{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:19:18Z","timestamp":1760573958198,"version":"build-2065373602"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"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. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Cognitive impairment is a common issue for individuals ascending to high-altitude regions, and there is currently a lack of effective preventive or therapeutic medications. Tetramethylpyrazine (TMP), a small-molecule compound with blood-brain barrier permeability, has shown neuroprotective effects in various neurological disorders. This study aimed to investigate its potential protective role against hypoxia-induced cognitive deficits.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The neuroprotective effects of TMP were evaluated both <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. A simulated high-altitude hypobaric hypoxia mouse model was used to assess survival, cognitive function, cerebral ATP levels, and hippocampal histopathology. <jats:italic>In vitro<\/jats:italic> studies were conducted to examine hypoxia-induced neuronal death using primary neurons and HT22 cells. Furthermore, mechanistic investigations were performed to identify the molecular target of TMP and its functional impact.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>TMP treatment significantly prolonged survival and alleviated cognitive impairment in mice exposed to hypobaric hypoxia. It also elevated cerebral ATP levels and reduced hippocampal cellular edema. <jats:italic>In vitro<\/jats:italic>, TMP reduced hypoxia-induced neuronal death. Mechanistically, TMP was identified to potentially bind to the ion channel protein KCNK2 (TREK-1) and inhibit TREK-1-mediated current.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our findings demonstrate that TMP provides significant neuroprotection under hypobaric hypoxia conditions. The mechanism is linked, at least in part, to the inhibition of the TREK-1 channel. These results position TMP as a promising therapeutic candidate for preventing or treating high-altitude-induced cognitive dysfunction.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1662389","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T05:43:39Z","timestamp":1760507019000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tetramethylpyrazine exerts neuroprotective effects in a mouse model of acute hypobaric hypoxia"],"prefix":"10.3389","volume":"16","author":[{"given":"Xiong","family":"Lan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huifang","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pan","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhijie","family":"Bai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chaoji","family":"Huangfu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ningning","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengrong","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zengchun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengfei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"10179","DOI":"10.3390\/ijms241210179","article-title":"The brain at high altitude: from molecular signaling to cognitive performance","volume":"24","author":"Aboouf","year":"2023","journal-title":"Int. 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