Hydrogen restores central tryptophan and metabolite levels and maintains mitochondrial homeostasis to protect rats from chronic mild unpredictable stress damage

The field of hydrogen medicine has garnered extensive attention since Professor Ohsawa established that low concentrations of hydrogen (2%–4%) exert antioxidant effects. The present study aimed to evaluate the therapeutic effect of molecular hydrogen in a CUMS rat model. A total of 40 SD rats were randomly divided into a control group, a model group, a hydrogen group, and a positive drug group. Four weeks post-modeling, hydrogen inhalation and other treatments were administered. Behavioral, biochemical, and immunohistochemical evaluations were performed after treatment. Hydrogen inhalation alleviated depressive behavior and hippocampal neuronal damage in CUMS rats, as well as restored the levels of neurotransmitters, inflammatory factors, and oxidative stress. Moreover, it maintained mitochondrial homeostasis and up-regulated the expression of PGC-1α, PINK1, and Parkin. The results collectively indicated that hydrogen significantly attenuated CUMS-induced depressive-like behavior and monoamine neurotransmitter deficiency, as well as protected the brain from oxidative stress and inflammatory damage and effectively preserved mitochondrial homeostasis. •Protecting mitochondrial homeostasis helps to reduce oxidative stress and inflammatory response in depression.•Hydrogen is a safe and effective medical gas without toxicity and discomfort.•Molecules hydrogen are particularly protective of mitophagy and mitochondrial biosynthesis.•Molecular hydrogen promoted a significant recovery of 5-HT and kynurenine levels.