34 results on '"Männistö, Pekka T."'
Search Results
2. Strong preferences of dopamine and l-dopa towards lipid head group: importance of lipid composition and implication for neurotransmitter metabolism.
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Orłowski, Adam, Grzybek, Michał, Bunker, Alex, Pasenkiewicz-Gierula, Marta, Vattulainen, Ilpo, Männistö, Pekka T., and Róg, Tomasz
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DOPAMINE ,DOPA ,BILAYER lipid membranes ,NEUROTRANSMITTERS ,PHOSPHATIDYLSERINES ,HYDROGEN bomb - Abstract
J. Neurochem. (2012) 122, 681-690. Abstract The interactions of the neurotransmitter dopamine, and its precursor l-dopa, with membrane lipids were investigated through a set of molecular dynamic simulations with all atom resolution. The results obtained indicate that both dopamine and l-dopa have a pronounced association with the lipid head groups, predominantly mediated through H-bonds. As a result the molecules are anchored to the interfacial region of the membrane. The strength of this interaction is dependent on lipid composition - the presence of phosphatidylserine leads to an increase in the strength of this interaction, resulting in an H-bond network with a lifetime much longer than the timescale of our simulations. Also, bilayers that include sphingomieline and cholesterol interact strongly with dopamine and l-dopa. We postulate that the high membrane association that we have observed for both dopamine and l-dopa could have the following effects: 1) when on the plasma membrane exterior, favour the availability of these compounds for cell membrane uptake processes and, 2) when on an internal membrane surface, accentuate the importance of membrane-bound metabolizing enzymes over their soluble counterparts. [ABSTRACT FROM AUTHOR]
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- 2012
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3. A Transient Inhibition and Permanent Lack of Catechol- O-Methyltransferase have Minor Effects on Feeding Pattern of Female Rodents.
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Schendzielorz, Nadia, Männistö, Pekka T., Karayiorgou, Maria, Gogos, Joseph A., and Raasmaja, Atso
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CATECHOL-O-methyltransferase , *DOPAMINE , *DOPAMINERGIC neurons , *PREFRONTAL cortex , *LABORATORY rats - Abstract
Abnormal feeding behaviours have long been linked to disruptions in brain dopaminergic activity. Dopamine is metabolized, amongst others, by catechol- O-methyltransferase (COMT). Normally, COMT only plays a subordinate role in dopamine metabolism. However, changes in COMT activity, especially in the prefrontal cortex, become more important during events that evoke dopamine release. The current study investigated the effect of acute COMT inhibition on feeding in Wistar rats and C57BL/6 mice using a selective, brain penetrating COMT inhibitor (OR-1139). Furthermore, the effect of a long-term lack of COMT on feeding behaviour was studied in COMT-deficient (COMT −/−) mice. Apart from following the gross feeding behaviour of fasted rats and mice, the first 4 hr of re-feeding were recorded with a video camera to allow a more detailed analysis of feeding microstructure. In the acute study, rats and mice received a single injection of OR-1139 (3, 10 or 30 mg/kg), just before the experiment. We found that rats and mice receiving OR-1139 had fewer very short meals but more long meals than the controls. Treated mice even ate more frequently than the controls, but other feeding parameters remained unchanged. Conversely, COMT −/− mice displayed an increased latency to initiate the first meal and spent less total time eating than wild-type mice. In conclusion, although decreased/lack of COMT activity did not robustly alter feeding behaviour of female rodents, we observed some alterations in the microstructure of feeding. However, these minor changes were highly dependent on the extent and fashion in which COMT was manipulated. [ABSTRACT FROM AUTHOR]
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- 2012
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4. Minocycline protects SH-SY5Y cells from 6-hydroxydopamine by inhibiting both caspase-dependent and -independent programmed cell death.
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Ossola, Bernardino, Lantto, Tiina A., Puttonen, Katja A., Tuominen, Raimo K., Raasmaja, Atso, and Männistö, Pekka T.
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- 2012
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5. Unpredictable Rotational Responses to L-dopa in the Rat Model of Parkinson's Disease: the Role of L-dopa Pharmacokinetics and Striatal Dopamine Depletion.
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Kääriäinen, Tiina M., Käenmäki, Mikko, Forsberg, Markus M., Oinas, Niko, Tammimäki, Anne, and Männistö, Pekka T.
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PARKINSON'S disease ,EXTRAPYRAMIDAL disorders ,BRAIN diseases ,LABORATORY rats ,DRUG therapy - Abstract
L-dopa is still the gold standard in the symptomatic treatment of Parkinson's disease (PD), and thus, it is the most commonly used drug in the non-clinical assessment of new drug therapies to PD, including those intended to improve the effect of L-dopa. In unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD, the results from L-dopa-induced rotation tests are often unpredictable. While repeated administration of L-dopa improves the rotation, the exact mechanisms underlying the extensive variability in rotation responses between rats and testing times are unclear. In the present study, we aimed to assess whether the route of administration (oral or intraperitoneal) or the form of L-dopa (base or methyl ester) is associated with the extensive variation in rotation responses to L-dopa in 6-OHDA rats. We also wanted to examine the dependence between L-dopa (base or methyl ester)-induced rotational behaviour and the extent of dopamine and dopa decarboxylase enzyme loss in the lesioned striatum. It was found that variation in plasma levels of L-dopa as well as the administration route explains a part of the variability in rotation. There were small but significant differences in striatal dopamine depletion (indicative of degree of lesion) between the groups, which may partially account for the various patterns in L-dopa-induced rotational behaviour. While apomorphine-induced rotation test is a useful tool for primary screening of the success of 6-OHDA lesion, it is not useful at predicting the rotational performance of 6-OHDA rats to L-dopa. The exact mechanisms and causes of the variability in the rotation responses to L-dopa in 6-OHDA rats still remain to be clarified. [ABSTRACT FROM AUTHOR]
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- 2012
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6. Nitecapone reduces development and symptoms of neuropathic pain after spinal nerve ligation in rats
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Kambur, Oleg, Männistö, Pekka T., Pusa, Anne M., Käenmäki, Mikko, Kalso, Eija A., and Kontinen, Vesa K.
