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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 ameliorates astrocytosis 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 (left panel) and Thy1mγSN mice treated with dimebon from the age of 3 months (right panel) immunostained for reactive astroglia marker GFAP. Scale bar = 50 μm
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Fig4: Dimebon treatment ameliorates astrocytosis 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 (left panel) and Thy1mγSN mice treated with dimebon from the age of 3 months (right panel) immunostained for reactive astroglia marker GFAP. Scale bar = 50 μm

Mentions: Chronic neuroinflammation characterized by appearance of activated microglial and astroglial cells in affected regions of the nervous system plays one of the central roles in the progression of neurodegeneration (Glass et al. 2010). Although dimebon has been originally developed as an antihistamine, and therefore might ameliorate inflammatory response in the degenerating neural tissues, this effect of the drug has not been assessed so far. In Thy1mγSN mice, the development of motor pathology is accompanied by progressing neuroinflamation characterized by a marked activation of astroglial cells in the spinal cord (Ninkina et al. 2009). We compared the severity of reactive astrogliosis in the spinal cord of dimebon-treated and control transgenic mice. Considerable reduction in the number of activated astrocytes revealed by immunostaining with antibody against GFAP was observed in animals that received the drug for 9 months (Fig. 4). Thus, reducing inflammatory response may contribute to neuroprotective action of dimebon.Fig. 4


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 ameliorates astrocytosis 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 (left panel) and Thy1mγSN mice treated with dimebon from the age of 3 months (right panel) immunostained for reactive astroglia marker GFAP. Scale bar = 50 μm
© Copyright Policy
Related In: Results  -  Collection

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

Fig4: Dimebon treatment ameliorates astrocytosis 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 (left panel) and Thy1mγSN mice treated with dimebon from the age of 3 months (right panel) immunostained for reactive astroglia marker GFAP. Scale bar = 50 μm
Mentions: Chronic neuroinflammation characterized by appearance of activated microglial and astroglial cells in affected regions of the nervous system plays one of the central roles in the progression of neurodegeneration (Glass et al. 2010). Although dimebon has been originally developed as an antihistamine, and therefore might ameliorate inflammatory response in the degenerating neural tissues, this effect of the drug has not been assessed so far. In Thy1mγSN mice, the development of motor pathology is accompanied by progressing neuroinflamation characterized by a marked activation of astroglial cells in the spinal cord (Ninkina et al. 2009). We compared the severity of reactive astrogliosis in the spinal cord of dimebon-treated and control transgenic mice. Considerable reduction in the number of activated astrocytes revealed by immunostaining with antibody against GFAP was observed in animals that received the drug for 9 months (Fig. 4). Thus, reducing inflammatory response may contribute to neuroprotective action of dimebon.Fig. 4

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