Inhibition of TRPC1, TRPM4 and CHRNA6 ion channels ameliorates depression-like behavior in rats

• Published in: Behavioural brain research 2022-04, Vol.423, p.113765-113765, Article 113765
• Main Authors: Kavuran Buran, İlay, Onalan Etem, Ebru, Tektemur, Ahmet
• Format: Article
• Language: English
• Subjects: Chronic unpredictable mild stress; Ion channel inhibitor; Major depressive disorder; MicroRNA
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2022.113765

The roles of ion channels, miRNAs and, neurotransmitters in the pathophysiology of major depressive disorder (MDD) are not yet fully elucidated. The current study aims to investigate ion channel gene expressions in the brain, the therapeutic efficacies of TRPC1, TRPM4, and CHRNA6 inhibitors, miRNAs specific to these ion channels and, neurotransmitter interactions in a chronic unpredictable mild stress (CUMS) induced MDD rat model. 48 two-month-old male albino Wistar rats were divided into Control, CUMS, Sham, CUMS+Pico145 (TRPC1 inhibitor), CUMS+ 9-Phe (TRPM4 inhibitor), and CUMS+BPiDl (CHRNA6 inhibitor) groups. Seven-week CUMS was used to induce MDD. Inhibitors were administered subacutely on the final of CUMS. Rats were subjected to behavioral tests. Gene expression levels were analyzed using qRT-PCR and neurotransmitter levels using ELISA. CUMS lead to a significant upregulation in the expression of channels in the hippocampus, and channels in the prefrontal cortex. Behavioral experiments determined the antidepressant effects as follows: Pico145 > BPiDl > 9-Phe. Compared to the Control, serotonin and noradrenaline levels remained unchanged, whereas dopamine levels increased. Acetylcholine levels decreased in CUMS and CUMS+Pico145 groups. CUMS significantly altered the expression of 6 miRNAs in the brain. BPiDl upregulated the expression of miR-6334 and Pico145 upregulated the expression of miR-135b-5p and miR-875 in the prefrontal cortex. The interactions of ion channels, miRNAs, and disruptions of neurotransmitter networks can play an important role in the pathophysiology of MDD. Moreover, as shown in this study, ion channel inhibitors have significant potential in the treatment of this disease. •Ion channels, miRNAs, and disruptions of neurotransmitter networks can play an important role in the pathophysiology of MDD.•CUMS caused a significant alteration in the expression of certain ion channels in the hippocampus and prefrontal cortex.•Ion channel inhibitors, especially TRPC1/4/5 inhibitor Pico145, have significant potential in the treatment of MDD.