The determination of therapeutic effects of ion channel inhibitors in rat depression model of induced with chronic mild stress

Major depressive disorder (MDD) is a common mental health problem. It is known that ion channels and miRNAs have function in the pathophysiology of depression. In our study, we aimed to evaluate the expression of 115 ion channels synthesized in the prefrontal cortex and hippocampus tissues of the brain in the Chronic Mild Stress (CMS) MDD model and to use the specific inhibitors of upregulated 3 ion channels as treatment. It was also aimed to investigate the effect of these inhibitors on miRNAs targeting selected channels. Wistar albino male rats were used in the study. The subjects were divided into: Control, CMS, Sham, and CMS+Inhibitor. 7 weeks of CMS was used to induce MDD. Expression of ion channels in Control and CMS groups was determined through qRT-PCR. The rats were treated with inhibitors (Pico145, BpiD1, 9-Phenanthrol) that are specific to the 3 upregulated ion channels (TRPC1, CHRNA6, TRPM4). The expressions of miRNAs targeting these 3 ion channels were evaluated. The effect of CMS and the treatments was determined by behavioral experiments and by measuring neurotransmitter levels. We found that CMS lead to a significant increase in the expression of 13 ion channels in the hippocampus, and 16 ion channels in the prefrontal cortex. It was determined that Pico145, BpiDl and 9-Phenanthrol had antidepressant-like effects in forced swimming test and elevated plus maze test and just Pico145 had antidepressant-like effects in open field test. In all groups, serotonin and noradrenaline levels remained unchanged, whereas dopamine levels increased. Also, acetylcholine levels decreased in the CMS and the CMS+Pico145 groups. Significant changes in the expression of 6 miRNAs in CMS were determined in both tissues evaluated. It was observed that BpiD1 only increased the expression of miR-6334 and Pico145 altered the expression of miR-875. Our findings showed that ion channels and miRNAs play a role in the pathophysiology of depression, especially the treatment efficacy of TRPC1/4/5 inhibitor Pico145 is high and acetylcholine and dopamine are important in neurotransmitter network. It is thought that our findings will contribute to the pharmacological studies related to the use of ion channels in the treatment of MDD and to elucidate the different mechanisms related to its pathophysiology.