CHRONIC TREADMILL RUNNING PROTECTS HIPPOCAMPAL NEURONS FROM HYPOBARIC HYPOXIA-INDUCED APOPTOSIS IN RATS

摘要

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 9000 m high (0.303 atm) for 7 h and the brains were examined at 0, 4, and 24 h 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 24 h, respectively, n = 5) and induced apoptosis (cell number, 205.7 +- 8.8,342.3 +- 33.4, 403.0 +- 12.2 for 0, 4 and 24 h vs. 7.7 +- 1.4 baseline control, n = 3) in the hippocampal CA1 pyramidal neurons. The expression levels (% of control for 0, 4 and 24 h, respectively, n = 5) of hypoxia inducible factor-1a (HIF-1a; 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 24 h, 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-1a (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.