Synergistic effects of melatonin and hydrogen sulfide in alleviating cognitive decline and BDNF dysregulation in a rat model of depression

Abstract

ABSTRACT This research aimed to investigate the possible anti-amnesic effects of a combined therapy involving melatonin and H2S in a rat model displaying Depressive-Like Behaviors caused by Chronic Unpredictable Mild Stress (CUMS). Our study aims to assess the efficacy of this treatment in mitigating oxidative stress and neuroinflammation in the striatum and hippocampus. Furthermore, we seek to investigate its ability to restore BDNF levels within this specific rat model. The rats underwent a 4-week CUMS protocol and were administered sodium hydrosulfide (a H2S donor) at a dose of 5.6 μmol/100 g/day, as well as melatonin at a dose of 1 mg/100 g/day from the first day of the CUMS protocol. Following the CUMS exposure, the rats were assessed through various behavioral tests. Subsequently, the rats were euthanized after the behavioral tests, and blood samples were collected for corticosterone analysis. Oxidative stress (OS) markers, BDNF and TNF-α levels were analyzed in both the striatum and HP. Concurrently administering H2S and melatonin in a rat model of CUMS-induced depression demonstrates antidepressant-like effects. Furthermore, this combined treatment effectively prevents the development of learning and memory impairments associated with CUMS. Additionally, it reduces Malondialdehyde and nitric oxide levels, enhances glutathione peroxidase and superoxide dismutase activity in the striatum and HP, and mitigates CUMS-induced elevations in TNF-α levels in both brain regions. Significantly, long-term administration of this combination reverses the chronic stress-induced reduction of hippocampal BDNF levels. These findings suggest that the synergy between H2S and melatonin holds promise in alleviating cognitive impairments.