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

Zinaida I Storozheva¹ , Andrey T Proshin¹ , Vladimir V Sherstnev¹ , Tatiana P Storozhevykh² , Yana E Senilova² , Nadezhda A Persiyantseva² , Vsevolod G Pinelis² , Natalia A Semenova³ , Elena I Zakharova⁴ and Igor A Pomytkin⁵

¹P.K. Anokhin Institute of Normal Physiology, RAMS, Mohovaya 11-4, 125009, Moscow, Russia

²Scientific Centre for Children's Health, RAMS, Lomonosovsky prospect 2/62, 119991, Moscow, Russia

³Semenov Institute of Chemical Physics, RAS, Kosygina 4, 119991, Moscow, Russia

⁴Institute of General Pathology and Pathophysiology, RAMS, Baltijskaya 8, 125315, Moscow, Russia

⁵Biosignal Ltd., M. Gruzinskaya 29-153, 123557, Moscow, Russia

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BMC Pharmacology 2008, 8:1doi:10.1186/1471-2210-8-1


Published:	23 January 2008

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 H₂O₂production, 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.

Conclusion

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.