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KETONES ,SPINAL nerves ,LIGATURE (Surgery) ,SYMPTOMS ,NEUROPATHY ,NEUROSURGERY ,ALLODYNIA ,LABORATORY rats - Abstract
Abstract: Neuropathic pain is caused by damage or malfunctioning of the nervous system. It is fairly common and more resistant to treatment than other types of pain. Since nitecapone, an inhibitor of catechol-O-methyl-transferase (COMT), has decreased neuropathic symptoms in diabetic rats, we studied its effects in another model of neuropathic pain, the spinal nerve ligation (SNL) model. Spinal nerves L5–6 were ligated in male Wistar rats under anaesthesia to produce the SNL model of neuropathic pain. Nitecapone (30mg/kg, i.p.) or vehicle was administered once daily starting either 1h before or 2days after surgery and continued for 14–19days. Threshold for mechanical allodynia was measured with the digital von Frey test and responses to cold stimuli with the acetone test, before surgery and every other day after it 1h before drug administration. Mechanical and cold allodynia developed in all study groups. Both nitecapone treatments significantly reduced mechanical allodynia and withdrawal thresholds were 80–95% higher compared with the control group. In the acetone test, both nitecapone groups also showed less signs of cold allodynia than the control groups. In nitecapone-naïve animals a single dose of nitecapone also reduced mechanical allodynia on the 14th day after the surgery. Nitecapone reduced the symptoms of neuropathic pain after the SNL, which is in line with the earlier study. Our results suggest that nitecapone and other COMT inhibitors should be studied further in the treatment of neuropathic pain. [Copyright &y& Elsevier]
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- 2011
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7. Effects of Diverse Psychopharmacological Substances on the Activity of Brain Prolyl Oligopeptidase.
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Peltonen, Iida and Männistö, Pekka T.
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MENTAL depression , *PATHOLOGICAL psychology , *ANTIDEPRESSANTS , *PSYCHIATRIC drugs , *TRANQUILIZING drugs - Abstract
Prolyl oligopeptidase (POP) has been connected to learning, memory and mood. Changes in serum or plasma POP activity have been linked to psychiatric disorders. POP has been thought to interfere in these conditions by cleaving neuroactive peptides or via the phosphatidylinositol second messenger system. However, little is known about the possible POP inhibition of commonly used psychoactive drugs. In this study, we measured the effects of various psychotropic drugs, including antidepressants, antipsychotics, mood stabilisers and anxiolytics, on the activity of the rat brain homogenate POP. Of the 38 compounds tested, 18 inhibited POP by at least 20% at 10 μM (buspirone, chlorpromazine, citalopram, clozapine, desipramine, duloxetine, escitalopram, flupenthixol, imipramine, ketanserin, lamotrigine, levomepromazine, prazosin, prochlorperazine, promazine, risperidone ritanserin and thioridazine). Thioridazine and valproate (VPA) acted at therapeutic plasma levels. Kinetically, VPA was a competitive inhibitor, thioridazine a non-competive inhibitor and ketanserin a mixed type inhibitor. Being lipophilic, many of the psychoactive compounds are present in the brain at several-times higher concentrations than in plasma. At concentrations reported to be reached in the brain, chlorpromazine, clozapine, desipramine, imipramine, prochlorperazine and promazine inhibited POP by 30-50% suggesting that they could inhibit POP in vivo. However, when studied ex vivo, a single dose of 10 mg/kg thioridazine caused a deep sedation in the mice but did not inhibit the activity of POP. In conclusion, compared with conventional POP inhibitors, all psychopharmacological compounds tested are very weak inhibitors in vitro, and we doubt that their POP inhibition would be therapeutically meaningful. [ABSTRACT FROM AUTHOR]
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- 2011
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8. Effect of Genetic Modifications in the Synaptic Dopamine Clearance Systems on Addiction-like Behaviour in Mice.
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Tammimäki, Anne and Männistö, Pekka T.
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DOPAMINE , *MONOAMINE oxidase , *LABORATORY mice , *SEXUAL dimorphism in animals ,SEX differences (Biology) - Abstract
During the last 15 years, genetically modified mouse lines have proved to be a valuable research tool. This review summarizes research that studied addiction-like behaviour in mice that had a targeted mutation in the genes of the synaptic dopamine removal systems, i.e. in the dopamine transporter (DAT), a vesicular monoamine transporter 2 (VMAT2) or two dopamine-metabolizing enzymes (monoamine oxidase, MAO, mainly MAO-A isoenzyme, and catechol-O-methyltransferase, COMT). Majority of the mice are knockouts but also some knockin and knock down mouse lines are included. Most studies have explored DAT, and it has been shown to be the critical target in addiction to psychostimulants. Its role in the development of addiction-like behaviour to nicotine, opioids or ethanol is less clear. VMAT2 also seems to be linked to psychostimulant addiction. MAO-A and COMT have a minor role in addiction-like behaviour that is further complicated by a sexual dimorphism. [ABSTRACT FROM AUTHOR]
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- 2011
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9. Distribution of catechol- O-methyltransferase (COMT) proteins and enzymatic activities in wild-type and soluble COMT deficient mice.
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Myöhänen, Timo T., Schendzielorz, Nadia, and Männistö, Pekka T.
