Treadmill Exercise in Rats Attenuates Chronic Unpredictable Stress-Induced Depressive-like Behavior Associated with Melatonin-SIRT1/Nrf2 Signaling in the Prefrontal Cortex.

To explore the ameliorating effect of treadmill exercise on depression-like behavior in rats with chronic unpredictable stress (CUS). Thirty-six Sprague-Dawley rats were divided into three groups (n=12 per group): a control group, a CUS group and a CUS+exercise (CUS+EX) group. The CUS and CUS+EX groups received a 4-week CUS treatment, and the CUS+EX group began a 4-week moderate-intensity treadmill exercise at the second week of CUS treatment. Following the CUS treatment and treadmill exercise, the depressive-like behavior of rats was assessed using the open field test (OFT) and tail suspension test (TST). Plasma melatonin levels were measured using an enzyme-linked immunosorbent assay, and the superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels in the prefrontal cortex (PFC) were detected using commercial kits. Compared with the control group, the CUS group showed shortened latency to first immobility and prolonged total immobility time in the TST, and decreased time spent in the center and reduced crossing and vertical activities in the OFT. Additionally, the SOD activity and the protein expressions of sirtuin 1 (SIRT1) and nuclear factor E2 associated factor 2 (Nrf2) in the PFC decreased, whereas the MDA level increased in the CUS group. Four weeks of concurrent treadmill exercise attenuated the effects of CUS: compared with the CUS group, the CUS+EX group exhibited reduced depressive-like behaviors, prevention of the CUS-induced decline in PFC SOD activity and SIRT1/Nrf2 protein expression and attenuation of the CUS-induced increase in PFC MDA levels. Treadmill exercise concurrently increased plasma melatonin levels and activated the SIRT1/Nrf2 antioxidant pathway in the PFC, which may contribute to the observed improvement in depressive-like behavior.