence on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of salvinorin A on seizure thresholds in three acute seizure tests in mice. We also examined its effect on muscular strength and motor coordination. The obtained results showed that salvinorin A (0.1-10 mg/kg, i.p.) did not significantly affect the thresholds for the first myoclonic twitch, generalized clonic seizure, or forelimb tonus in the intravenous pentylenetetrazole seizure threshold test in mice. Likewise, it failed to affect the thresholds for tonic hindlimb extension and psychomotor seizures in the maximal electroshock- and 6 Hz-induced seizure threshold tests, respectively. Moreover, no changes in motor coordination (assessed in the chimney test) or muscular strength (assessed in the grip-strength test) were observed. This is a preliminary report only, and further studies are warranted to better characterize the effects of salvinorin A on seizure and epilepsy.

Although a lot of information can be found on the specific dual role of the endocannabinoid system in the emotional-related responses, little is known whether stimulation or inhibition of the cannabinoid (CB) receptors may affect the activity of the frequently prescribed antidepressant drugs. Our interests have been particularly focused on the potential influence of the CB 2 receptors, as the ones whose central effects are relatively poorly documented when compared to the central effects of the CB 1 receptors. Therefore, we evaluated the potential interaction between the CB 2 receptor ligands (i.e., JWH133 - CB 2 receptor agonist and AM630 - CB 2 receptor inverse agonist) and several common antidepressant drugs that influence the monoaminergic system (i.e., imipramine, escitalopram, reboxetine). In order to assess the antidepressant-like effects we used two widely recognized behavioural tests, the mouse forced swim test (FST) and the tail suspension test (TST). Brain concentrations of the tested antidepressants were evaluated by the HPLC method. Intraperitoneal co-administration of per se ineffective doses of JWH133 (0.25 mg/kg) or AM630 (0.25 mg/kg) with imipramine (15 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg) significantly shortened the immobility time of mice in the FST and the TST, whereas it did not disturb their spontaneous locomotor activity. Furthermore, the brain levels of antidepressants were not changed. Summarizing, the results of the present study revealed that both activation and inhibition of the CB 2 receptor function have a potential to strengthen the antidepressant activity of drugs targeting the monoaminergic system. Most probably, the described interaction has a pharmacodynamic background., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Available data support the notion that cannabinoids, whose therapeutic value is limited due to severe adverse reactions, could be beneficial as adjunctive agents in the management of mood disorders. Polytherapy, which is superior to monotherapy in the terms of effectiveness, usually requires lower doses of the individual components. Therefore, the main objective of our study was to determine whether administration of cannabinoid (CB) receptor ligands would enhance the antidepressant activity of atypical antidepressant drugs, i.e. agomelatine and tianeptine. To evaluate the antidepressant-like potential of the tested combinations, the mouse forced swim test (FST) and the tail suspension test (TST) were used. The HPLC method was applied to assess the brain levels of agomelatine and tianeptine. Both behavioural tests demonstrated that per se an ineffective intraperitoneal dose of oleamide (CB 1 receptor agonist, 5 mg/kg) potentiated the anti-immobility activity of tianeptine (15 mg/kg), whereas AM251 (CB 1 receptor inverse agonist/antagonist, 0.25 mg/kg) enhanced the antidepressant effects of tianeptine and agomelatine (20 mg/kg). Intraperitoneal co-administration of per se inactive doses of AM630 (CB 2 receptor inverse agonist/antagonist) and agomelatine or tianeptine significantly reduced the immobility time of animals only in the FST. CB receptor ligands did not affect the brain levels of the tested atypical antidepressants. In summary, the outcomes of the present study showed that activation and inhibition of CB 1 receptors as well as inhibition of CB 2 receptors may increase the antidepressant activity of tianeptine, whereas only inhibition of CB 1 and CB 2 receptors has a potential to augment the antidepressant activity of agomelatine., (Copyright © 2019. Published by Elsevier Inc.)

