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Dimebon slows progression of proteinopathy in γ-synuclein transgenic mice.

Bachurin SO, Shelkovnikova TA, Ustyugov AA, Peters O, Khritankova I, Afanasieva MA, Tarasova TV, Alentov II, Buchman VL, Ninkina NN - Neurotox Res (2011)

Bottom Line: We detected statistically significant improvement of motor performance in a rotarod test in both dimebon-treated animal groups, with more pronounced effect in a group that received dimebon from an earlier age.We also revealed substantially reduced number of amyloid inclusions, decreased amount of insoluble γ-synuclein species and a notable amelioration of astrogliosis in the spinal cord of dimebon-treated compared with control transgenic animals.However, dimebon did not prevent the loss of spinal motor neurons in this model.

View Article: PubMed Central - PubMed

Affiliation: Institute of Physiologically Active Compounds of RAS, 1 Severniy Proezd, Chernogolovka, 142432, Moscow Region, Russian Federation.

ABSTRACT
Intermediates and final products of protein aggregation play crucial role in the development of degenerative changes in a number of neurological diseases. Pathological protein aggregation is currently regarded as one of the most promising therapeutic targets for treatment of these diseases. Transgenic mouse models of proteinopathies are an effective tool for screening and validation of compounds, which can selectively affect metabolism of aggregate-prone proteins. In this study, we assessed effects of dimebon, a compound with known neuroprotective properties, on a recently established transgenic mouse model recapitulating key pathological features of amyotrophic lateral sclerosis (ALS) as the consequence of neuron-specific overexpression of γ-synuclein. Cohorts of experimental transgenic mice received dimebon in drinking water with this chronic treatment starting either before or after the onset of clinical signs of pathology. We detected statistically significant improvement of motor performance in a rotarod test in both dimebon-treated animal groups, with more pronounced effect in a group that received dimebon from an earlier age. We also revealed substantially reduced number of amyloid inclusions, decreased amount of insoluble γ-synuclein species and a notable amelioration of astrogliosis in the spinal cord of dimebon-treated compared with control transgenic animals. However, dimebon did not prevent the loss of spinal motor neurons in this model. Our results demonstrated that chronic dimebon administration is able to slow down but not halt progression of γ-synucleinopathy and resulting signs of pathology in transgenic animals, suggesting potential therapeutic use of this drug for treatment of this currently incurable disease.

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Lifespan and motor performance of control and dimebon-treated γ-synuclein transgenic mice. Thy1mγSN transgenic mice (TG) were tested on accelerating rotarod after 3 and 6 months of drug administration in both dimebon-treated groups, and additionally after 9 months in the group with an early start of treatment. Line graphs show means ± SEM of latency to fall from the rotarod (a). Statistically significant differences between the control group of transgenic animals and each of the treated groups (*P < 0.05, **P < 0.01) as well as between dimebon-treated groups (#P < 0.05) were detected at all time points. b Kaplan–Meier survival analysis of dimebon-treated and control Thy1mγSN transgenic mice demonstrates increased survival in the group that received dimebon from the age of 3 months. In both panels, results for wild-type animals (WT) animals are given for reference
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Fig1: Lifespan and motor performance of control and dimebon-treated γ-synuclein transgenic mice. Thy1mγSN transgenic mice (TG) were tested on accelerating rotarod after 3 and 6 months of drug administration in both dimebon-treated groups, and additionally after 9 months in the group with an early start of treatment. Line graphs show means ± SEM of latency to fall from the rotarod (a). Statistically significant differences between the control group of transgenic animals and each of the treated groups (*P < 0.05, **P < 0.01) as well as between dimebon-treated groups (#P < 0.05) were detected at all time points. b Kaplan–Meier survival analysis of dimebon-treated and control Thy1mγSN transgenic mice demonstrates increased survival in the group that received dimebon from the age of 3 months. In both panels, results for wild-type animals (WT) animals are given for reference

Mentions: Mouse motor function was assessed using accelerating rotarod test before and at several time points after beginning of drug administration. Animals from the first experimental cohort (early drug start) were tested at the age of 4, 6, 9 and 12 months, and animals from the second experimental cohort (late drug start) at the age of 9 and 12 months. Statistically significant improvement of animal performance compared with non-treated controls was achieved in both groups after 3 and 6 months of dimebon treatment, though treated animals never reached the same level of performance as wild-type mice (Fig. 1a). Notably, mice in the group with late start of drug treatment significantly underperformed compared with mice that were treated from the earlier age. Because the beneficial effect of the drug on the motor function was significantly more prominent for the latter group, our subsequent studies were performed mostly with mice from this group.Fig. 1


Dimebon slows progression of proteinopathy in γ-synuclein transgenic mice.

