Antidepressant-Like Effects of Edaravone and Minocycline: Investigation of Oxidative Stress, Neuroinflammation, Neurotrophic, and Apoptotic Pathways.

Depression is a very common mental disorder and mechanism that is associated with mitochondrial dysfunction. In the present study, we examined the mechanisms of action of isolated brain mitochondria in rats with depression for the first time. This will help identify the mitochondrial protective pathways of the two drugs and shed light on new therapeutic goals for developing antidepressants. Forced swimming, tail suspension, and sucrose preference tests were used to assess depressive-like behaviors and the oxidative stress factors of brain tissue, and measure the gene expression of apoptotic and anti-apoptotic, neuroplasticity, and neuroinflammatory factors by RT-PCR and acetylcholinesterase (AChE) activity in brain tissue (hippocampus and prefrontal) and the serum levels of corticosterone and fasting blood sugar. The results showed that the separation of neonatal rats from their mothers induced depressive-like behaviors, weight loss, mitochondrial dysfunction, increased expression of genes involved in neuroinflammation, apoptosis, genes involved in the depressive process, and decreased expression of genes involved in mood in both the hippocampus and prefrontal cortex. Maternal separation increased serum corticosterone levels, caused dysfunction of the cholinergic system, and also increased AChE activity. Treatment with different concentrations of minocycline and edaravone (1, 20, and 50 mg/kg), 5MTHF, and citalopram for 14 days showed that these drugs improved depression-like behaviors and mitochondrial function. It also reduced the expression of genes involved in neuroinflammation, apoptosis, and depression and increased the expression of genes involved in mood. In conclusion, minocycline and edaravone have neuroprotective, mitochondrial protective, antioxidant, anti-inflammatory, and anti-apoptotic effects against depressive-like behaviors caused by chronic stress.