Background: Adenosine, an endogenous nucleoside, modulates the release of monoamines, e.g., noradrenaline, serotonin, and dopamine in the brain. Both nonselective and selective stimulation of adenosine receptors produce symptoms of depression in some animal models. Therefore, the main objective of our study was to assess the influence of a selective adenosine A 1 receptor antagonist (DPCPX) and a selective adenosine A 2A receptor antagonist (DMPX) on the activity of agomelatine and tianeptine., Methods: The forced swim test (FST) and tail suspension test (TST) were performed to assess the effects of DPCPX and DMPX on the antidepressant-like activity of agomelatine and tianeptine. Drug serum and brain levels were analyzed using HPLC., Results: Co-administration of agomelatine (20 mg/kg) or tianeptine (15 mg/kg) with DMPX (3 mg/kg), but not with DPCPX (1 mg/kg), significantly reduced the immobility time both in the FST and TST in mice. These effects were not associated with an enhancement in animals' spontaneous locomotor activity. The observed changes in the mouse behavior after concomitant injection of DMPX and the tested antidepressant agents were associated with elevated brain concentration of agomelatine and tianeptine., Conclusion: Our study shows a synergistic action of the selective A 2A receptor antagonist and the studied antidepressant drugs, and a lack of such interaction in the case of the selective A 1 receptor antagonist. The interaction between DMPX and agomelatine/tianeptine at least partly occurs in the pharmacokinetic phase. A combination of a selective A 2A receptor antagonist and an antidepressant may be a new strategy for treating depression., (Copyright © 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Antidepressants that target the monoaminergic system are prescribed most frequently in the psychiatric practice. However, not all patients benefit from their use. It is generally known that co-administration of agents aiming distinct targets may increase the therapeutic effect and at the same time permit dose reduction. A number of studies have suggested a CB 1 receptor-mediated interplay between the endocannabinoid system and the monoaminergic signalling in the brain. Therefore, we wanted to determine whether the CB 1 receptor ligands (oleamide and AM251) affect the activity of the common antidepressant drugs that influence the monoaminergic system. In order to determine the antidepressant-like activity, the forced swim test and the tail suspension test in mice were used. Additionally, brain concentrations of the tested antidepressants were evaluated by the HPLC method. Concurrent intraperitoneal administration of per se inactive doses of oleamide (5 mg/kg) or AM251 (0.25 mg/kg) and imipramine (15 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg) reduced the immobility time of animals in the forced swim test and the tail suspension test. The observed effect was not associated with hyperlocomotion of animals. Summarizing, the outcomes of the present study demonstrated that modulation (i.e., activation or inhibition) of the CB 1 receptor function potentiates the antidepressant activity of common drugs that influence the monoaminergic (serotonergic and noradrenergic) system. This effect is most probably predominantly pharmacodynamic in nature instead of pharmacokinetic., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The aims of the study were to determine the effectiveness of blebbistatin (BLEB) on detrusor overactivity (DO) in an animal model induced by retinyl acetate (RA) and, because of potential urothelial permeability, to evaluate the degenerative impact of BLEB on the urothelium. Three days after RA instillation into the urinary bladder, BLEB was administered into the bladder and immediately after cystometric assessment was performed. Furthermore, Evans Blue extravasation into bladder tissue and urothelium thickness were measured. Sixty female Wistar rats were used and randomly assigned to one of four groups (n = 15 in each group): (1) control, (2) RA, (3) BLEB, and (4) RA + BLEB. RA administration induced changes in cystometric parameters reflecting DO, as previously reported. Treatment with BLEB did not significantly alter cystometric parameters in rats which did not receive RA. Administration of BLEB to rats pretreated with RA reversed changes in cystometric parameters induced by RA in basal pressure, threshold pressure, detrusor overactivity index, amplitude of nonvoiding contractions, frequency of nonvoiding contractions, voided volume, volume threshold, intercontraction interval, bladder compliance, and volume threshold to elicit nonvoiding contractions. There were no significant differences in Evans Blue extravasation into bladder tissue or urothelium thickness between the groups. The current research provides new data on the possible utility of blebbistatin in the pharmacotherapy of DO, which is an important feature of overactive bladder (OAB). Further studies in human patients with DO/OAB are warranted to confirm these preclinical results.

