The neuronal insulin sensitizer dicholine succinate reduces stress-induced depressive traits and memory deficit: possible role of insulin-like growth factor 2

Abstract

Background: A number of epidemiological studies have established a link between insulin resistance and the prevalence of depression. The occurrence of depression was found to precede the onset of diabetes and was hypothesized to be associated with inherited inter-related insufficiency of the peripheral and central insulin receptors. Recently, dicholine succinate, a sensitizer of the neuronal insulin receptor, was shown to stimulate insulin-dependent H2O2 production of the mitochondrial respiratory chain leading to an enhancement of insulin receptor autophosphorylation in neurons. As such, this mechanism can be a novel target for the elevation of insulin signaling.

Results: Administration of DS (25 mg/kg/day, intraperitoneal) in CD1 mice for 7 days prior to the onset of stress procedure, diminished manifestations of anhedonia defined in a sucrose test and behavioral despair in the forced swim test. Treatment with dicholine succinate reduced the anxiety scores of stressed mice in the dark/light box paradigm, precluded stress-induced decreases of long-term contextual memory in the step-down avoidance test and hippocampal gene expression of IGF2.

Conclusions: Our data suggest that dicholine succinate has an antidepressant-like effect, which might be mediated via the up-regulation of hippocampal expression of IGF2, and implicate the neuronal insulin receptor in the pathogenesis of stress-induced depressive syndrome.

Figure 1

Insulin receptor subfamily of receptor tyrosine kinase family. (Only functionally important areas of interaction shown). (A) The neuronal insulin receptor (INSR), insulin-like growth factor 1 receptor (IGF1R), insulin receptor-related protein (INSRR), and receptors to neurotrophins NGF (NTRK1), BDNF and NT-4 (NTRK2), and NT-3 (NTRK3) belong to an insulin receptor subfamily of receptor tyrosine kinases whose members are well documented to regulate cell survival and differentiation and play a role in synaptic plasticity. (B) Analysis with the UniProt/KB Swiss-Prot data bank reveals high structural homology between the catalytic site sequences of the insulin receptor, insulin-like growth factor 1 receptor, and NTRK2 (TrkB) receptor. (C) Structure comparison with the UniProt/KB Swiss-Prot data bank suggests high structural homology of the activation loop sequences of the insulin receptor, insulin-like growth factor 1 receptor, NTRK1, NTRK2 (TrkB), and NTRK3 receptors.

Figure 2

Timeline of study. Application of stress, drugs and behavioral testing in the chronic stress study.

Figure 3

Imipramine and dicholine succinate counteract stress-induced decrease in sucrose preference and sucrose intake. (A) Groups of mice assigned for planned treatment had similar means of sucrose preference before the beginning of dosing. (B) Two-way ANOVA revealed a significant effect for the stress condition in sucrose preference F = 11.9, DFn = 1, DFd = 12, p =0.0058 ^* vs respected control. (C) NoT stress mice showed a significant reduction for sucrose preference at days 7 and 10 in relation to the stress condition F = 12.75, DFn = 1, DFd = 87, p =0.0006, Bonferroni day 7, p < 0.05 ^* respected control; day 10, p < 0.01 ^** vs control. (D,E) Imi and DS stress mice did not show significant differences neither at day 7 nor day 10 for the stress condition F = 1.686, DFn = 1, DFd = 89, p = 0.1975 and F = 2.252, DFn = 1, DFd = 90, p = 0.1369 respectively. (F) Following chronic stress, the total sucrose intake was measured and two-way ANOVA revealed an overall condition effect while Bonferroni showed a significant reduction in sucrose intake only in the NoT stress group F = 5.352, DFn = 1, DFd = 88, p = 0.0230, Bonferroni: NoT p < 0.05, DS, Imi p > 0.05 ^* vs respected control. NoT: non-treated group; Imi: imipramine-treated group, DS: DS-treated group. Data is shown as mean ± SEM.

Figure 4

Dicholine succinate reduces stress-induced floating and anxiety-like behaviors, but not a decrease of body weight. (A) Latency of floating had an overall significant difference for treatment while the duration of floating had an overall significant difference for the stress condition F = 4.652, DFn = 2, DFd = 89, p = 0.0120 and F = 5.333, DFn = 1, DFd = 89, p = 0.0232 respectively two-way ANOVA; * vs non-treated, # vs respected controls. (B) ANOVA revealed a significant difference for time spent in the lit compartment with Tukey showing only a difference between the Not and DS treated stress groups F = 4.469, DFn = 3, DFd = 39, p = 0.0086, Tukey p < 0.01 ;*vs respected control. No significant difference in latency of exit was observed. (C) Two-way ANOVA revealed a significant difference in body weight for the stress condition in all groups F = 66.81, DFn = 1, DFd = 89, p < 0.0001. ^* vs respected controls NoT: non-treated group; Imi: imipramine-treated group, DS: DS-treated group. All data is shown as mean ± SEM.

Figure 5

Effect of imipramine and dicholine succinate on step-down avoidance learning and hippocampal expression of IGF2. (A) All groups showed a significant increase in the latency to step down as compared to their respective baselines one-way ANOVA F = 23.27, DFn = 7, DFd = 192, p < 0.0001 *** vs baseline while the NoT group was significantly lower for the recall test compared to control indicating a disruption in contextual learning # vs control. (B) There was an overall significant difference seen in the hippocampal gene expression for IGF2, while Tukey's post-test revealed differences for IGF2 gene expression between DS and Imi treated groups and DS and NoT treated groups p < 0.01, F = 6.232, DFn = 3, DFd = 33, p = 0.0018. # vs NoT & vs Imi; NoT: non-treated group; Imi: imipramine-treated group, DS: DS-treated group. All data is shown as mean ± SEM.