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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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Related in: MedlinePlus

Effects of CS on spatial learning in the water-maze test in middle-aged mice. Path lengths and latencies to escape to the hidden platform in water maze were measured during the 4-day training period on days as indicated in the experimental schedule (Figure 2). A, B: The day 1 of the trial. C, D: The day 2 of the trial. E, F: The day 3 of the trial. G, H: The day 4 of the trial. YNG, young adult mice (i.p. saline for 7 days); MID, middle-aged mice (i.p. saline for 7 days, control); CS1, CS10, and CS25, middle-aged mice 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 mice. Columns represent the path lengths or latencies means ± SEM. *P < 0.05 vs. MID. †P < 0.05 vs. YNG.
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Figure 5: Effects of CS on spatial learning in the water-maze test in middle-aged mice. Path lengths and latencies to escape to the hidden platform in water maze were measured during the 4-day training period on days as indicated in the experimental schedule (Figure 2). A, B: The day 1 of the trial. C, D: The day 2 of the trial. E, F: The day 3 of the trial. G, H: The day 4 of the trial. YNG, young adult mice (i.p. saline for 7 days); MID, middle-aged mice (i.p. saline for 7 days, control); CS1, CS10, and CS25, middle-aged mice 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 mice. Columns represent the path lengths or latencies means ± SEM. *P < 0.05 vs. MID. †P < 0.05 vs. YNG.

Mentions: As shown in Figure 5, both path length and latency to escape to the hidden platform in the Morris water maze decreased progressively (i.e., learning was progressive) during the 4-day training period in all groups of mice. Two-way ANOVA revealed significant day effect in all experimental groups (P < 0.01). There was a significant difference, however, between middle-aged mice and young adult mice on the third day (P < 0.01 for both measures) and the fourth day (P < 0.001 for both measures) of the training, indicating that spatial learning in middle-aged mice was slower, as compared to young adult mice. Two-way ANOVA revealed significant group effect across days (F1,16 = 26.9, P < 0.01) and group × day interaction (F1,3,70 = 7.51, P < 0.05), when groups of young adult and middle-aged mice were compared. CS significantly decreased the escape latencies in middle-aged mice, as compared to age-matched controls, at the fourth day of the training, when administered in doses of 1–25 mg/kg (P < 0.05). Two-way ANOVA revealed significant effect for CS doses of 1 mg/kg (F1,14 = 8.47, P < 0.05) and 25 mg/kg (F1,15 = 7.26, P < 0.05) across days and significant both group effect (F1,14 = 10.48, P < 0.05) and group × day interaction (F1,1,62 = 6.79, P < 0.05) for dose of 10 mg/kg. CS significantly decreased the path lengths in middle-aged mice, as compared to age-matched controls, on the day 4 of training, when administered in doses of 1–25 mg/kg (P < 0.05). Two-way ANOVA revealed significant group effects for CS doses of 1 mg/kg (F1,14 = 8.01, P < 0.05) and 25 (F1,15 = 6.95 P < 0.05) across days and significant both group effect (F1,14 = 9.84, P < 0.05) and group × day interaction (F1,1,62 = 7.01, P < 0.05) for CS dose of 10 mg/kg. These data suggest that CS significantly improved spatial learning in middle-aged mice, as compared to the age-matched controls.


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 middle-aged mice. Path lengths and latencies to escape to the hidden platform in water maze were measured during the 4-day training period on days as indicated in the experimental schedule (Figure 2). A, B: The day 1 of the trial. C, D: The day 2 of the trial. E, F: The day 3 of the trial. G, H: The day 4 of the trial. YNG, young adult mice (i.p. saline for 7 days); MID, middle-aged mice (i.p. saline for 7 days, control); CS1, CS10, and CS25, middle-aged mice 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 mice. Columns represent the path lengths or latencies means ± SEM. *P < 0.05 vs. MID. †P < 0.05 vs. YNG.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Effects of CS on spatial learning in the water-maze test in middle-aged mice. Path lengths and latencies to escape to the hidden platform in water maze were measured during the 4-day training period on days as indicated in the experimental schedule (Figure 2). A, B: The day 1 of the trial. C, D: The day 2 of the trial. E, F: The day 3 of the trial. G, H: The day 4 of the trial. YNG, young adult mice (i.p. saline for 7 days); MID, middle-aged mice (i.p. saline for 7 days, control); CS1, CS10, and CS25, middle-aged mice 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 mice. Columns represent the path lengths or latencies means ± SEM. *P < 0.05 vs. MID. †P < 0.05 vs. YNG.
Mentions: As shown in Figure 5, both path length and latency to escape to the hidden platform in the Morris water maze decreased progressively (i.e., learning was progressive) during the 4-day training period in all groups of mice. Two-way ANOVA revealed significant day effect in all experimental groups (P < 0.01). There was a significant difference, however, between middle-aged mice and young adult mice on the third day (P < 0.01 for both measures) and the fourth day (P < 0.001 for both measures) of the training, indicating that spatial learning in middle-aged mice was slower, as compared to young adult mice. Two-way ANOVA revealed significant group effect across days (F1,16 = 26.9, P < 0.01) and group × day interaction (F1,3,70 = 7.51, P < 0.05), when groups of young adult and middle-aged mice were compared. CS significantly decreased the escape latencies in middle-aged mice, as compared to age-matched controls, at the fourth day of the training, when administered in doses of 1–25 mg/kg (P < 0.05). Two-way ANOVA revealed significant effect for CS doses of 1 mg/kg (F1,14 = 8.47, P < 0.05) and 25 mg/kg (F1,15 = 7.26, P < 0.05) across days and significant both group effect (F1,14 = 10.48, P < 0.05) and group × day interaction (F1,1,62 = 6.79, P < 0.05) for dose of 10 mg/kg. CS significantly decreased the path lengths in middle-aged mice, as compared to age-matched controls, on the day 4 of training, when administered in doses of 1–25 mg/kg (P < 0.05). Two-way ANOVA revealed significant group effects for CS doses of 1 mg/kg (F1,14 = 8.01, P < 0.05) and 25 (F1,15 = 6.95 P < 0.05) across days and significant both group effect (F1,14 = 9.84, P < 0.05) and group × day interaction (F1,1,62 = 7.01, P < 0.05) for CS dose of 10 mg/kg. These data suggest that CS significantly improved spatial learning in middle-aged mice, as compared to the age-matched controls.

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