Unsatisfactory therapeutic effects of currently used antidepressants force to search for new pharmacological treatment strategies. Recent research points to the relationship between depressive disorders and the adenosinergic system. Therefore, the main goal of our studies was to evaluate the effects of DMPX (3 mg/kg, i.p.), which possesses selectivity for adenosine A 2A receptors versus A 1 receptors, on the activity of imipramine (15 mg/kg, i.p.), escitalopram (2.5 mg/kg, i.p.), and reboxetine (2 mg/kg, i.p.) given in subtherapeutic doses. The studies carried out using the forced swim and tail suspension tests in mice showed that DMPX at a dose of 6 and 12 mg/kg exerts antidepressant-like effect and does not affect the locomotor activity. Co-administration of DMPX at a dose of 3 mg/kg with the studied antidepressant drugs caused the reduction of immobility time in both behavioral tests. The observed effect was not associated with an increase in the locomotor activity. To evaluate whether the observed effects were due to a pharmacokinetic/pharmacodynamic interaction, the levels of the antidepressants in blood and brain were measured using high-performance liquid chromatography. It can be assumed that the interaction between DMPX and imipramine was exclusively pharmacodynamic in nature, whereas an increased antidepressant activity of escitalopram and reboxetine was at least partly related to its pharmacokinetic interaction with DMPX.

Recently, compound KA-11 was identified as a promising candidate for a new broad-spectrum anticonvulsant. This compound revealed wide protective activity across the most important animal models of seizures such as the maximal electroshock test (MES), the subcutaneous pentylenetetrazole test ( scPTZ), and the six-hertz test (6 Hz, 32 mA). Importantly, KA-11 was devoid of acute neurological activity, which was assessed by applying the chimney test (TD 50 value higher than 1500 mg/kg). The preliminary in vivo results confirmed favorable anticonvulsant and safety properties of KA-11. With the aim of further biological characterization of KA-11, in the current studies we evaluated its antiepileptogenic activity in the kindling model of epilepsy induced by repeated injection of PTZ in mice. Furthermore, we assessed the antinociceptive activity of KA-11 in several animal pain models. As a result, KA-11 (at all doses applied: 25, 50, and 100 mg/kg) significantly delayed the progression of kindling induced by repeated injection of PTZ in mice. Additionally, KA-11 revealed potent antinociceptive activity in the formalin-induced tonic pain and, importantly, in the oxaliplatin-induced neuropathic pain model in mice. Moreover, KA-11 did not induce motor deficits in the rotarod test. Patch-clamp experiments revealed that one of the mechanisms of action of KA-11 is inhibition of voltage-gated sodium currents. Compound KA-11 appeared to be safe in relation to hepatotoxic properties as no phospholipidosis induction was determined in HepG2 cells at 50 μM, and a small, statistically significant decrease of cell viability was observed only at the highest used dose of 100 μM. Moreover, KA-11 did not affect the function of CYP2D6. The aforementioned hybrid substance proved to penetrate the biological membranes in the in vitro permeability assays.

