title: Dimebon slows progression of proteinopathy in γ-synuclein transgenic mice.
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.
authors.affiliation: Institute of Physiologically Active Compounds of RAS, 1 Severniy Proezd, Chernogolovka, 142432, Moscow Region, Russian Federation.
authors.forename: Sergey O
authors.initials: SO
authors.lastname: Bachurin
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Shelkovnikova
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Ustyugov
authors.forename: Owen
authors.initials: O
authors.lastname: Peters
authors.forename: Ina
authors.initials: I
authors.lastname: Khritankova
authors.forename: Marina A
authors.initials: MA
authors.lastname: Afanasieva
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Tarasova
authors.forename: Igor I
authors.initials: II
authors.lastname: Alentov
authors.forename: Vladimir L
authors.initials: VL
authors.lastname: Buchman
authors.forename: Natalia N
authors.initials: NN
authors.lastname: Ninkina
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D045442:Rotarod Performance Test; D013116:Spinal Cord / Q000187:drug effects*; D051845:gamma-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D007211:Indoles; D018696:Neuroprotective Agents; D051845:gamma-Synuclein; C010119:latrepirdine