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

• Published in: BMC pharmacology Vol. 8; no. 1; p. 1
• Main Authors: Storozheva, Zinaida I, Proshin, Andrey T, Sherstnev, Vladimir V, Storozhevykh, Tatiana P, Senilova, Yana E, Persiyantseva, Nadezhda A, Pinelis, Vsevolod G, Semenova, Natalia A, Zakharova, Elena I, Pomytkin, Igor A
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 23.01.2008; BioMed Central
• Subjects: Aging - psychology; Amnesia - chemically induced; Amnesia - prevention & control; Amyloid beta-Peptides - pharmacology; Animals; Care and treatment; Cerebrovascular Circulation - drug effects; Choline - analogs & derivatives; Choline - pharmacology; Cognition disorders; Cognition Disorders - prevention & control; Dosage and administration; Insulin - pharmacology; Mice; Mice, Inbred C57BL; Models, Animal; Neurons - drug effects; Neurons - metabolism; Peptide Fragments - pharmacology; Phosphorylation; Physiological aspects; Pipecolic Acids - pharmacology; Receptor, Insulin - metabolism; Risk factors; Succinic acid; Succinic Acid - pharmacology; Russia
• ISSN: 1471-2210; 1471-2210
• DOI: 10.1186/1471-2210-8-1

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. 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. 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.