Melatonin ameliorates anxiety-like behaviors induced by sleep deprivation in mice: Role of oxidative stress, neuroinflammation, autophagy and apoptosis.

Increasing evidence suggests there is a relationship between anxiety disorders and sleep deprivation (SD). However, underlying molecular mechanism remains elusive and currently there is no effective therapy to negate the effects of SD. We established a mouse model of acute SD with or without melatonin supplementation. We found that melatonin supplementation suppressed an increase of corticosterone level caused by SD. Behavioral data indicated that 72 h SD exposure induced anxiety-like behaviors, as evidenced by the reduced central area travels in OFT. Immunohistochemical staining and western blot analysis revealed that SD promoted neuronal loss by inducing pro-apoptotic protein Bax and cleaved-caspase-3 and autophagic proteins (LC3II, ATG5 and Beclin1) and reducing the levels of the anti-apoptotic protein Bcl-2. In contrast, the aforementioned SD-inductions were reversed by supplementation using 20 mg/kg and 40 mg/kg melatonin in SD mice. Meanwhile, we observed that melatonin reduced activated gliosis via attenuation of Iba1, and inhibited increase of anti-inflammatory cytokines (IL-4 and IL-10) and the decrease of pro-inflammatory cytokines (IL-6 and TNF-α). Furthermore, melatonin supplementation inverted the SD-induced the decline of antioxidant enzyme activities (T-AOC and CAT etc) and the increase of p-P65 and p-IκB proteins in the hippocampus. On the whole, our findings revealed that melatonin attenuated SD-induced anxiety-like behavior via ameliorating oxidative stress, activation of NF-κB pathway, neuroinflammation, apoptosis and excessive autophagy.