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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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Dimebon treatment reduces the number of amyloid inclusions in the spinal cord of γ-synuclein transgenic mice. Representative images of histological sections through the spinal cord of 12-month-old control Thy1mγSN mice (a) and Thy1mγSN mice treated with dimebon from the age of 3 months (b) stained for amyloid deposits using Congo Red. Scale bar = 100 μm. The bar chart (c) shows means ± SEM of the number of inclusions in the anterior horn of the spinal cord. Statistically significant difference between the control and each experimental group (*P < 0.05, Mann–Whitney U-test) as well as total number of sections analysed per three animals for each group are shown
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Fig2: Dimebon treatment reduces the number of amyloid inclusions in the spinal cord of γ-synuclein transgenic mice. Representative images of histological sections through the spinal cord of 12-month-old control Thy1mγSN mice (a) and Thy1mγSN mice treated with dimebon from the age of 3 months (b) stained for amyloid deposits using Congo Red. Scale bar = 100 μm. The bar chart (c) shows means ± SEM of the number of inclusions in the anterior horn of the spinal cord. Statistically significant difference between the control and each experimental group (*P < 0.05, Mann–Whitney U-test) as well as total number of sections analysed per three animals for each group are shown

Mentions: Presence of proteinaceous inclusions in the nervous tissue is a hallmark of advanced stage pathology in proteinopathies (Skovronsky et al. 2006). There is no general consensus about the role and hazardous potential for these structures. Widely accepted current view is that they are non-toxic and even protective in contrast to toxic soluble oligomers (Bucciantini et al. 2002; Lashuel et al. 2002; Caughey and Lansbury 2003), whereas there is clear evidence of correlation between inclusion load and disease stage (Thal et al. 2002). In Thy1mγSN transgenic mice, multiple amyloid inclusions of various size can be detected throughout the nervous system, and the number of inclusions in the spinal cord directly correlates with the severity of motor impairment (Ninkina et al. 2009). We assessed the number of pathological inclusions, revealed by Congo Red staining, which selectively detect amyloid structures, in the anterior horn area of the spinal cord sections from dimebon-treated and control transgenic animals. Significantly lesser number of inclusions was detected in treated animals (Fig. 2). Although the difference between two dimebon-treated groups was not statistically significant, the trend of more pronounced decrease in inclusion numbers in the group with early introduction to the drug was obvious (41.2 vs. 27.5% decrease), which is consistent with the results of rotarod performance of these animals.Fig. 2


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)

Dimebon treatment reduces the number of amyloid inclusions in the spinal cord of γ-synuclein transgenic mice. Representative images of histological sections through the spinal cord of 12-month-old control Thy1mγSN mice (a) and Thy1mγSN mice treated with dimebon from the age of 3 months (b) stained for amyloid deposits using Congo Red. Scale bar = 100 μm. The bar chart (c) shows means ± SEM of the number of inclusions in the anterior horn of the spinal cord. Statistically significant difference between the control and each experimental group (*P < 0.05, Mann–Whitney U-test) as well as total number of sections analysed per three animals for each group are shown
© Copyright Policy
Related In: Results  -  Collection

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

Fig2: Dimebon treatment reduces the number of amyloid inclusions in the spinal cord of γ-synuclein transgenic mice. Representative images of histological sections through the spinal cord of 12-month-old control Thy1mγSN mice (a) and Thy1mγSN mice treated with dimebon from the age of 3 months (b) stained for amyloid deposits using Congo Red. Scale bar = 100 μm. The bar chart (c) shows means ± SEM of the number of inclusions in the anterior horn of the spinal cord. Statistically significant difference between the control and each experimental group (*P < 0.05, Mann–Whitney U-test) as well as total number of sections analysed per three animals for each group are shown
Mentions: Presence of proteinaceous inclusions in the nervous tissue is a hallmark of advanced stage pathology in proteinopathies (Skovronsky et al. 2006). There is no general consensus about the role and hazardous potential for these structures. Widely accepted current view is that they are non-toxic and even protective in contrast to toxic soluble oligomers (Bucciantini et al. 2002; Lashuel et al. 2002; Caughey and Lansbury 2003), whereas there is clear evidence of correlation between inclusion load and disease stage (Thal et al. 2002). In Thy1mγSN transgenic mice, multiple amyloid inclusions of various size can be detected throughout the nervous system, and the number of inclusions in the spinal cord directly correlates with the severity of motor impairment (Ninkina et al. 2009). We assessed the number of pathological inclusions, revealed by Congo Red staining, which selectively detect amyloid structures, in the anterior horn area of the spinal cord sections from dimebon-treated and control transgenic animals. Significantly lesser number of inclusions was detected in treated animals (Fig. 2). Although the difference between two dimebon-treated groups was not statistically significant, the trend of more pronounced decrease in inclusion numbers in the group with early introduction to the drug was obvious (41.2 vs. 27.5% decrease), which is consistent with the results of rotarod performance of these animals.Fig. 2

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