Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression

Abstract

Central insulin receptor-mediated signaling is attracting the growing attention of researchers because of rapidly accumulating evidence implicating it in the mechanisms of plasticity, stress response, and neuropsychiatric disorders including depression. Dicholine succinate (DS), a mitochondrial complex II substrate, was shown to enhance insulin-receptor mediated signaling in neurons and is regarded as a sensitizer of the neuronal insulin receptor. Compounds enhancing neuronal insulin receptor-mediated transmission exert an antidepressant-like effect in several pre-clinical paradigms of depression; similarly, such properties for DS were found with a stress-induced anhedonia model. Here, we additionally studied the effects of DS on several variables which were ameliorated by other insulin receptor sensitizers in mice. Pre-treatment with DS of chronically stressed C57BL6 mice rescued normal contextual fear conditioning, hippocampal gene expression of NMDA receptor subunit NR2A, the NR2A/NR2B ratio and increased REM sleep rebound after acute predation. In 18-month-old C57BL6 mice, a model of elderly depression, DS restored normal sucrose preference and activated the expression of neural plasticity factors in the hippocampus as shown by Illumina microarray. Finally, young naïve DS-treated C57BL6 mice had reduced depressive- and anxiety-like behaviors and, similarly to imipramine-treated mice, preserved hippocampal levels of the phosphorylated (inactive) form of GSK3 beta that was lowered by forced swimming in pharmacologically naïve animals. Thus, DS can ameliorate behavioral and molecular outcomes under a variety of stress- and depression-related conditions. This further highlights neuronal insulin signaling as a new factor of pathogenesis and a potential pharmacotherapy of affective pathologies.

Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment

“…Various challenges, such as acute hypoxia, exposure to toxicity, chronic stress, and cerebral ischemia, were shown to stimulate IGF‐2 expression, which is considered to be neuroprotective . Our own work revealed that treatment with insulin receptor sensitizers upregulated hippocampal IGF‐2 during stress and interfered with susceptibility to a stress‐induced syndrome . Binding of IGF‐2 to IR‐A was also shown to result in preferential activation of numerous signaling pathways regulating metabolic and mitogenic responses, which were not shown for insulin, such as IGF‐2‐induced neural stem cell proliferation …”

Stressed and Inflamed, Can GSK3 Be Blamed?

“…Increased activation of GSK3 was detected in postmortem brain regions from patients with major depression [31] and in brains of rodents displaying depression-like behaviors, such as learned helplessness [9], social defeat stress [10], and anhedonia [32]. Expression of constitutively active GSK3 in knockin mice increases susceptibility to depression-like behaviors [9].…”

“…This has tremendous consequences for diseases with an inflammatory component, such as multiple sclerosis, as inhibiting GSK3 even after the first episode is sufficient to reduce the relapse and the severity of EAE in mice [19,20]. Although controlling Th17 and IL-17 signaling may be one of the mechanisms whereby GSK3 promotes EAE, other actions of GSK3 may be involved in disease progression, such as promoting infiltration of inflammatory cells through the weakened BBB [14,32,47] and the production of cytokines [16], and decreasing PD-1 expression [60]. Altogether, inhibiting GSK3 may provide therapeutic benefits for multiple sclerosis and other inflammatory diseases.…”

Role of Adiposity-Driven Inflammation in Depressive Morbidity

“…In addition, insulin resistance displayed by obese db/db mice in brain areas with high density of insulin receptors, such as the hippocampus and cortex, is associated with emotional alterations Kim et al, 2011). Conversely, compounds enhancing neuronal insulin receptor-mediated transmission in the hippocampus show antidepressant-like effects in preclinical paradigms of depression (Cline et al, 2012;Cline et al, 2015). In line with these findings, recent pharmacological studies highlight the antidepressant properties of several antidiabetic drugs, which may involve, beyond improvement of hyperglycemia, positive impact on inflammation and neuronal activity Pomytkin et al, 2015).…”