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ANIMAL diseases ,HIPPOCAMPUS (Brain) ,CATECHOL ,METHYLTRANSFERASES ,MACROPHAGES - Abstract
J. Neurochem. (2010) 113, 1632–1643. Catechol- O-methyltranferase (COMT) has both soluble (S-COMT) and membrane-bound (MB-COMT) isoforms. A specific COMT antibody was used in immunohistochemical and confocal co-localization studies to explore the distribution of COMT in general in normal mice and MB-COMT in particular, in an S-COMT deficient mouse line. In the peripheral tissues, high COMT protein and activity levels were observed in liver and kidney, whereas in the brain, COMT expression and activity were much lower. MB-COMT was widely distributed throughout all tissues, and overall, the MB-COMT distribution mimicked the distribution of S-COMT. MB-COMT displayed some preference for brain tissue, notably in the hippocampus. MB-COMT related enzymatic activity was also pronounced in the cerebral cortical areas and hypothalamus. MB-COMT, like S-COMT, was found to be an intracellular enzyme but it was not associated with plasma membranes in the brain. Both COMT forms were abundantly found in microglial cells and intestinal macrophages, but also in astroglial cells. COMT was also present in some neuronal cells, like pyramidal neurons, cerebellar Purkinje and granular cells and striatal spiny neurons, but not in major long projection neurons. Finally, it seemed that nuclear COMT is not visible in S-COMT deficient mice. [ABSTRACT FROM AUTHOR]
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- 2010
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10. Different Effects of Scopolamine and Inhibition of Prolyl Oligopeptidase on Mnemonic and Motility Functions of Young and 8- to 9-Month-Old Rats in the Radial-Arm Maze.
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Peltonen, Iida, Jalkanen, Aaro J., Sinervä, Veijo, Puttonen, Katja A., and Männistö, Pekka T.
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SCOPOLAMINE ,OLIGOPEPTIDES ,MNEMONICS ,PEPTIDES ,RATS - Abstract
Prolyl oligopeptidase (POP) has been connected to memory and mood through regulation of the brain levels of its biologically active peptide substrates and phosphatidylinositol system. This is the first study in a radial-arm maze of the effects of a single dose of a novel potent prolyl oligopeptidase inhibitor, KYP-2047 (5 mg/kg, dissolved in 5% Tween 80), on memory and learning of scopolamine-treated (0.4 mg/kg, dissolved in saline) rats. Habituated (days 1 and 2) and trained (days 3–11) young (3 months) and old (8–9 months) male Wistar rats were given (i) saline + Tween, (ii) saline + KYP-2047, (iii) scopolamine + Tween or (iv) scopolamine + KYP-2047 30 min. prior to testing their memory. Food rewards located in four randomly chosen arms of the maze. The rat had 10 min. to find and eat the rewards. Time spent in the maze, visits to each arm and number of eaten rewards were measured. Old rats made generally more errors, spent more time and visited fewer arms per minute in the maze than young rats. The memory- and function-impairing effects of scopolamine were also seen more clearly in old than young rats. KYP-2047 had no or only a marginal effect on memory of either age group, but when given without scopolamine, it slightly increased the maze motility of young rats and decreased the motility of old rats. In a separate locomotor activity test, KYP-2047 enhanced the motility of young rats supporting a suggested role of POP in motor functions. [ABSTRACT FROM AUTHOR]
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- 2010
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11. Increase in Free Choice Oral Ethanol Self-Administration in Catechol- O-Methyltransferase Gene-Disrupted Male Mice.
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Tammimäki, Anne, Forsberg, Markus M., Karayiorgou, Maria, Gogos, Joseph A., and Männistö, Pekka T.
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GENETIC research ,MICE ,ALCOHOL ,CATECHOL ,METHYLTRANSFERASES ,COCAINE ,CATECHOL-O-methyltransferase gene - Abstract
The effect of catechol- O-methyltransferase ( Comt) gene disruption on the voluntary oral consumption of water, ethanol (2.5–20%, v/v) and cocaine (0.1–0.8 mg/ml) was studied in the free-choice, two-bottle paradigm in male and female mice. Solutions containing ethanol or cocaine, or tap water were available ad libitum from drinking burettes for 4 weeks. Catechol- O-methyltransferase-deficient male mice consumed significantly more ethanol than their wild-type male littermates. In contrast, female mice did not show genotype differences in the consumption of ethanol solutions. During the cocaine experiment, male mice developed either a side preference or an aversion that obscured cocaine consumption. This pattern of drinking was not dependent on Comt genotype. In female mice, Comt genotype was not associated with cocaine consumption. In conclusion, disruption of Comt gene influenced ethanol consumption in a gender-dependent manner in mice, supporting the hypothesis that low catechol- O-methyltransferase activity is one of the predisposing factors for high alcohol consumption in males. [ABSTRACT FROM AUTHOR]
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- 2008
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12. Beneficial Effect of Prolyl Oligopeptidase Inhibition on Spatial Memory in Young but Not in Old Scopolamine-Treated Rats.
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Jalkanen, Aaro J., Puttonen, Katja A., Venäläinen, Jarkko I., Sinervä, Veijo, Mannila, Anne, Ruotsalainen, Sirja, Jarho, Elina M., Wallén, Erik A. A., and Männistö, Pekka T.
