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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.

Storozheva ZI, Proshin AT, Sherstnev VV, Storozhevykh TP, Senilova YE, Persiyantseva NA, Pinelis VG, Semenova NA, Zakharova EI, Pomytkin IA - BMC Pharmacol. (2008)

Bottom Line: In a primary culture of cerebellar granule neurons, CS significantly enhanced insulin-stimulated insulin receptor autophosphorylation.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: P.K. Anokhin Institute of Normal Physiology, RAMS, Mohovaya 11-4, 125009, Moscow, Russia. storozheva_zi@mail.ru

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.

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Effects of CS on the autophosphorylation of insulin receptor in cerebellar granule neurons. CGN cultures were stimulated with insulin, CS, or combinations of insulin and CS at indicated concentrations for 20 min. Autophosphorylation of insulin receptor was measured as described in Materials and Methods. In each experiment, amount of phosphorylated insulin receptor β-subunit (pYpY-IR) was normalized to total amount of insulin receptor β-subunit and expressed as a percentage of the response produced to 100 nmol/L insulin. Columns represent the means ± SEM of pYpY-IR values obtained from five to nine separate experiments, each performed in duplicate. *P < 0.05 vs. control. †P < 0.05 vs. insulin 100 nmol/L, #P < 0.05 vs. insulin 5 nmol/L.
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Figure 1: Effects of CS on the autophosphorylation of insulin receptor in cerebellar granule neurons. CGN cultures were stimulated with insulin, CS, or combinations of insulin and CS at indicated concentrations for 20 min. Autophosphorylation of insulin receptor was measured as described in Materials and Methods. In each experiment, amount of phosphorylated insulin receptor β-subunit (pYpY-IR) was normalized to total amount of insulin receptor β-subunit and expressed as a percentage of the response produced to 100 nmol/L insulin. Columns represent the means ± SEM of pYpY-IR values obtained from five to nine separate experiments, each performed in duplicate. *P < 0.05 vs. control. †P < 0.05 vs. insulin 100 nmol/L, #P < 0.05 vs. insulin 5 nmol/L.

Mentions: To examine whether CS enhances the insulin-stimulated autophosphorylation of insulin receptor in neurons, we studied an effect of CS on insulin-stimulated insulin receptor autophosphorylation in a primary culture of rat cerebellar granule neurons (CGN). Figure 1 shows that, whereas by itself, 50 μmol/L of CS does not stimulate insulin receptor autophosphorylation significantly (P = 0.065 vs. control), this concentration of CS significantly enhances the effect of suboptimal concentration of 5 nmol/L insulin (P < 0.001 vs. 5 nmol/L insulin). CS significantly enhances insulin-stimulated insulin receptor autophosphorylation in the range of concentrations from 10 to 100 μmol/L (P < 0.05 vs. 5 nmol/L insulin), although no significant difference is observed between the effects of different concentrations of CS. These results suggest that CS is a neuronal insulin sensitizer, which works in concert with insulin to stimulate insulin receptor autophosphorylation in neurons.


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.

Storozheva ZI, Proshin AT, Sherstnev VV, Storozhevykh TP, Senilova YE, Persiyantseva NA, Pinelis VG, Semenova NA, Zakharova EI, Pomytkin IA - BMC Pharmacol. (2008)

Effects of CS on the autophosphorylation of insulin receptor in cerebellar granule neurons. CGN cultures were stimulated with insulin, CS, or combinations of insulin and CS at indicated concentrations for 20 min. Autophosphorylation of insulin receptor was measured as described in Materials and Methods. In each experiment, amount of phosphorylated insulin receptor β-subunit (pYpY-IR) was normalized to total amount of insulin receptor β-subunit and expressed as a percentage of the response produced to 100 nmol/L insulin. Columns represent the means ± SEM of pYpY-IR values obtained from five to nine separate experiments, each performed in duplicate. *P < 0.05 vs. control. †P < 0.05 vs. insulin 100 nmol/L, #P < 0.05 vs. insulin 5 nmol/L.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2262060&req=5

Figure 1: Effects of CS on the autophosphorylation of insulin receptor in cerebellar granule neurons. CGN cultures were stimulated with insulin, CS, or combinations of insulin and CS at indicated concentrations for 20 min. Autophosphorylation of insulin receptor was measured as described in Materials and Methods. In each experiment, amount of phosphorylated insulin receptor β-subunit (pYpY-IR) was normalized to total amount of insulin receptor β-subunit and expressed as a percentage of the response produced to 100 nmol/L insulin. Columns represent the means ± SEM of pYpY-IR values obtained from five to nine separate experiments, each performed in duplicate. *P < 0.05 vs. control. †P < 0.05 vs. insulin 100 nmol/L, #P < 0.05 vs. insulin 5 nmol/L.
Mentions: To examine whether CS enhances the insulin-stimulated autophosphorylation of insulin receptor in neurons, we studied an effect of CS on insulin-stimulated insulin receptor autophosphorylation in a primary culture of rat cerebellar granule neurons (CGN). Figure 1 shows that, whereas by itself, 50 μmol/L of CS does not stimulate insulin receptor autophosphorylation significantly (P = 0.065 vs. control), this concentration of CS significantly enhances the effect of suboptimal concentration of 5 nmol/L insulin (P < 0.001 vs. 5 nmol/L insulin). CS significantly enhances insulin-stimulated insulin receptor autophosphorylation in the range of concentrations from 10 to 100 μmol/L (P < 0.05 vs. 5 nmol/L insulin), although no significant difference is observed between the effects of different concentrations of CS. These results suggest that CS is a neuronal insulin sensitizer, which works in concert with insulin to stimulate insulin receptor autophosphorylation in neurons.

Bottom Line: In a primary culture of cerebellar granule neurons, CS significantly enhanced insulin-stimulated insulin receptor autophosphorylation.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: P.K. Anokhin Institute of Normal Physiology, RAMS, Mohovaya 11-4, 125009, Moscow, Russia. storozheva_zi@mail.ru

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.

Show MeSH
Related in: MedlinePlus