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

BMC Pharmacol. 2008 Jan 23;8:1. doi: 10.1186/1471-2210-8-1.

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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / psychology*
  • Amnesia / chemically induced
  • Amnesia / prevention & control*
  • Amyloid beta-Peptides / pharmacology*
  • Animals
  • Cerebrovascular Circulation / drug effects*
  • Choline / analogs & derivatives*
  • Choline / pharmacology
  • Cognition Disorders / prevention & control*
  • Insulin / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Peptide Fragments / pharmacology*
  • Phosphorylation
  • Pipecolic Acids / pharmacology*
  • Receptor, Insulin / metabolism
  • Succinic Acid / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Insulin
  • Peptide Fragments
  • Pipecolic Acids
  • amyloid beta-protein (25-35)
  • dicolin
  • Succinic Acid
  • Receptor, Insulin
  • Choline