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OLIGOPEPTIDES ,SCOPOLAMINE ,NEUROPEPTIDES ,PEPTIDE hormones ,NEUROTENSIN ,LABORATORY rats ,CLINICAL pharmacology - Abstract
The effects of a novel prolyl oligopeptidase (POP) inhibitor KYP-2047 on spatial memory of young (3-month-old) and old (8- to 9-month-old) scopolamine-treated rats (0.4 mg/kg intraperitoneally) was investigated in the Morris water maze. In addition, the concentrations of promnesic neuropeptide substrates of POP, substance P and neurotensin in various brain areas after acute and chronic POP inhibition were measured in young rats. In addition, inositol-1,4,5-trisphosphate (IP
3 ) levels were assayed in rat cortex and hippocampus after effective 2.5-day POP inhibition. KYP-2047 (1 or 5 mg/kg 30 min. before daily testing) dose-dependently improved the escape performance (i.e. latency to find the hidden platform and swimming path length) of the young but not the old rats in the water maze. POP inhibition had no consistent effect on substance P levels in cortex, hippocampus or hypothalamus, and only a modest increase in neurotensin concentration was observed in the hypothalamus after a single dose of KYP-2047. Moreover, IP3 concentrations remained unaffected in cortex and hippocampus after POP inhibition. In conclusion, the behavioural data support the earlier findings of the promnesic action of POP inhibitors, but the mechanism of the memory-enhancing action remains unclear. [ABSTRACT FROM AUTHOR]- Published
- 2007
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13. Evolutionary relationships of the prolyl oligopeptidase family enzymes.
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Venäläinen, Jarkko I., Juvonen, Risto O., and Männistö, Pekka T.
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ENZYMES ,PROTEINS ,AMINO acids ,HORMONES ,HUNTINGTON disease ,ENDOCRINE diseases ,PEPTIDES - Abstract
The prolyl oligopeptidase (POP) family of serine proteases includes prolyl oligopeptidase, dipeptidyl peptidase IV, acylaminoacyl peptidase and oligopeptidase B. The enzymes of this family specifically hydrolyze oligopeptides with less than 30 amino acids. Many of the POP family enzymes have evoked pharmaceutical interest as they have roles in the regulation of peptide hormones and are involved in a variety of diseases such as dementia, trypanosomiasis and type 2 diabetes. In this study we have clarified the evolutionary relationships of these four POP family enzymes and analyzed POP sequences from different sources. The phylogenetic trees indicate that the four enzymes were present in the last common ancestor of all life forms and that the β-propeller domain has been part of the family for billions of years. There are striking differences in the mutation rates between the enzymes and POP was found to be the most conserved enzyme of this family. However, the localization of this enzyme has changed throughout evolution, as three archaeal POPs seem to be membrane bound and one third of the bacterial as well as two eukaryotic POPs were found to be secreted out of the cell. There are also considerable distinctions between the mutation rates of the different substrate binding subsites of POP. This information may help in the development of species-specific POP inhibitors. [ABSTRACT FROM AUTHOR]
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- 2004
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14. Agonists for neuropeptide Y receptors Y[sub1] and Y[sub5] stimulate different phases of feeding in guinea pigs.
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Lecklin, Anne, Lundell, Ingrid, Salmela, Suvi, Männistö, Pekka T., Beck-Sickinger, Annette G., and Larhammar, Dan
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NEUROPEPTIDE Y ,GUINEA pigs ,NEUROPEPTIDES ,INGESTION - Abstract
1 The stimulatory effect of neuropeptide Y (NPY) on food intake is well established but the roles of the receptor subtypes Y[SUB1] and Y[SUB5] have been difficult to define. We have studied the effects of two novel Y[SUB1]-preferring and two Y[SUB5]-preferring agonists on feeding in guinea pigs. 2. The Y[SUB1]-preferring receptor agonists [Arg[SUP6],Pro[SUP34]]pNPY and [Phe[SUP7],Pro[SUP34]]pNPY had high affinity for the Y[SUB1] receptor (K[SUBi] values 0.07 and 0.04 nM, respectively) and nanomolar affinity for the Y[SUB5] receptor. Administration of either compound into the third brain ventricle increased food intake equally to NPY. 3 The Y[SUB5] agonist [Ala[SUP31],Aib[SUP32]pNPY displayed a moderate affinity for the YSUB5] receptor (K[SUBi] 7.42 nM) and a low affinity for Y[SUB1] (K[SUBi] 1.7 μM). This compound had only a modest effect on feeding. 4 The other Y[SUB5]-preferring peptide [cPP[SUP1-7],NPY[SUP19-23],Ala[SUP31],Aib[SUP32],Gln[SUP34]]hPP had a higher affinity at the Y[SUB5] receptor (K[SUBi] 1.32 nM) and also at the Y[SUB1] receptor (K[SUBi] 85 nm). It potently stimulated feeding: the food consumption after administration of this peptide was two-fold compared to NPY. 5 Our results support the view that both the receptor subtypes Y[SUB1] and Y[SUB5] are involved in the stimulation of feeding. As the action profiles of the Y[SUB1] and Y[SUB5] agonists on feeding parametric were different, it seems that they influence different phase of eating. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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15. Pharmacodynamic Response of Entacapone in Rats after Administration of Entacapone Formulations and Prodrugs with Varying Bioavailabilities.
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Forsberg, Markus, Savolainen, Jouko, Järvinen, Tomi, Leppänen, Jukka, Gynther, Jukka, and Männistö, Pekka T.
- Abstract
The aim of this in vivo study was to assess the effect of improved oral bioavailability of entacapone on its actual pharmacodynamic response, COMT inhibition in erythrocytes. Rats were administered entacapone orally as a suspension, as a plain solution, an entacapone/HP-β-CD solution, two N-alkyl-carbamate ester prodrugs and intravenously as a solution. Also the relationship between pharmacodynamic and pharmacokinetic responses of entacapone was investigated. The administration of entacapone as a solution (plain solution pH 7.4; F=34.8% or entacapone/HP-β-CD solution pH 3.0; F=18.5%) resulted in significantly higher degree of COMT inhibition in erythrocytes than could be achieved by administering entacapone as a suspension (pH 3.0; F=8.9%). The inhibitory E
max model did not reveal any significant differences in EC50 estimates of entacapone suspension, entacapone/HP-β-CD solution or entacapone solution. The overall pharmacodynamic response of entacapone (AUE; area under effect-time curve) was dependent on the pharmacokinetic response (AUC; area under concentration-time curve) irrespective of the entacapone formulation and dosage form. However, this dependency did not extend to formulations producing very high peak concentrations of entacapone in plasma; high plasma concentrations reached transiently after administration of entacapone solution had only a minor effect on the overall pharmacodynamic response (AUE). The inhibitory Emax model revealed that a plateau of COMT inhibition near to Emax is attained by plasma concentrations under 2000 ng/ml, irrespective of the formulation. This supports the results concerning the dependence of AUE on AUC. [ABSTRACT FROM AUTHOR]- Published
- 2002
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16. Receptor subtypes Y[sub1] and Y[sub5] mediate neuropeptide Y induced feeding in the guinea-pig.
