title: Dicholine salt of succinic acid, a neuronal insulin sensitizer, ameliorates cognitive deficits in rodent models of normal aging, chronic cerebral hypoperfusion, and beta-amyloid peptide-(25-35)-induced amnesia.
abstract: BACKGROUND
  Accumulated evidence suggests that insulin resistance and impairments in cerebral insulin receptor signaling may contribute to age-related cognitive deficits and Alzheimer's disease. The enhancement of insulin receptor signaling is, therefore, a promising strategy for the treatment of age-related cognitive disorders. The mitochondrial respiratory chain, being involved in insulin-stimulated H2O2 production, has been identified recently as a potential target for the enhancement of insulin signaling. The aim of the present study is to examine: (1) whether a specific respiratory substrate, dicholine salt of succinic acid (CS), can enhance insulin-stimulated insulin receptor autophosphorylation in neurons, and (2) whether CS can ameliorate cognitive deficits of various origins in animal models.
  
  
  RESULTS
  In a primary culture of cerebellar granule neurons, CS significantly enhanced insulin-stimulated insulin receptor autophosphorylation. In animal models, CS significantly ameliorated cognitive deficits, when administered intraperitoneally for 7 days. In 16-month-old middle-aged C57Bl/6 mice (a model of normal aging), CS enhanced spatial learning in the Morris water maze, spontaneous locomotor activity, passive avoidance performance, and increased brain N-acetylaspartate/creatine levels, as compared to the age-matched control (saline). In rats with chronic cerebral hypoperfusion, CS enhanced spatial learning, passive avoidance performance, and increased brain N-acetylaspartate/creatine levels, as compared to control rats (saline). In rats with beta-amyloid peptide-(25-35)-induced amnesia, CS enhanced passive avoidance performance and increased activity of brain choline acetyltransferase, as compared to control rats (saline). In all used models, CS effects lasted beyond the seven-day treatment period and were found to be significant about two weeks following the treatment.
  
  
  CONCLUSIONS
  The results of the present study suggest that dicholine salt of succinic acid, a novel neuronal insulin sensitizer, ameliorates cognitive deficits and neuronal dysfunctions in animal models relevant to age-related cognitive impairments, vascular dementia, and Alzheimer's disease.
authors.affiliation: P.K. Anokhin Institute of Normal Physiology, RAMS, Mohovaya 11-4, 125009, Moscow, Russia. storozheva_zi@mail.ru
authors.forename: Zinaida I
authors.initials: ZI
authors.lastname: Storozheva
authors.forename: Andrey T
authors.initials: AT
authors.lastname: Proshin
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Sherstnev
authors.forename: Tatiana P
authors.initials: TP
authors.lastname: Storozhevykh
authors.forename: Yana E
authors.initials: YE
authors.lastname: Senilova
authors.forename: Nadezhda A
authors.initials: NA
authors.lastname: Persiyantseva
authors.forename: Vsevolod G
authors.initials: VG
authors.lastname: Pinelis
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Semenova
authors.forename: Elena I
authors.initials: EI
authors.lastname: Zakharova
authors.forename: Igor A
authors.initials: IA
authors.lastname: Pomytkin
mesh_terms: D000375:Aging / Q000523:psychology*; D000647:Amnesia / Q000139:chemically induced / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002794:Choline / Q000031:analogs & derivatives* / Q000494:pharmacology; D003072:Cognition Disorders / Q000517:prevention & control*; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D010875:Pipecolic Acids / Q000494:pharmacology*; D011972:Receptor, Insulin / Q000378:metabolism; D019802:Succinic Acid / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D007328:Insulin; D010446:Peptide Fragments; D010875:Pipecolic Acids; C074636:amyloid beta-protein (25-35); C016374:dicolin; D019802:Succinic Acid; D011972:Receptor, Insulin; D002794:Choline