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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 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 all used models, CS effects lasted beyond the seven-day treatment period and were found to be significant about two weeks following the treatment.

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 spatial learning in the water-maze test in 2VO rats. Path lengths to escape to the hidden platform in water maze were measured during the 2-day training period on days as indicated in the experimental schedule (Figure 7). A: The day 1 of the trial. B: The day 2 of the trial. SH, sham-operated rats (i.p. saline for 7 days); CTR, 2VO rats (i.p. saline for 7 days, control); CH, 2VO rats treated i.p. for 7 days with choline chloride in dose of 10 mg/kg; CS1, CS10, and CS25, 2VO rats treated i.p. for 7 days with CS in doses of 1, 10, or 25 mg/kg respectively. Each group comprised a minimum of eight rats. Columns represent the path lengths means ± SEM. *P < 0.05 vs. CTR. †P < 0.05 vs. SH.
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Figure 9: Effects of CS on spatial learning in the water-maze test in 2VO rats. Path lengths to escape to the hidden platform in water maze were measured during the 2-day training period on days as indicated in the experimental schedule (Figure 7). A: The day 1 of the trial. B: The day 2 of the trial. SH, sham-operated rats (i.p. saline for 7 days); CTR, 2VO rats (i.p. saline for 7 days, control); CH, 2VO rats treated i.p. for 7 days with choline chloride in dose of 10 mg/kg; CS1, CS10, and CS25, 2VO rats treated i.p. for 7 days with CS in doses of 1, 10, or 25 mg/kg respectively. Each group comprised a minimum of eight rats. Columns represent the path lengths means ± SEM. *P < 0.05 vs. CTR. †P < 0.05 vs. SH.

Mentions: Figure 9 shows that path length to escape to the hidden platform in Morris water maze task decreased during the 2-day training period, in all groups of rats. There was, however, a significant difference between control 2VO rats and sham-operated rats on the first day and the second day of training (P < 0.01), indicating impairments in spatial learning induced by chronic cerebral hypoperfusion. CS significantly decreased the path lengths in 2VO rats, as compared to control 2VO rats, on day 1 and, particularly, on day 2 of training, when administered in doses of 1–25 mg/kg (P < 0.01). These data suggest that CS significantly improved spatial learning in rats with chronic cerebral hypoperfusion.


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 spatial learning in the water-maze test in 2VO rats. Path lengths to escape to the hidden platform in water maze were measured during the 2-day training period on days as indicated in the experimental schedule (Figure 7). A: The day 1 of the trial. B: The day 2 of the trial. SH, sham-operated rats (i.p. saline for 7 days); CTR, 2VO rats (i.p. saline for 7 days, control); CH, 2VO rats treated i.p. for 7 days with choline chloride in dose of 10 mg/kg; CS1, CS10, and CS25, 2VO rats treated i.p. for 7 days with CS in doses of 1, 10, or 25 mg/kg respectively. Each group comprised a minimum of eight rats. Columns represent the path lengths means ± SEM. *P < 0.05 vs. CTR. †P < 0.05 vs. SH.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 9: Effects of CS on spatial learning in the water-maze test in 2VO rats. Path lengths to escape to the hidden platform in water maze were measured during the 2-day training period on days as indicated in the experimental schedule (Figure 7). A: The day 1 of the trial. B: The day 2 of the trial. SH, sham-operated rats (i.p. saline for 7 days); CTR, 2VO rats (i.p. saline for 7 days, control); CH, 2VO rats treated i.p. for 7 days with choline chloride in dose of 10 mg/kg; CS1, CS10, and CS25, 2VO rats treated i.p. for 7 days with CS in doses of 1, 10, or 25 mg/kg respectively. Each group comprised a minimum of eight rats. Columns represent the path lengths means ± SEM. *P < 0.05 vs. CTR. †P < 0.05 vs. SH.
Mentions: Figure 9 shows that path length to escape to the hidden platform in Morris water maze task decreased during the 2-day training period, in all groups of rats. There was, however, a significant difference between control 2VO rats and sham-operated rats on the first day and the second day of training (P < 0.01), indicating impairments in spatial learning induced by chronic cerebral hypoperfusion. CS significantly decreased the path lengths in 2VO rats, as compared to control 2VO rats, on day 1 and, particularly, on day 2 of training, when administered in doses of 1–25 mg/kg (P < 0.01). These data suggest that CS significantly improved spatial learning in rats with chronic cerebral hypoperfusion.

Bottom Line: In a primary culture of cerebellar granule neurons, CS significantly enhanced insulin-stimulated insulin receptor autophosphorylation.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 all used models, CS effects lasted beyond the seven-day treatment period and were found to be significant about two weeks following the treatment.

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