Evidence from both preclinical and clinical studies suggest the importance of zinc homeostasis in seizures/epilepsy. Undoubtedly, zinc, via modulation of a variety of targets, is necessary for maintaining the balance between neuronal excitation and inhibition, while an imbalance between excitation and inhibition underlies seizures. However, the relationship between zinc signaling and seizures/epilepsy is complex as both extracellular and intracellular zinc may produce either protective or detrimental effects. This review provides an overview of preclinical/behavioral, functional and molecular studies, as well as clinical data on the involvement of zinc in the pathophysiology and treatment of seizures/epilepsy. Furthermore, the potential of targeting elements associated with zinc signaling or homeostasis and zinc levels as a therapeutic strategy for epilepsy is discussed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Overactive bladder (OAB) coexists with depression in women. Here, we assessed the effects of a 1-week treatment with blebbistatin, a myosin II inhibitor, on changes in behavior and detrusor overactivity (DO) symptoms induced by a 6-week administration of 13-cis-retinoic acid (13-cis-RA), with the aid of the forced swim test (FST), spontaneous locomotor activity test, and in vivo cystometric investigations in female Wistar rats. 13-cis-RA-induced depressive-like behavior and DO symptoms were associated with increased corticotropin-releasing factor (CRF) level in the plasma, prefrontal cortex (PFC), hippocampus (Hp), Barrington's nucleus (BN), and urinary bladder. Moreover, 13-cis-RA decreased brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in plasma, PFC, Hp, and BN, while it increased BDNF and NGF levels in urinary bladder. Blebbistatin exerted antidepressant-like effect and attenuated changes in the cystometric parameters as well as the central and peripheral levels of CRF, BDNF, and NGF that were induced by 13-cis-RA, while it did not affect urine production, mean, systolic or diastolic blood pressure, or heart rate. The results point to blebbistatin as a potential treatment option for OAB coexisting with depression.

The main goal of the present study was to evaluate the influence of the adenosine A1 receptor (A1R) antagonist - DPCPX - on depressive-like behavior in mice, as well as the effect of DPCPX on the activity of imipramine, escitalopram, and reboxetine, each at non-effective doses. The influence of DPCPX on behavior and its influence on the activity of selected antidepressants was evaluated in the forced swim test (FST) and the tail suspension test (TST) in mice. Locomotor activity was measured to verify and exclude false-positive data obtained in the FST and TST. Moreover, serum and brain concentrations of tested antidepressants were determined using HPLC. DPCPX, at doses of 2 and 4 mg/kg, exhibited antidepressant activity in the FST and TST, which was not related to changes in the spontaneous locomotor activity. Co-administration of DPCPX with imipramine, escitalopram, or reboxetine, each at non-active doses, significantly reduced the immobilization period in the FST and TST in mice, which was not due to the increase in locomotor activity. Both antagonists of 5-HT receptors (WAY 100635 and ritanserin) completely antagonized the effect elicited by DPCPX in the behavioral tests. Results of assessment of the nature of the interaction between DPCPX and test drugs show that in the case of DPCPX and imipramine or reboxetine, there were pharmacodynamic interactions, whereas the DPCPX-escitalopram interaction is at least partially pharmacokinetic in nature. Presented outcomes indicate that an inhibition of A1Rs and an increase of monoaminergic transduction in the CNS may offer a novel strategy for the development of antidepressant drugs.

Tadalafil, a selective phosphodiesterase type 5 inhibitor, is a long-acting oral agent for the treatment of erectile dysfunction of multiple etiologies. Although generalized tonic-clonic seizures were reported in a healthy man after taking tadalafil, the influence of tadalafil on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of tadalafil on seizure threshold as well as on the activity of some first- and second-generation antiepileptic drugs in three acute seizure tests in mice. The obtained results showed that tadalafil, at the highest dose tested (20 mg/kg), significantly decreased the threshold for the first myoclonic twitch in the intravenous pentylenetetrazole (i.v. PTZ) seizure test. It did not affect the threshold for generalized clonic seizure and forelimb tonus in the i.v. PTZ, for tonic hindlimb extension in the maximal electroshock seizure threshold test, and for psychomotor seizure in the 6-Hz-induced seizure threshold test. Tadalafil did not alter the anticonvulsant activity of any of the studied antiepileptic drugs in electrically induced seizure tests. Interestingly, tadalafil potentiated the anticonvulsant activity of clonazepam and decreased the anticonvulsant activity of oxcarbazepine in the i.v. PTZ test. These interactions were pharmacodynamic in nature, as tadalafil did not alter clonazepam and oxcarbazepine concentrations both in serum and brain tissue. Furthermore, neither tadalafil alone nor its combinations with the studied antiepileptic drugs produced any significant impairment of motor coordination (assessed in the chimney test), muscular strength (investigated in the grip-strength test), and long-term memory (assessed in the passive avoidance task). In conclusion, tadalafil may increase the risk of myoclonic seizure and decrease the anticonvulsant efficacy of oxcarbazepine. Further studies are warranted to evaluate the safety of tadalafil usage in patients with epilepsy.