Bachurin SO, Shelkovnikova TA, Ustyugov AA, Peters O, Khritankova I, Afanasieva MA, Tarasova TV, Alentov II, Buchman VL, Ninkina NN - Neurotox Res (2011)

Lifespan and motor performance of control and dimebon-treated γ-synuclein transgenic mice. Thy1mγSN transgenic mice (TG) were tested on accelerating rotarod after 3 and 6 months of drug administration in both dimebon-treated groups, and additionally after 9 months in the group with an early start of treatment. Line graphs show means ± SEM of latency to fall from the rotarod (a). Statistically significant differences between the control group of transgenic animals and each of the treated groups (*P < 0.05, **P < 0.01) as well as between dimebon-treated groups (#P < 0.05) were detected at all time points. b Kaplan–Meier survival analysis of dimebon-treated and control Thy1mγSN transgenic mice demonstrates increased survival in the group that received dimebon from the age of 3 months. In both panels, results for wild-type animals (WT) animals are given for reference
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351599&req=5

Fig1: Lifespan and motor performance of control and dimebon-treated γ-synuclein transgenic mice. Thy1mγSN transgenic mice (TG) were tested on accelerating rotarod after 3 and 6 months of drug administration in both dimebon-treated groups, and additionally after 9 months in the group with an early start of treatment. Line graphs show means ± SEM of latency to fall from the rotarod (a). Statistically significant differences between the control group of transgenic animals and each of the treated groups (*P < 0.05, **P < 0.01) as well as between dimebon-treated groups (#P < 0.05) were detected at all time points. b Kaplan–Meier survival analysis of dimebon-treated and control Thy1mγSN transgenic mice demonstrates increased survival in the group that received dimebon from the age of 3 months. In both panels, results for wild-type animals (WT) animals are given for reference
Mentions: Mouse motor function was assessed using accelerating rotarod test before and at several time points after beginning of drug administration. Animals from the first experimental cohort (early drug start) were tested at the age of 4, 6, 9 and 12 months, and animals from the second experimental cohort (late drug start) at the age of 9 and 12 months. Statistically significant improvement of animal performance compared with non-treated controls was achieved in both groups after 3 and 6 months of dimebon treatment, though treated animals never reached the same level of performance as wild-type mice (Fig. 1a). Notably, mice in the group with late start of drug treatment significantly underperformed compared with mice that were treated from the earlier age. Because the beneficial effect of the drug on the motor function was significantly more prominent for the latter group, our subsequent studies were performed mostly with mice from this group.Fig. 1

Bottom Line: We detected statistically significant improvement of motor performance in a rotarod test in both dimebon-treated animal groups, with more pronounced effect in a group that received dimebon from an earlier age.We also revealed substantially reduced number of amyloid inclusions, decreased amount of insoluble γ-synuclein species and a notable amelioration of astrogliosis in the spinal cord of dimebon-treated compared with control transgenic animals.However, dimebon did not prevent the loss of spinal motor neurons in this model.

View Article: PubMed Central - PubMed

Affiliation: Institute of Physiologically Active Compounds of RAS, 1 Severniy Proezd, Chernogolovka, 142432, Moscow Region, Russian Federation.

ABSTRACT
Intermediates and final products of protein aggregation play crucial role in the development of degenerative changes in a number of neurological diseases. Pathological protein aggregation is currently regarded as one of the most promising therapeutic targets for treatment of these diseases. Transgenic mouse models of proteinopathies are an effective tool for screening and validation of compounds, which can selectively affect metabolism of aggregate-prone proteins. In this study, we assessed effects of dimebon, a compound with known neuroprotective properties, on a recently established transgenic mouse model recapitulating key pathological features of amyotrophic lateral sclerosis (ALS) as the consequence of neuron-specific overexpression of γ-synuclein. Cohorts of experimental transgenic mice received dimebon in drinking water with this chronic treatment starting either before or after the onset of clinical signs of pathology. We detected statistically significant improvement of motor performance in a rotarod test in both dimebon-treated animal groups, with more pronounced effect in a group that received dimebon from an earlier age. We also revealed substantially reduced number of amyloid inclusions, decreased amount of insoluble γ-synuclein species and a notable amelioration of astrogliosis in the spinal cord of dimebon-treated compared with control transgenic animals. However, dimebon did not prevent the loss of spinal motor neurons in this model. Our results demonstrated that chronic dimebon administration is able to slow down but not halt progression of γ-synucleinopathy and resulting signs of pathology in transgenic animals, suggesting potential therapeutic use of this drug for treatment of this currently incurable disease.

Show MeSH
Related in: MedlinePlus