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6 mice
S120
P.1. Basic and clinical neuroscience
Present study was undertaken to evaluate the possible role of the MAOA-VNTR polymorphism in AD either alone, or in genetic interaction with Apolipoprotein (APOE) E4 allele, the most important known genetic risk factor for late-onset AD. The study included 247 AD patients (age = 76.8±7.3 years, 34% male) and 201 healthy control (HC) probands (age = 74.2±6.9 years, 32% male). The diagnosis of probable AD was based on NINCDS-ADRDA criteria. The cognitive performances were assessed according to the Mini Mental State Examination (mean scores±SD: AD: 18.5±5.9; HC: 29.1±0.9). DNA was extracted from peripheral blood leukocytes. The genetic analyses were performed by PCR amplifications. Pearson’s c2 test was used to compare genotype frequencies between the AD and HC groups. A logistic regression model was applied to test for interaction between the investigated polymorphisms. We found five different alleles of the MAOA-VNTR polymorphism in our samples with 2, 3, 3.5, 4 and 5 repeats (2R, 3R, 3.5R, 4R, 5R), however the 2R, 3.5R and the 5R alleles occurred with very low frequency both in the AD and in the HC groups. Comparison of MAOA genotype and allele frequencies between AD and HC groups showed no statistically significant difference (p = 0.835 for genotypes, p = 0.896 for alleles). Since the longer alleles (3.5R, 4R and 5R) result in higher transcriptional activity as compared to the shorter alleles (2R and 3R), we also formed two groups of alleles: long and short. The statistical analyses was also conducted with these genotypic groups, but no difference was found between the AD and HC groups (p = 0.545). As expected from many previous studies the genotypes with the APOE û4 allele occurred with significantly higher frequency in the AD group as compared to the controls (p < 0.0001). The interaction between the MAOA long and APOE E4 alleles did not contribute significantly to the logistic regression model (p = 0.131). Our results do not support the hypothesis that MAOA-VNTR polymorphism is associated with late onset AD, since we found no significant differences between genotype distribution comparing the AD and the HC groups. We also failed to detect a genetic interaction between the MAOA and APOE polymorphisms in the development of AD. This work was supported by grants from Hungarian Scientific Research Fund 60589/2006 and Hungarian Ministry of Health 052−07/2009. P.1.007 Protective effect of the antiparkinsonian drug hemantane in an MPTP model using C57BL/6 mice
study was to assess whether pretreatment with H is able to protect against MPTP toxicity. The experiments were performed in male C57BL/6 mice. H (10 mg/kg) was administered intraperitoneally along with different doses of MPTP using three different schedules. Behavioral changes, tremor and rigidity were monitored daily. Motor activity was assessed by actometer. Schedule 1. 1st group − saline, 2nd − MPTP 30 mg/kg, 3d − H 40 min before MPTP, 4th − H 30 min after MPTP 30 mg/kg. MPTP caused a pronounced decrease in locomotor activity assessed 90 min after the injection. H administered prior to MPTP failed to cause significant reduction in the oligokinesia, rigidity and tremor; however, H administered after MPTP significantly decreased manifestations of parkinsonian syndrome. Schedule 2. 1st group − saline, 2nd − H and MPTP 20 mg/kg − 4 days daily and H without MPTP on day 5, 3d − MPTP 20 mg/kg − 4 days daily. Behavior testing on day 4 revealed that animals in groups 2 and 3 had pronounced oligokinesia, indicating no protective effect of H. On day 5 a less pronounced, but still significant decrease in motor activity was revealed in the MPTP-treated group, but in the 2nd group after H administration the locomotor activity was restored to the level of the saline group. Testing on day 8 revealed significantly lower motor activity in both MPTP-treated groups compared to that of the saline group. Schedule 3. 1st group − saline, 2nd − H for 5 days daily, 3d − H for 5 days daily and MPTP 30 mg/kg single injection on day 5, 40 min after H, 4th − saline 5 days and MPTP on day 5. Measurement of locomotor activity performed on day 5 revealed no stimulatory activity of H in the 2nd group. A significant decrease in motor activity was registered in MPTP-treated animals of group 4. The motor activity in mice of group 3, treated with H subchronically prior to MPTP injection, was significantly higher than that in animals of group 4. In our study in schedules 1 and 2 H was able only to decrease the symptoms of existing parkinsonian syndrome induced by MPTP. In schedule 3 subchronic pretreatment with H decreased the degree of parkinsonian syndrome following acute MPTP administration. The results obtained prove that H is able to protect the brain from neurotoxic effects of MPTP. Further studies are necessary to elucidate the exact molecular mechanism of this action. P.1.009 Effects of the novel antiparkinsonian drug hemantane on brain bioelectric activity in mice with parkinsonian syndrome