Objective: The main goal of our study was to investigate whether a selective antagonism of the adenosine A 1 or A 2A receptors is able to enhance the antidepressant activity of commonly prescribed drugs., Materials and Methods: All experiments were carried out on male Albino Swiss mice. The forced swim test and the tail suspension test were used to evaluate the antidepressant-like potential. Drug concentrations in animals' serum and brains were measured by high-performance liquid chromatography., Key Findings: The antidepressant potential of moclobemide (1.5 mg/kg), venlafaxine (1 mg/kg) and bupropion (10 mg/kg) was enhanced by a co-administration with 3,7-dimethyl-1-propargylxanthine (DMPX; an antagonist of adenosine A 2A receptors; 3 mg/kg) or 8-cyclopentyl-1,3-dipropylxanthine (an antagonist of adenosine A 1 receptors; 1 mg/kg). However, significant interactions between the tested substances were detected only in the experiments with DMPX. The nature of the observed interplays is rather pharmacodynamic than pharmacokinetic, because neither serum nor brain concentrations of the used drugs were significantly increased., Conclusions: Blockage of the adenosine receptors (particularly the A 2A subtypes) could be considered in future as a novel, promising part of the combined antidepressant therapy. However, further studies on this subject are needed., (© 2018 Royal Pharmaceutical Society.)

Rationale: Depressed patients often present increased consumption of caffeine., Objectives: We aimed to investigate the effects of chronic treatment with caffeine (5 mg/kg, twice daily for 14 days) on the activity of single, ineffective doses of agomelatine (20 mg/kg) or mianserin (10 mg/kg) given on day 15 alone or simultaneously with caffeine., Methods: We used the forced swim test (FST), tail suspension test (TST), and locomotor activity test in mice and quantitative real-time PCR analysis of the selected genes in the cerebral cortex (Cx)., Results: There were no changes in the immobility time between mice that received saline and caffeine for 14 days. Administration of agomelatine or mianserin on day 15 did not produce an antidepressant-like effect, but such effect was observed after administration of agomelatine or mianserin simultaneously with caffeine on day 15, in both mice that received saline and caffeine for 14 days. In mice treated with caffeine for 14 days, joint administration of agomelatine or mianserin and caffeine on day 15 decreased solute carrier family 6, member 15 (Slc6a15), messenger RNA (mRNA) level in the Cx, compared to the group which received only the respective antidepressant on this day. Moreover, in mice treated with caffeine for 14 days, joint administration of mianserin and caffeine on day 15 decreased adenosine A1 receptor (Adora1) and catechol-O-methyltransferase (Comt) mRNA level in the Cx, compared to the group which received mianserin without caffeine on this day., Conclusions: Withdrawal of caffeine after its chronic intake can modify the activity of antidepressants. Adora1, Slc6a15, and Comt may be involved in the antidepressant-like effect observed after joint administration of caffeine and mianserin or agomelatine, following chronic treatment with caffeine.