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Lecklin, Anne, Lundell, Ingrid, Paananen, Leena, Wikberg, Jarl E.S., Männistö, Pekka T., and Larhammar, Dan
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NEUROPEPTIDE Y ,INGESTION ,STIMULANTS ,GUINEA pigs as laboratory animals - Abstract
1 Neuropeptide Y (NPY) is one of the most potent stimulants of food intake* It has been debated which receptor subtype mediates this response. Initially Y[sub1] was proposed, but later Y[sub5] was announced as a 'feeding' receptor in rats and mice. Very little is known regarding other mammals. The present study attempts to characterize the role of NPY in feeding behaviour in the distantly related guinea-pig. When infused intracerebroventricularly, NPY dose-dependently increased food intake. 2 PYY, (Leu[sup31],Pro[sup34])NPY and NPY(2-36) stimulated feeding, whereas NPY(13-36) had no effect. These data suggest that either Y[sub1] or Y[sub5] receptors or both may mediate NPY induced food intake in guinea-pigs. 3 The Y, receptor antagonists, BIBO 3304 and H 409/22 displayed nanomolar affinity for the Y[sub1] receptor (K[sub1] values 1.1 7plusmn;0.2 nM and 5.6 ±0.9 nM, respectively), but low affinity for the Y[sub2] or Y[sub5] receptors. When guinea-pigs were pretreated with BIBO 3304 and H 409/22, the response to NPY was inhibited. 4 The Y[sub5] antagonist, CGP 71683A had high affinity for the Y[sub5] receptor (K[sub1] 1.3 ±0.05 nM) without having any significant activities at the Y[sub1] and Y[sub2] receptors. When CGP 71683A was infused into brain ventricles, the feeding response to NPY was attenuated. 5 The present study shows that NPY stimulates feeding in guinea-pigs through Y[sup1] and Y[sub5] receptors. As the guinea-pig is very distantly related to the rat and mouse, this suggests that both Y[sub1] and Y[sub5] receptors may mediate NPY-induced hyperphagia also in other orders of mammals [ABSTRACT FROM AUTHOR]
- Published
- 2002
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17. The use of low-molecular-weight PEIs as gene carriers in the monkey fibroblastoma and rabbit smooth muscle cell cultures.
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Lampela, Pasi, Räisänen, Johanna, Männistö, Pekka T., Ylä-Herttuala, Seppo, and Raasmaja, Atso
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- 2002
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18. Brain catecholamine metabolism in catechol-O -methyltransferase (COMT)-deficient mice.
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Huotari, Marko, Gogos, Joseph A., Karayiorgou, Maria, Koponen, Olli, Forsberg, Markus, Raasmaja, Atso, Hyttinen, Juha, and Männistö, Pekka T.
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CATECHOLAMINES ,MICRODIALYSIS ,NEUROCHEMISTRY - Abstract
Abstract Catechol-O -methyltransferase (COMT) catalyses the O -methylation of compounds having a catechol structure and its main function involves the elimination of biologically active or toxic catechols and their metabolites. By means of homologous recombination in embryonic stem cells, a strain of mice has been produced in which the gene encoding the COMT enzyme is disrupted. We report here the levels of catecholamines and their metabolites in striatal extracellular fluid in these mice as well as in homogenates from different parts of the brain, under normal conditions and after acute levodopa administration. In immunoblotting studies, COMT-knockout mice had no COMT protein in brain or kidney tissues but the amounts of catecholamine synthesizing and other metabolizing enzyme proteins were normal. Under normal conditions, COMT deficiency does not appear to affect significantly brain dopamine and noradrenaline levels in spite of relevant changes in their metabolites. This finding is consistent with previous pharmacological studies with COMT inhibitors and confirms the pivotal role of synaptic reuptake processes and monoamine oxidase-dependent metabolism in terminating the actions of catecholamines at nerve terminals. In contrast, when COMT-deficient mice are challenged with l-dihydroxyphenylalanine, they show an extensive accumulation of 3,4-dihydroxyphenylacetic acid and dihydroxyphenylglycol and even dopamine, revealing an important role for COMT under such situations. Notably, in some cases these changes appear to be Comt gene dosage-dependent, brain-region specific and sexually dimorphic. Our results may have implications for improving the treatment of Parkinson's disease and for understanding the contribution of the natural variation in COMT activity to psychiatric phenotypes. [ABSTRACT FROM AUTHOR]
- Published
- 2002
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19. Modulation of histamine H3 receptors in the brain of 6-hydroxydopamine-lesioned rats.
