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Astragaloside IV (AS-IV) is widely used in the antiapoptotic therapy of brain injury diseases. However, its mechanism of action is still not fully understood. In this study, we investigated the effect of AS-IV on hypoxia-induced oxidative stress and apoptosis in hippocampal neurons and explored its possible mechanism. In vivo, mice were placed in a hypoxic circulatory device containing 10% O2 and gavaged with AS-IV (60 and 120\u2009mg\/kg\/d) for 4 weeks. In vitro, mouse hippocampal neuronal cells (HT22) were treated with hypoxia (1% O2) for 24 hours in the presence or absence of AS-IV, MDL-28170 (calpain-1 inhibitor), or YC-1 (HIF-1\u03b1 inhibitor). The protective effect of AS-IV on brain injury was further explored by examining calpain-1 knockout mice. The results showed that hypoxia induced damage to hippocampal neurons, impaired spatial learning and memory abilities, and increased oxidative stress and apoptosis. Treatment with AS-IV or calpain-1 knockout improved the damage to hippocampal neurons and spatial learning and memory, attenuated oxidative stress and inhibited cell apoptosis. These changes were verified in HT22 cells. Overexpression of calpain-1 abolished the improvement of AS-IV on apoptosis and oxidative stress. In addition, the effects of AS-IV were accompanied by decreased calpain-1 and HIF-1\u03b1 expression, and YC-1 showed a similar effect as AS-IV on calpain-1 and caspase-3 expression. In conclusion, this study demonstrates that AS-IV can downregulate the calpain-1\/HIF-1\u03b1\/caspase-3 pathway and inhibit oxidative stress and apoptosis of hippocampal neurons induced by hypoxia, which provides new ideas for studying the antiapoptotic activity of AS-IV.<\/jats:p>","DOI":"10.1155\/2022\/6509981","type":"journal-article","created":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T21:50:08Z","timestamp":1670104208000},"page":"1-21","source":"Crossref","is-referenced-by-count":8,"title":["Astragaloside IV Alleviates Brain Injury Induced by Hypoxia via the Calpain-1 Signaling Pathway"],"prefix":"10.1155","volume":"2022","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0450-1094","authenticated-orcid":true,"given":"Yan","family":"Meng","sequence":"first","affiliation":[{"name":"Department of Liaoning Key Laboratory of Cardiovascular and Cerebrovascular Drugs, Jinzhou Medical University, Jinzhou 121000, 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