A. Nepoklonov1 ° , I. Kapitsa1 , T. Voronina1 , E. Valdman1 . 1 Zakusov Institute of Pharmacology, psychopharmacology, Moscow, Russia
I. Kapitsa1 ° , L.N. Nerobkova1 , K.B. Kurakhmaeva1 , I.I. Kokschenev1 , A.V. Nepoklonov1 , E.A. Valdman1 , T.A. Voronina1 . 1 Zakusov Institute of Pharmacology, psychopharmacology, Moscow, Russia
The novel antiparkinsonian drug hemantane (H) [N-2(adamantyl)hexamethylenimine hydrochloride] has been shown to decrease oligokinesia, rigidity and tremor in animal models with MPTP- and MPP+ -induced parkinsonian syndrome. The antiparkinsonian effect was confirmed in patients with early stages of Parkinson’s disease in a pilot clinical study. The complex mechanism of action − dopamine-positive effects, NMDA antagonism, MAO-B inhibition, antiradical properties− suggests that H is a potential neuroprotector that can slow or even prevent disease progression in subjects who are genetically predisposed and/or are exposed to environmental neurotoxins. The aim of the present
At the present time it is generally recognized that on the early stages of Parkinson disease the treatment should be started with dopamine agonists, amantadine and other medicines with potential neuroprotective effect. New antiparkinsonian drug hemantane (H) with complex mechanism of action has been developed in Zakusov Institute of Pharmacology. The aim of current study was to assess the effect of H on brain bioelectric activity of C57BL/6 mice in the different stages of MPTP-induced (30 mg/kg, intraperitonial) parkinsonian syndrome (PS). H was administrated in single dose 20 mg/kg 30 min after single MPTP administration. Study of oligokinesia, rigidity, tremor and
P.1. Basic and clinical neuroscience
Present study was undertaken to evaluate the possible role of the MAOA-VNTR polymorphism in AD either alone, or in genetic interaction with Apolipoprotein (APOE) E4 allele, the most important known genetic risk factor for late-onset AD. The study included 247 AD patients (age = 76.8±7.3 years, 34% male) and 201 healthy control (HC) probands (age = 74.2±6.9 years, 32% male). The diagnosis of probable AD was based on NINCDS-ADRDA criteria. The cognitive performances were assessed according to the Mini Mental State Examination (mean scores±SD: AD: 18.5±5.9; HC: 29.1±0.9). DNA was extracted from peripheral blood leukocytes. The genetic analyses were performed by PCR amplifications. Pearson’s c2 test was used to compare genotype frequencies between the AD and HC groups. A logistic regression model was applied to test for interaction between the investigated polymorphisms. We found five different alleles of the MAOA-VNTR polymorphism in our samples with 2, 3, 3.5, 4 and 5 repeats (2R, 3R, 3.5R, 4R, 5R), however the 2R, 3.5R and the 5R alleles occurred with very low frequency both in the AD and in the HC groups. Comparison of MAOA genotype and allele frequencies between AD and HC groups showed no statistically significant difference (p = 0.835 for genotypes, p = 0.896 for alleles). Since the longer alleles (3.5R, 4R and 5R) result in higher transcriptional activity as compared to the shorter alleles (2R and 3R), we also formed two groups of alleles: long and short. The statistical analyses was also conducted with these genotypic groups, but no difference was found between the AD and HC groups (p = 0.545). As expected from many previous studies the genotypes with the APOE û4 allele occurred with significantly higher frequency in the AD group as compared to the controls (p < 0.0001). The interaction between the MAOA long and APOE E4 alleles did not contribute significantly to the logistic regression model (p = 0.131). Our results do not support the hypothesis that MAOA-VNTR polymorphism is associated with late onset AD, since we found no significant differences between genotype distribution comparing the AD and the HC groups. We also failed to detect a genetic interaction between the MAOA and APOE polymorphisms in the development of AD. This work was supported by grants from Hungarian Scientific Research Fund 60589/2006 and Hungarian Ministry of Health 052−07/2009. P.1.007 Protective effect of the antiparkinsonian drug hemantane in an MPTP model using C57BL/6 mice
