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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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The loss of spinal motor neurons in γ-synuclein transgenic mice is not affected by dimebon treatment. a Representative images of Nissle-stained histological sections through the spinal cord of 12-month-old control wild-type (WT), Thy1mγSN mice (TG) and Thy1mγSN mice treated with dimebon from the age of 3 months (TG + DIM). Scale bar = 30 μm. bThe bar chart shows means ± SEM of the number of motor neurons in the anterior horn of the spinal cord of 12-month-old control wild-type (WT), Thy1mγSN transgenic mice (TG) and Thy1mγSN mice treated with dimebon from the age of 3 months (three to four animals per group). Thy1mγSN mice have significantly less motor neurons than wild-type mice (**P < 0.01, Mann–Whitney U-test) but no significant difference between two groups of transgenic mice was found
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Fig5: The loss of spinal motor neurons in γ-synuclein transgenic mice is not affected by dimebon treatment. a Representative images of Nissle-stained histological sections through the spinal cord of 12-month-old control wild-type (WT), Thy1mγSN mice (TG) and Thy1mγSN mice treated with dimebon from the age of 3 months (TG + DIM). Scale bar = 30 μm. bThe bar chart shows means ± SEM of the number of motor neurons in the anterior horn of the spinal cord of 12-month-old control wild-type (WT), Thy1mγSN transgenic mice (TG) and Thy1mγSN mice treated with dimebon from the age of 3 months (three to four animals per group). Thy1mγSN mice have significantly less motor neurons than wild-type mice (**P < 0.01, Mann–Whitney U-test) but no significant difference between two groups of transgenic mice was found

Mentions: Another pathological feature typical to Thy1mγSN mice is age-dependent loss of motor neurons in the spinal cord (Ninkina et al. 2009). It was feasible to suggest that physiological, behavioural and morphological improvements observed in dimebon-treated groups of transgenic mice might be because of the survival-promoting effect of this drug on spinal motor neurons. To assess this, we stereologically counted motor neurons in the anterior horns of the thorasic spinal cord of the same animal cohorts that were used for histological studies described above. Consistent with previously published data, significant (~50%) reduction in the number of motor neurons was revealed in Thy1mγSN compared with age-matching wild-type mice. However, no difference in the number of motor neurons was observed between dimebon-treated and control transgenic animals (Fig. 5).Fig. 5


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)

The loss of spinal motor neurons in γ-synuclein transgenic mice is not affected by dimebon treatment. a Representative images of Nissle-stained histological sections through the spinal cord of 12-month-old control wild-type (WT), Thy1mγSN mice (TG) and Thy1mγSN mice treated with dimebon from the age of 3 months (TG + DIM). Scale bar = 30 μm. bThe bar chart shows means ± SEM of the number of motor neurons in the anterior horn of the spinal cord of 12-month-old control wild-type (WT), Thy1mγSN transgenic mice (TG) and Thy1mγSN mice treated with dimebon from the age of 3 months (three to four animals per group). Thy1mγSN mice have significantly less motor neurons than wild-type mice (**P < 0.01, Mann–Whitney U-test) but no significant difference between two groups of transgenic mice was found
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3351599&req=5

Fig5: The loss of spinal motor neurons in γ-synuclein transgenic mice is not affected by dimebon treatment. a Representative images of Nissle-stained histological sections through the spinal cord of 12-month-old control wild-type (WT), Thy1mγSN mice (TG) and Thy1mγSN mice treated with dimebon from the age of 3 months (TG + DIM). Scale bar = 30 μm. bThe bar chart shows means ± SEM of the number of motor neurons in the anterior horn of the spinal cord of 12-month-old control wild-type (WT), Thy1mγSN transgenic mice (TG) and Thy1mγSN mice treated with dimebon from the age of 3 months (three to four animals per group). Thy1mγSN mice have significantly less motor neurons than wild-type mice (**P < 0.01, Mann–Whitney U-test) but no significant difference between two groups of transgenic mice was found
Mentions: Another pathological feature typical to Thy1mγSN mice is age-dependent loss of motor neurons in the spinal cord (Ninkina et al. 2009). It was feasible to suggest that physiological, behavioural and morphological improvements observed in dimebon-treated groups of transgenic mice might be because of the survival-promoting effect of this drug on spinal motor neurons. To assess this, we stereologically counted motor neurons in the anterior horns of the thorasic spinal cord of the same animal cohorts that were used for histological studies described above. Consistent with previously published data, significant (~50%) reduction in the number of motor neurons was revealed in Thy1mγSN compared with age-matching wild-type mice. However, no difference in the number of motor neurons was observed between dimebon-treated and control transgenic animals (Fig. 5).Fig. 5

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