It has been reported that the use of certain stimuli can lead to anxiety-like behavior in zebrafish. Moreover, visual stimulation of zebrafish is becoming a popular tool. Here we evaluated the effects of six colors combinations and alprazolam, a benzodiazepine which is widely used in the treatment of anxiety disorders, on the behavior of adult zebrafish in a two-chambered apparatus, which chambers were illuminated by red/yellow, green/blue, red/green, green/yellow, red/blue and blue/yellow light. The following parameters were measured: time spent in the zone, number of entries to the zone, time of freezing, distance traveled and average speed in the zone. We report that the adult zebrafish spent more time in the red zone compared to yellow or green as well as in the yellow or blue compared to green. The zebrafish displayed a concomitant increase in time freezing in the red zone compared to yellow or green as well as in the yellow or blue compared to green. Moreover, average speed was decreased in the red zone compared to yellow or green and in the yellow zone compared to green. Treatment with alprazolam significantly affected the behavior of the zebrafish, e.g., following alprazolam administration time spent in the zone and time freezing were longer in the green zone than in red. Based on these observations, we suggest that light color combinations could be effective to manipulate zebrafish behavior and could be useful in neuropsychopharmacological studies, perhaps to study anxiety-like behavior and the effects of anxiolytic agents., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Recent preclinical and clinical data suggest that low dose of caffeine enhances the effects of common antidepressants. Here we investigated the effects of chronic administration of caffeine (5mg/kg, twice daily for 14days) and its withdrawal on day 15th on the activity of per se ineffective doses of fluoxetine (5mg/kg) and escitalopram (2mg/kg) given on day 15th. We found decreased immobility time in the forced swim and tail suspension tests in mice in which caffeine was administered simultaneously with antidepressants on day 15th following a 14-day caffeine treatment and no alterations in the spontaneous locomotor activity. A decrease in the level of escitalopram and an increase in the level of caffeine in serum were observed after concomitant administration of these compounds, while the joint administration of caffeine and fluoxetine was not associated with changes in their levels in serum or brain. Caffeine withdrawal caused a decrease in Adora1 mRNA level in the cerebral cortex (Cx). Administration of escitalopram or fluoxetine followed by caffeine withdrawal caused an increase in this gene expression, whereas administration of escitalopram, but not fluoxetine, on day 15th together with caffeine caused a decrease in Adora1 mRNA level in the Cx. Furthermore, antidepressant-like activity observed after joint administration of the tested drugs with caffeine was associated with decreased Slc6a15 mRNA level in the Cx. The results show that withdrawal of caffeine after its chronic intake may change activity of antidepressants with concomitant alterations within monoamine, adenosine and glutamate systems., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Overactive bladder (OAB) often co-exists with depression in women. The corticotropin-releasing factor (CRF) system participates in the pathophysiology of both disorders. Therefore, we tested the effects of acute treatment with a reversible CRF receptor type-1 (CRF 1 ) antagonist, SN003 (1mg/kg, i.v.), representatives of first (solifenacin, 0.03mg/kg, i.v.) and second (mirabegron, 1mg/kg, i.v.) line treatments for OAB as well as an antidepressant imipramine (30mg/kg, i.p.) on changes in depressive-like behavior and detrusor overactivity (DO) symptoms induced by a 6-week administration of 13-cis-retinoic acid (13-cis-RA, 1mg/kg/day, i.p.) in female Wistar rats, using in vivo cystometric investigations, forced swim test (FST) and spontaneous locomotor activity test. Following cystometric and behavioral studies, tissue was harvested and CRF level was assessed in the hypothalamus, amygdala and plasma. 13-cis-RA-induced depressive-like behavior and DO symptoms were associated with increased CRF levels in the hypothalamus, amygdala and plasma. Solifenacin and mirabegron attenuated DO symptoms induced by 13-cis-RA, did not display antidepressant-like activity and did not influence CRF levels in brain tissues or plasma. Imipramine and SN003 displayed antidepressant-like activity and lowered increased levels of CRF in brain tissues and plasma. Imipramine attenuated changes in some of the cystometric parameters, which are associated with OAB dry (without urge incontinence), whereas SN003 attenuated changes in almost all cystometric parameters that were induced by 13-cis-RA. CRF 1 antagonist may be beneficial in case of OAB wet (with urge incontinence) or dry co-existing with depression. The possible mechanism may be related to the effects on central/peripheral CRF system., (Copyright © 2017. Published by Elsevier B.V.)