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Anichtchik, Oleg V., Huotari, Marko, Peitsaro, Nina, Haycock, John W., Männistö, Pekka T., and Panula, Pertti
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HISTAMINE receptors ,PARKINSON'S disease ,ANIMAL models in research - Abstract
AbstractParkinson's disease is a major neurological disorder that primarily affects the nigral dopaminergic cells. Nigral histamine innervation is altered in human postmortem Parkinson's disease brains. However, it is not known if the altered innervation is a consequence of dopamine deficiency. The aim of the present study was to investigate possible changes in the H
3 receptor system in a well-characterized model of Parkinson's disease – the 6-hydroxydopamine (6-OHDA) lesioned rats. Histamine immunohistochemistry showed a minor increase of the fibre density index but we did not find any robust increase of histaminergic innervation in the ipsilateral substantia nigra on the lesioned side. In situ hybridization showed equal histidine decarboxylase mRNA expression on both sides in the posterior hypothalamus. H3 receptors were labelled with N-alpha-[3H]-methyl histamine dihydrochloride ([3 H] NAMH). Upregulation of binding to H3 receptors was found in the substantia nigra and ventral aspects of striatum on the ipsilateral side. An increase of GTP-γ-[35 S] binding after H3 agonist activation was found in the striatum and substantia nigra on the lesioned side. In situ hybridization of H3 receptor mRNA demonstrated region-specific mRNA expression and an increase of H3 receptor mRNA in ipsilateral striatum. Thus, the histaminergic system is involved in the pathological process after 6-OHDA lesion of the rat brain at least through H3 receptor. On the later stages of the neurotoxic damage, less H3 receptors became functionally active. Increased H3 receptor mRNA expression and binding may, for example, modulate GABAergic neuronal activity in dopamine-depleted striatum. [ABSTRACT FROM AUTHOR]- Published
- 2000
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20. Effects of aqueous solubility and dissolution characteristics on oral bioavailability of entacapone.
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Savolainen, Jouko, Forsberg, Markus, Taipale, Hannu, Männistö, Pekka T., Järvinen, Kristiina, Gynther, Jukka, Jarho, Pekka, and Järvinen, Tomi
- Published
- 2000
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21. Microdialysis Studies on the Action of Tolcapone on Pharmacologically-Elevated Extracellular Dopamine Levels in Conscious Rats.
- Author
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Huotari, Marko, Gainetdinov, Raul, and Männistö, Pekka T.
- Abstract
To elucidate the importance of catechol-O-methyltransferase, we performed striatal microdialysis studies in conscious rats given tolcapone, an inhibitor of catechol-O-methyltransferase, together with four compounds each of which elevates the extracellular dopamine content through a different mechanism. Tolcapone itself did not alter dopamine levels in the striatal microdialysis fluid but increased DOPAC and decreased homovanillic acid levels. However, tolcapone pretreatment (30 mg/kg) multiplied the already high dopamine levels after levodopa, and less so the moderately elevated dopamine levels after GBR-12909 (at 20 mg/kg) alone, but the minor (insignificant) dopamine-elevating effects of haloperidol and (+)-U232 were not altered. In all cases, a tolcapone pretreatment decreased homovanillic acid levels and elevated DOPAC levels. In further combination studies, GBR-12909 did not alter significantly the effects of levodopa/carbidopa on dopamine, DOPAC and homovanillic acid levels. In these rats, tolcapone enhanced the effect of GBR-12909 on extracellular dopamine but not on DOPAC. In conclusion, when levodopa and carbidopa are given together, COMT inhibition becomes extremely meaningful, and dopamine levels are multiplied by tolcapone. Otherwise, tolcapone is able to further elevate extracellular dopamine levels only when dopamine turnover is normal or low but not when it is high. Overall, the role of COMT in the elimination of synaptic dopamine remains minor compared to the dominance of the reuptake process. [ABSTRACT FROM AUTHOR]
- Published
- 1999
- Full Text
- View/download PDF
22. Effects of Repeated Low Dose Administration and Withdrawal of Haloperidol on Sexual Behaviour of Male Rats.
- Author
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Tupala, Erkki, Haapalinna, Antti, Viitamaa, Timo, Männistö, Pekka T., and Saano, Veijo
- Abstract
Neuroleptics are known to cause anhedonia and attenuate sexual behaviour at therapeutic doses in humans. These effects are assumed to result from the dopamine antagonism of the drugs. It has been observed that a mixed dopamine D
1 /D2 antagonist, haloperidol, may cause a reduction in the number of intromissions required to achieve ejaculation. On the other hand, dopamine antagonists are considered unable to modify sexual behaviour once the copulatory sequence is initiated. In this study, male rats received low doses of haloperidol (30 or 60 μg/kg) before the investigation of sexual behaviour in five consecutive days and the mating test was repeated after withdrawal periods of four and five days. Haloperidol dose-dependently reduced intromission frequency, and this effect was maintained for four days after withdrawal. Ejaculation latency was reduced in all groups, including controls. The results indicate that at low doses haloperidol dose-dependently reduces intromission frequency, and the effect of a repeated dosage may persist several days after cessation of medication. [ABSTRACT FROM AUTHOR]- Published
- 1999
- Full Text
- View/download PDF
23. Lack of Effect of Leptin on the Behaviour of Mice Predicting the Level of Anxiety and Depression.
- Author
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Suomalainen, Maija and Männistö, Pekka T.
- Published
- 1998
- Full Text
- View/download PDF
24. Minor Effect of Tolcapone, a Catechol- O-Methyltransferase Inhibitor, on Extracellular Dopamine Levels Modified by Amphetamine or Pargyline: A Microdialysis Study in Anaesthetized Rats.
- Author
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Tuomainen, Paivi, Törnwall, Martti, and Männistö, Pekka T.
- Abstract
In vivo microdialysis was used to examine the effects of tolcapone (30 mg/kg) on dopamine metabolism in amphetamine (5 mg/kg) and pargyline (75 mg/kg) treated rats. Amphetamine- or pargyline-induced decreases in the extracellular dihydroxyphenyl acetic acid (DOPAC) levels were counteracted by additional tolcapone. Tolcapone also decreased homovanillic acid effluxes below those caused by amphetamine or pargyline. However, dopamine effluxes were not further enhanced by additional tolcapone. These results show that central metabolism of dopamine can be modulated by catechol-O-methyltransferase (COMT) inhibition also without exogenous L-DOPA. However, extracellular dopamine levels are not easily increased. [ABSTRACT FROM AUTHOR]
- Published
- 1996
- Full Text
- View/download PDF
25. Neurochemical Mediators of Anxiety have Inconsistent Effects on Hypothalamic Self-Stimulation in Rats.
- Author
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Borisenko, Sergey A., Meng, Quing He, Rauhala, Pekka, and Männistö, Pekka T.