study was to assess whether pretreatment with H is able to protect against MPTP toxicity. The experiments were performed in male C57BL/6 mice. H (10 mg/kg) was administered intraperitoneally along with different doses of MPTP using three different schedules. Behavioral changes, tremor and rigidity were monitored daily. Motor activity was assessed by actometer. Schedule 1. 1st group − saline, 2nd − MPTP 30 mg/kg, 3d − H 40 min before MPTP, 4th − H 30 min after MPTP 30 mg/kg. MPTP caused a pronounced decrease in locomotor activity assessed 90 min after the injection. H administered prior to MPTP failed to cause significant reduction in the oligokinesia, rigidity and tremor; however, H administered after MPTP significantly decreased manifestations of parkinsonian syndrome. Schedule 2. 1st group − saline, 2nd − H and MPTP 20 mg/kg − 4 days daily and H without MPTP on day 5, 3d − MPTP 20 mg/kg − 4 days daily. Behavior testing on day 4 revealed that animals in groups 2 and 3 had pronounced oligokinesia, indicating no protective effect of H. On day 5 a less pronounced, but still significant decrease in motor activity was revealed in the MPTP-treated group, but in the 2nd group after H administration the locomotor activity was restored to the level of the saline group. Testing on day 8 revealed significantly lower motor activity in both MPTP-treated groups compared to that of the saline group. Schedule 3. 1st group − saline, 2nd − H for 5 days daily, 3d − H for 5 days daily and MPTP 30 mg/kg single injection on day 5, 40 min after H, 4th − saline 5 days and MPTP on day 5. Measurement of locomotor activity performed on day 5 revealed no stimulatory activity of H in the 2nd group. A significant decrease in motor activity was registered in MPTP-treated animals of group 4. The motor activity in mice of group 3, treated with H subchronically prior to MPTP injection, was significantly higher than that in animals of group 4. In our study in schedules 1 and 2 H was able only to decrease the symptoms of existing parkinsonian syndrome induced by MPTP. In schedule 3 subchronic pretreatment with H decreased the degree of parkinsonian syndrome following acute MPTP administration. The results obtained prove that H is able to protect the brain from neurotoxic effects of MPTP. Further studies are necessary to elucidate the exact molecular mechanism of this action. P.1.009 Effects of the novel antiparkinsonian drug hemantane on brain bioelectric activity in mice with parkinsonian syndrome
A. Nepoklonov1 ° , I. Kapitsa1 , T. Voronina1 , E. Valdman1 . 1 Zakusov Institute of Pharmacology, psychopharmacology, Moscow, Russia
I. Kapitsa1 ° , L.N. Nerobkova1 , K.B. Kurakhmaeva1 , I.I. Kokschenev1 , A.V. Nepoklonov1 , E.A. Valdman1 , T.A. Voronina1 . 1 Zakusov Institute of Pharmacology, psychopharmacology, Moscow, Russia
The novel antiparkinsonian drug hemantane (H) [N-2(adamantyl)hexamethylenimine hydrochloride] has been shown to decrease oligokinesia, rigidity and tremor in animal models with MPTP- and MPP+ -induced parkinsonian syndrome. The antiparkinsonian effect was confirmed in patients with early stages of Parkinson’s disease in a pilot clinical study. The complex mechanism of action − dopamine-positive effects, NMDA antagonism, MAO-B inhibition, antiradical properties− suggests that H is a potential neuroprotector that can slow or even prevent disease progression in subjects who are genetically predisposed and/or are exposed to environmental neurotoxins. The aim of the present
At the present time it is generally recognized that on the early stages of Parkinson disease the treatment should be started with dopamine agonists, amantadine and other medicines with potential neuroprotective effect. New antiparkinsonian drug hemantane (H) with complex mechanism of action has been developed in Zakusov Institute of Pharmacology. The aim of current study was to assess the effect of H on brain bioelectric activity of C57BL/6 mice in the different stages of MPTP-induced (30 mg/kg, intraperitonial) parkinsonian syndrome (PS). H was administrated in single dose 20 mg/kg 30 min after single MPTP administration. Study of oligokinesia, rigidity, tremor and