Hemorrhagic cystitis often develops in patients treated with cyclophosphamide (CYP). Studies have indicated that Rho kinase (ROCK) inhibitors may suppress detrusor overactivity symptoms and possess anti-inflammatory properties. The aim of the present study was to investigate whether inhibition of ROCK reduces cystometric and histopathological changes associated with CYP-induced cystitis. The rats received GSK 269962, a ROCK inhibitor, at a dose of 30 mg/kg daily, or vehicle for 7 days. Then, acute chemical cystitis leading to bladder overactivity was induced by CYP injection (200 mg/kg i.p.). Following CYP injection, cystometric studies with physiological saline were performed. Moreover, bladder edema (by the Evans Blue dye leakage technique) and urothelium thickness were measured. CYP injection resulted in a significant increase in cystometric parameters: basal pressure, threshold pressure, bladder contraction duration, relaxation time, detrusor overactivity index, non-voiding contractions amplitude, and non-voiding contractions frequency as well as increased Evans Blue extravasation into bladder tissue, whereas micturition voiding pressure, voided volume, post-void residual, volume threshold, intercontraction interval, bladder compliance, and volume threshold to elicit non-voiding contractions as well as urothelium thickness were significantly decreased in CYP-injected rats. Administration of GSK 269962 normalized the abovementioned CYP injection-induced changes. Inhibition of ROCK was found to ameliorate CYP-induced detrusor overactivity and bladder inflammation. Our data indicate uroprotective effects following ROCK inhibition, which further suggests that this strategy may become an interesting pharmacological tool to prevent urinary adverse effects in patients treated with chemotherapy using CYP.

Preclinical and clinical studies have demonstrated that zinc possesses antidepressant properties and that it may augment the therapy with conventional, that is, monoamine-based, antidepressants. In this review we aim to discuss the role of zinc in the pathophysiology and treatment of depression with regard to the monoamine hypothesis of the disease. Particular attention will be paid to the recently described zinc-sensing GPR39 receptor as well as aspects of zinc deficiency. Furthermore, an attempt will be made to give a possible explanation of the mechanisms by which zinc interacts with the monoamine system in the context of depression and neural plasticity., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this article.

Our previous study showed that dietary zinc restriction induces depression-like behavior with concomitant up-regulation of the N-methyl-D-aspartate receptor (NMDAR). Because metal ions, oxidative stress, and inflammation are involved in depression/NMDAR function, in the present study, bio-elements (zinc, copper, iron, magnesium, and calcium), oxidative (thiobarbituric acid-reactive substances; protein carbonyl content), and inflammatory (IL-1α, IL-1β) factors were measured in serum, hippocampus (Hp), and prefrontal cortex (PFC) of male Sprague-Dawley rats subjected to a zinc-adequate (ZnA) (50 mg Zn/kg) or a zinc-deficient (ZnD) (3 mg Zn/kg) diet for 4 or 6 weeks. Both periods of dietary zinc restriction reduced serum zinc and increased serum iron levels. At 4 weeks, lowered zinc level in the PFC and Hp as well as lowered iron level in the PFC of the ZnD rats was observed. At 6 weeks, however, iron level was increased in the PFC of these rats. Although at 6 weeks zinc level in the PFC did not differ between the ZnA and ZnD rats, extracellular zinc concentration after 100 mM KCl stimulation was reduced in the PFC of the ZnD rats and was accompanied by increased extracellular iron and glutamate levels (as measured by the in vivo microdialysis). The examined oxidative and inflammatory parameters were generally enhanced in the tissue of the ZnD animals. The obtained data suggest dynamic redistribution of bio-elements and enhancement of oxidative/inflammatory parameters after dietary zinc restriction, which may have a link with depression-like behavior/NMDAR function/neurodegeneration.

