Intermittent hypoxia promotes the recovery of motor function in rats with cerebral ischemia by regulating mitochondrial function

Abstract

Hypoxia preconditioning is neuroprotective, but the therapeutic effects of intermittent hypoxia were not fully considered. The present study investigated the neuroprotective effect and mechanism of intermittent hypoxia on motor function after cerebral ischemia and explored alternative clinical treatment options. In total, 36 8-week-old male Sprague-Dawley rats were subjected to 60 min of transient middle cerebral artery occlusion (tMCAO) and then randomly divided into a sham-operated group (SHAM), tMCAO-sedentary group (SED), and tMCAO-intermittent hypoxia group (IH). The intervention was performed 1 week after tMCAO and lasted 4 weeks. Rats in the IH group were placed in an animal hypoxic chamber (altitude 5000 m and oxygen concentration of 13%) for 4 h/day and 7 days/week, and rats in the SED group were placed in a normoxic environment for 4 weeks. Body weights, neurological deficit scores, cerebral infarction volume ratios, gait analyses, mitochondrial structure, adenosine triphosphate (ATP) content and AMO-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α), and silencing regulatory protein 3 (Sirt3) expression in the peri-ischemic region brain tissues were detected during the intervention. Compared with the SED group, the body weight of the IH group gradually recovered, and the neurological deficit scores were significantly reduced ( P < 0.05). The gait analysis results showed that the pressure of the affected paw and the maximum content area, swing speed, stride length, and other parameters were significantly restored ( P < 0.05). The cerebral infarction volume ratio was significantly reduced ( P < 0.01). Mitochondrial morphological structure damage in the peri-ischemic region brain tissues recovered, the number was significantly increased ( P < 0.05), and the expression of AMPK, PGC-1α, and Sirt3 proteins ( P < 0.05), and ATP content were significantly increased ( P < 0.05). Intermittent hypoxia may activate the AMPK–PGC-1α–Sirt3 signaling pathway, promote mitochondrial biogenesis, repair mitochondrial ultrastructural damage, and improve mitochondrial function to reduce brain damage and promote motor function recovery in rats with cerebral ischemia.