- Abstract
We studied effects of anxiogenic and anxiolytic compounds on the electric self-stimulation of the medial forebrain bundle in male rats to find out if there is a link between reward and anxiety-related behaviours. The cholecystokinin agonist, caerulein (25-100 μg/kg) and the 5-HT agonist 1-(3-chlorophenyl)piperazine (0.2-1 mg/kg) dose-dependently inhibited the electric self-stimulation. The 5-HT
2A antagonist, ketanserin, at 2.5 mg/kg, increased the self-stimulation at high currents but not at threshold current. The 5-HT3 antagonist ondansetron (10 and 100 μg/kg). The α1 -adrenergic antagonist, prazosin (0.125 and 0.5 mg/kg), the β-adrenergic antagonist, propranolol (5 and 10 mg/kg) and the α2 -adrenoreceptor antagonist, atipamezole (4 mg/kg), did not affect the self-stimulation. Nor did the benzodiazepine agonist, di-azepam (5-15 mg/kg), a benzodiazepine receptor antagonist flumazenil (at 10 and 25 mg/kg) or the inverse agonist of benzodiazepine receptors, N-methyl-β-carboline-3-carboxamide (10 and 20 mg/kg), cause any substantial changes of the self-stimulation. We conclude that only two anxiolytic drugs (caerulein and l-(3-chlorophenyl)piperazine) suppress the electric self-stimulation. These findings indicate that anxiogenicity as such is not able to weaken the hypothalamic electric self-stimulation. Anxiety and reward are apparently mediated through separate neural pathways. [ABSTRACT FROM AUTHOR]- Published
- 1996
- Full Text
- View/download PDF
26. Neuroendocrine Effects of Dexmedetomidine: Evidence of Cross-Tolerance Between a μ-Opioid Agonist and an α2-Adrenoceptor Agonist in Growth Hormone Secretion of the Male Rat.
- Author
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Idänpään-Heikkilä, Juhana J., Rauhala, Pekka, and Männistö, Pekka T.
- Abstract
The role of α
2 -adrenergic receptors (adrenoceptors) in the secretion of growth hormone, prolactin and thyrotropin was studied using highly selective agonists and antagonists of the α2 -adrenoceptor. The interplay between opiates and α2 -adrenergic drugs in the acute secretion of growth hormone and prolactin, as well as the possible cross-tolerance between morphine (μ-opioid receptor agonist) and dexmedetomidine (α2 -adrenoceptor agonist) in growth hormone secretion were also evaluated. Dexmedetomidine dose-dependently increased plasma growth hormone and prolactin levels and decreased thyrotropin levels. The enhanced secretion of both growth hormone and prolactin was antagonized by atipamezole (an α2 -adrenoceptor antagonist) but not by prazosin (an α1 -adrenoceptor antagonist). Morphine (5 mg/kg)-induced stimulation of growth hormone secretion was antagonized by both naloxone (u-opioid antagonist) and atipamezole. Naloxone, but not atipamezole, antagonized the morphine-induced increase in prolactin secretion. Dexmedetomidine increased growth hormone secretion in the saline pretreated rats, but did not do so in the morphine-tolerant rats. The stimulation of α2 -adrenoceptor enhances secretion of both growth hormone and prolactin. The adrenergic regulation of thyrotropin secretion still remains unclear. Evidently, adrenergic mechanisms are involved in the morphine-induced stimulation of growth hormone secretion, but not in the morphine-induced stimulation of prolactin secretion. In addition, there is a clear cross-tolerance between dexmedetomidine and morphine in growth hormone secretion of the rat. [ABSTRACT FROM AUTHOR]- Published
- 1996
- Full Text
- View/download PDF
27. Morphine Withdrawal Alters Anterior Pituitary Hormone Secretion, Brain Endopeptidase Activity and Brain Monoamine Metabolism in the Rat.
- Author
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Idänpään-Heikkilä, Juliana J., Rauhala, Pekka, Tuominen, Raimo K., Tuomainen, Päivi, Zolotov, Nikolai, and Männistö, Pekka T.
- Abstract
Rats were made tolerant to morphine by a 5-day regimen with increasing doses. The time course of changes in serum anterior pituitary hormone levels, brain endo- and exopeptidase activity, levels of brain biogenic amines and body weight were studied during abrupt morphine withdrawal. Cold stimulated secretion of thyrotropin and the secretion of growth hormone were both decreased whereas that of prolactin was increased. In the hypothalamus both prolyl endopeptidase and dipeptidyl peptidase IV activities were concomitantly increased. The hypothalamic 5 hydroxyindole acetic acid levels were also increased. Changes in hormone secretion, peptidase activity and monoamine turnover had returned to baseline levels by 92 hr. Our results indicate that morphine withdrawal and the associated stress produce alterations in anterior pituitary thyrotropin and growth hormone secretion. Concomitant increases in hypothalamic prolyl endopeptidase and dipeptidyl peptidase activities may contribute to these changes. [ABSTRACT FROM AUTHOR]
- Published
- 1996
- Full Text
- View/download PDF
28. Effects of Central and Peripheral Type Benzodiazepine Ligands on Growth Hormone and Gonadotropin Secretion in Male Rats*.