In this paper we continue to discuss the involvement of essential elements in depression and anxiety, and the possible mechanisms that link elements to the neurobiology underlying depression/anxiety. The present paper is focused on copper, selenium, manganese, iodine and vanadium. Different aspects of relationship between elements and depression or anxiety are reviewed, e.g. the association of the amount of an element in a diet or the serum level of an element and depressive or anxiety-like symptoms. Moreover, the relation of selected elements to the pathophysiology of depression or anxiety is discussed in the context of enzymes which require these elements as co-factors and are involved in the underlying pathophysiology of these disorders., (Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Rationale: Data indicated that zinc deficiency may contribute to the development of depression; however changes induced by zinc deficiency are not fully described., Objectives: In the present paper we tested whether the dietary zinc restriction in rats causes alterations in N-methyl-D-aspartate receptor (NMDAR) subunits in brain regions that are relevant to depression., Methods: Male Sprague Dawley rats were fed a zinc adequate diet (ZnA, 50 mg Zn/kg) or a zinc deficient diet (ZnD, 3 mg Zn/kg) for 4 or 6weeks. Then, the behavior of the rats was examined in the forced swim test, sucrose intake test and social interaction test. Western blot assays were used to study the alterations in NMDAR subunits GluN2A and GluN2B and proteins associated with NMDAR signaling in the hippocampus (Hp) and prefrontal cortex (PFC)., Results: Following 4 or 6 weeks of zinc restriction, behavioral despair, anhedonia and a reduction of social behavior occurred in rats with concomitant increased expression of GluN2A and GluN2B and decreased expression of the PSD-95, p-CREB and BDNF protein levels in the Hp. The up-regulation of GluN2A protein was also found in the PFC, but only after prolonged (6 weeks) zinc deprivation., Conclusions: The procedure of zinc restriction in rats causes behavioral changes that share some similarities to the pathophysiology of depression. Obtained data indicated that depressive-like behavior induced by zinc deficiency is associated with the changes in NMDAR signaling pathway., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The zinc deficiency animal model of depression has been proposed; however, it has not been validated in a detailed manner. We have recently shown that depression-like behavior induced by dietary zinc restriction is associated with up-regulation of hippocampal N-methyl-d-aspartate receptor (NMDAR). Here we examined the effects of chronic administration of a selective serotonin reuptake inhibitor, fluoxetine (FLX), on behavioral and biochemical alterations (within NMDAR signaling pathway) induced by zinc deficiency. Male Sprague Dawley rats were fed a zinc adequate diet (ZnA, 50mg Zn/kg) or a zinc deficient diet (ZnD, 3mg Zn/kg) for 4 weeks. Then, FLX treatment (10mg/kg, i.p.) begun. Following 2 weeks of FLX administration the behavior of the rats was examined in the forced swim test (FST) and the spontaneous locomotor activity test. Twenty four hours later tissue was harvested. The proteins of NMDAR (GluN1, GluN2A and GluN2B) or AMPAR (GluA1) subunits, p-CREB and BDNF in the hippocampus (Western blot) and serum zinc level (TXRF) were examined. Depression-like behavior induced by ZnD in the FST was sensitive to chronic treatment with FLX. ZnD increased levels of GluN1, GluN2A, GluN2B and decreased pS485-GluA1, p-CREB and BDNF proteins. Administration of FLX counteracted the zinc restriction-induced changes in serum zinc level and hippocampal GluN1, GluN2A, GluN2B and p-CREB but not BDNF or pS845-GluA1 protein levels. This finding adds new evidence to the predictive validity of the proposed zinc deficiency model of depression. Antidepressant-like activity of FLX in the zinc deficiency model is associated with NMDAR complex., (Copyright © 2015 Elsevier B.V. All rights reserved.)