Chronic Treadmill Running Protects Hippocampal Neurons from Hypobaric Hypoxia-induced Apoptosis in Rats

This study was designed to examine the effects of chronic running exercise (Ex) on the hypobaric hypoxia-induced neuronal injury in the hippocampus. Male Wistar rats (9 weeks old) were caged in a hypoxic altitude chamber simulating the condition of 9,000 m high (0.303 atm) for 7h and the brains were examined at 0, 4, and 24h after treatment. Hypoxia challenge increased the levels of caspase 3 (mean ± SEM, % of baseline control, 121.9 ± 11.8, 152.3 ± 15.3, 141.6 ± 7.0 for 0, 4 and 24h, respectively, n=5) and induced apoptosis (cell number, 205.7 ± 8.8, 342.3 ± 33.4, 403.0 ± 12.2 for 0, 4 and 24h vs. 7.7 ± 1.4 baseline control, n=3) in the hippocampal CA1 pyramidal neurons. The expression levels (% of control for 0, 4 and 24h, respectively, n=5) of hypoxia inducible factor-1α (HIF-1α; 150.5 ± 8.1, 176.7 ± 11.1, 136.2 ± 13.3), neuronal nitric oxide synthase (nNOS; 163.4 ± 9.6, 194.5 ± 13.6, 163.7 ± 10.9) and inducible nitric oxide synthase (iNOS; 139.4 ± 9.5, 169.2 ± 13.3, 134.3 ± 13.0) and the degrees of microglia (cell number, 255.3 ± 48.2, 349.0 ± 57.3, 433.7 ± 42.4 vs. 57.7 ± 13.0 baseline control, n=3) and astrocyte (150.0 ± 9.7, 199.3 ± 10.8, 154.2 ± 4.7) activation were increased by the hypoxia treatment, indicating that the brain was under hypoxic, oxidative and inflammatory stresses. Furthermore, the protein levels of hippocampal brain-derived neurotrophic factor (BDNF; 76.0 ± 2.5, 76.1 ± 7.1, 69.3 ± 1.7 for 0, 4 and 24h, respectively, mean % of control ± SEM, n=5) were reduced by the hypoxia treatment. Four weeks of treadmill Ex before hypoxia treatment significantly reduced the hypoxia-induced apoptosis (p<0.001, n=3) in the hippocampal CA1 neurons. Ex decreased the hypoxia-induced elevations of HIF-1α (p<0.001, n=5), nNOS (p<0.001, n=5) and iNOS (p<0.001, n=5) levels and activation of microglia (p=0.005, n=3) and astrocyte (p<0.001, n=5) status; whereas the hypoxia-reduced BDNF protein levels (p=0.013, n=5) were restored. Taken together, our results show that chronic Ex protects hippocampal CA1 neurons against hypobaric hypoxia insult. Ex-enhanced bioenergetic adaptation and anti-oxidative capacity may prevent neurons from hypoxia-induced apoptosis. Furthermore, activation of the BDNF signaling pathway may be involved in the Ex-induced protection.