- Author
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Männistö, Pekka T., Laakso, Maija-Lüsa, Järvinen, Asko, and Rägo, Lembit
- Abstract
The action of central and peripheral type benzodiazepine ligands on growth hormone, luteinizing hormone and follicle stimulating hormone levels in serum were studied in male rats. Graded doses of Ro 5-4864, that binds to the peripheral type benzodiazepine receptors, clonazepam, a fairly pure central type agonist and diazepam, a mixed-type agonist, were given intraperitoneally. Also a benzodiazepine partial inverse agonist, FG 7142, was investigated. Clonazepam increased growth hormone levels at 0.2 mg/kg while higher doses were not active. Diazepam (5-25 mg/kg) was not effective. FG 7142 (15 mg/kg) and Ro 5-4864 (25 mg/kg) decreased growth hormone levels. Flumazenil, a central-type antagonist, reversed at least partially the effects of clonazepam and FG 7142, suggesting an effect through GABA-benzodiazepine complex. Elevation of growth hormone could be associated with anxiolysis and decrease of growth hormone with enhanced anxiety. Clonazepam (0.2-5 mg/kg) and diazepam (5-25 mg/kg) increased luteinizing hormone concentrations, but only the effects of 1 mg/kg of clonazepam and 5 mg/kg of diazepam reached statistical significance. Even FG 7142 caused a modest increase of luteinizing hormone at 5 mg/kg, but Ro 5-4864 rather decreased luteinizing hormone, although not significantly. Flumazenil (25 mg/kg) antagonized partially the effects of diazepam and clonazepam. Effects of Ro 5-4864 and FG 7142 were not modified by flumazenil or PK 11195, a peripheral-type mixed antagonist/agonist. Luteinizing hormone stimulation by benzodiazepine ligands may be a pituitary action while inhibition could be caused by the activation of the central GABAergic system. Serum follicle stimulating hormone levels were not significantly altered by central or peripheral type benzodiazepine agonists or antagonists. [ABSTRACT FROM AUTHOR]
- Published
- 1992
- Full Text
- View/download PDF
29. Comparison of the Effects of Intraventricular Taurine, GABA and Homotaurine on Serum Prolactin Levels in Male Rats.
- Author
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Panula-Lehto, Elina, Ahtee, Liisa, Tuominen, Raimo K., and Männistö, Pekka T.
- Abstract
The effects of taurine (2-aminoethanesulphonic acid), γ-aminobutyric acid (GABA) and homotaurine (3-aminopropanesulphonic acid), a structural analogue of both taurine and GABA, on serum prolactin (PRL) levels were compared in conscious, unrestrained male rats. Taurine, injected into the lateral brain ventricles at doses of 6 and 10 μmol per rat, elevated serum PRL level by 52% (P<0.01) and 90% (P<0.001), respectively. GABA elevated serum PRL level (41%, P<0.05) only at the lowest dose (1 μmol) tested. Homotaurine was the most effective compound, eliciting increases of 353% and 449% (P<0.001) at 6 and 10 μmol per rat, respectively. The rank order of the three amino acids in elevating serum PRL level bears some similarity to their known rank order of potency in altering cerebral dopamine metabolism. [ABSTRACT FROM AUTHOR]
- Published
- 1989
- Full Text
- View/download PDF
30. Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models.
- Author
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Gacsályi, István, Schmidt, Éva, Gyertyán, István, Vasar, Eero, Lang, Aavo, Haapalinna, Antti, Fekete, Márton, Hietala, Jarmo, Syvälahti, Erkka, Tuomainen, Päivi, and Männistö, Pekka T.
- Published
- 1997
- Full Text
- View/download PDF
31. Amiridine (NIK-247) and cerebrocrast in the alleviation of cholinergic lesion-induced learning deficit in male rats.
- Author
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Männistö, Pekka T., Kutepova, Olga, Leinonen, Katri, Lang, Aavo, Soosaar, Andres, Suomela, Annika, and Borisenko, Sergey A.
- Published
- 1993
- Full Text
- View/download PDF
32. Modification of GABAergic Activity and Thyrotropin Secretion in Male Rats.
- Author
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Mattila, Jyrki and Männistö, Pekka T.
- Published
- 1980
- Full Text
- View/download PDF
33. Studies on the contact sensitizing activity of dithranol (anthralin) and 10-butyryl dithranol (butantrone).
- Author
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Viluksela, Matti, Hassio, Kristiina, and Männistö, Pekka T.
- Subjects
CONTACT dermatitis ,ANIMAL models in research ,GUINEA pigs as laboratory animals ,LABORATORY mice ,SKIN inflammation ,ALLERGIES - Abstract
The contact sensitizing activity of dithranol and butantrone (10-butyryl dithranol) was studied in 3 animal models: the guinea pig maximization test (GPMT), the closed patch test (CPT), and the ear swelling test (MEST) in 2 different mouse strains. In the GPMT, both dithranol and , to a greater extent, butantrone showed sensitizing potential. Because butantrone was less irritant, the concentrations used were 10 × higher than those of dithranol. In the CPT, only butantrone was slightly positive. In the MEST, with both CF-I and Balb.c mice, dithranol caused less swelling of the test ear after challenge than butantrone. According to the evaluation criteria of the MEST, only butantrone caused sensitization in 50% of the CF-I mice and in 40% of the Balb.c mice. Thus, the GPMT was the only test which indicated the minor contact sensitizing potential of dithranol. On the other hand, the 10-butyryl analogue of dithranol showed undoubtedly stronger contact sensitizing potential than the parent compound in all tests. Therefore, as compared to dithranol, an increased risk of sensitization should be considered. [ABSTRACT FROM AUTHOR]
- Published
- 1990
- Full Text
- View/download PDF
34. Opposite Effect of Ethanol on Recombinant Membrane-Bound and Soluble Activities of Catechol-O-methyltransferase.
- Author
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Reenilä, Ilkka, Tuomainen, Päivi, Tilgmann, Carola, and Männistö, Pekka T.
- Published
- 1995
- Full Text
- View/download PDF
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