Ji, Weizhong, Yaqing Zhang, Ri-li Ge, Yaqi Wan, and Jie Liu. NMDA receptor-mediated excitotoxicity is involved in neuronal apoptosis and cognitive impairment induced by chronic hypobaric hypoxia exposure at high altitude. High Alt Med Biol. 22:45-57, 2021. Aim: Exposure to chronic hypobaric hypoxia at high altitude can lead to cognitive impairment; however, its underlying mechanism is still unclear. Excessive expression of glutamate and its receptors can induce excitotoxicity and cause neuronal necrosis, which is an important causative factor for the occurrence of various diseases in the nervous system. Therefore, excitotoxicity may also occur after exposure to a chronic hypobaric hypoxic environment. This study concentrates on the action mechanism of glutamate and its receptor-mediated excitotoxicity in cognitive impairment, induced by chronic hypobaric hypoxic exposure. Methods: Sprague-Dawley rats were fed at regions with three different altitudes (4,300, 2,260, and 450 m) for 8 weeks, and had their behavioral changes assessed by the Morris water maze test. Morphological, molecular biological, and biochemical tests were used to determine the role of N-methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity in neuronal injury and cognitive impairment induced by chronic hypobaric hypoxia exposure. Results: We found that exposure to chronic hypobaric hypoxia at high altitudes could cause cognitive impairment, damage the neurons in the hippocampus and cortex, increase apoptosis, and lead to abnormal Caspase-3 protein expression. The expression of NMDA and a-amino-3-hydroxyl-5-methyl-4-isoxazole acid (AMPA) receptors increased significantly, as did the levels of oxidative stress and free radicals as well. However, no change in cognitive function was observed in the chronic hypobaric hypoxia environment at the middle altitude, there were no statistically significant differences in neuronal apoptosis and related protein expression compared with the rats in the flatland environment group. Conclusion:We show that high-altitude chronic hypobaric hypoxic environment could cause obvious cognitive impairments, which is related to the excitotoxicity mediated by glutamate and its receptors, in contrast to the chronic hypobaric hypoxia environment at middle altitude group and flatland environment group.
Neuronal death and neurologic deficits are the major causes of disability in patients following cerebral infarction. Acute/programmed necrosis, autophagy, and apoptosis of brain neurons result from complex biochemical events triggered by stroke. Current treatments for cerebral infarction are limited; therefore, the development of effective treatment strategies would be of great value. At present, delivering
Background: Moderate hypobaric hypoxia induces cerebral ischemic tolerance. We investigated the optimal method for applying hypobaric hypoxia preconditioning at 5,000 m to ischemic brain tissue and combined it with proteomics to determine the mechanisms underlying this effect.Methods: Male SD rats were randomly grouped as S (sham, n = 20), M (middle cerebral artery occlusion [MCAO], n = 28), H2M (intermittent hypobaric hypoxia preconditioned MCAO group, 2 h/day, 10 days, n = 20), H6M (intermittent hypobaric hypoxia preconditioned MCAO group, 6 h/day, 10 days, n = 28), and HpM (persistent hypobaric hypoxia preconditioned MCAO group, 10 days, n = 28). The permanent MCAO model was established based on the Zea Longa method. Infarction was assessed with the modified neurological severity score (mNSS) and 2,3,5-triphenyl tetrazolium chloride staining. The total protein expression of the neuron-specific nuclear protein (NeuN), cysteinyl aspartate specific proteinase 3 (caspase-3), cleaved-caspase-3, and interleukin 6 (IL-6) was determined using western blotting. We assessed the peri-infarct cortex's ultrastructural changes. A label-free proteomic study and western blot verification were performed on the most effective preconditioned group.Results: The H6M group showed a lower infarct volume (p = 0.0005), lower mNSS score (p = 0.0009) than the M group. The H2M showed a lower level of IL-6 (p = 0.0213) than the M group. The caspase-3 level decreased in the H2M (p = 0.0002), H6M (p = 0.0025), and HpM groups (p = 0.0054) compared with that in the M group. Cleaved-caspase-3 expression decreased in the H2M (p = 0.0011), H6M (p < 0.0001), and HpM groups (p < 0.0001) compared with that in the M group. The neurons' ultrastructure and the blood-brain barrier in the peri-infarct tissue improved in the H2M and H6M groups. Immunofluorescence revealed increased NeuN-positive cells in the peri-infarct tissue in the H6M group (p = 0.0003, H6M vs. M). Protein expression of Chmp1a, Arpc5, and Hspa2 factors related to endocytosis were upregulated in the H6M compared with those of the M group (p < 0.05 for all) on western blot verification of label-free proteomics.Conclusions: Intermittent hypobaric hypoxia preconditioning exerts a neuroprotective effect in a rat stroke model. Persistent hypobaric hypoxia stimulation exhibited no significant neuroprotective effect. Intermittent hypoxic preconditioning for 6 h/day for 10 days upregulates key proteins in clathrin-dependent endocytosis of neurons in the cortex.
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