{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T08:22:00Z","timestamp":1769761320798,"version":"3.49.0"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:00:00Z","timestamp":1639526400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> 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.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Male SD rats were randomly grouped as S (sham, <jats:italic>n<\/jats:italic> = 20), M (middle cerebral artery occlusion [MCAO], <jats:italic>n<\/jats:italic> = 28), H2M (intermittent hypobaric hypoxia preconditioned MCAO group, 2 h\/day, 10 days, <jats:italic>n<\/jats:italic> = 20), H6M (intermittent hypobaric hypoxia preconditioned MCAO group, 6 h\/day, 10 days, <jats:italic>n<\/jats:italic> = 28), and HpM (persistent hypobaric hypoxia preconditioned MCAO group, 10 days, <jats:italic>n<\/jats:italic> = 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.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> The H6M group showed a lower infarct volume (<jats:italic>p<\/jats:italic> = 0.0005), lower mNSS score (<jats:italic>p<\/jats:italic> = 0.0009) than the M group. The H2M showed a lower level of IL-6 (<jats:italic>p<\/jats:italic> = 0.0213) than the M group. The caspase-3 level decreased in the H2M (<jats:italic>p<\/jats:italic> = 0.0002), H6M (<jats:italic>p<\/jats:italic> = 0.0025), and HpM groups (<jats:italic>p<\/jats:italic> = 0.0054) compared with that in the M group. Cleaved-caspase-3 expression decreased in the H2M (<jats:italic>p<\/jats:italic> = 0.0011), H6M (<jats:italic>p<\/jats:italic> &amp;lt; 0.0001), and HpM groups (<jats:italic>p<\/jats:italic> &amp;lt; 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 (<jats:italic>p<\/jats:italic> = 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 (<jats:italic>p<\/jats:italic> &amp;lt; 0.05 for all) on western blot verification of label-free proteomics.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> 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.<\/jats:p>","DOI":"10.3389\/fneur.2021.750908","type":"journal-article","created":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T06:08:37Z","timestamp":1639548517000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Preconditioning With Intermittent Hypobaric Hypoxia Attenuates Stroke Damage and Modulates Endocytosis in Residual 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