{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T16:23:23Z","timestamp":1791563003569,"version":"4.3.4"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T00:00:00Z","timestamp":1629676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019492","name":"National Natural Science Foundation of China-China Academy of General Technology Joint Fund for Basic Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007279","name":"Shanghai Municipal Health Bureau","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007279","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["18DZ1910604"],"award-info":[{"award-number":["18DZ1910604"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>One-third of patients with epilepsy suffer from drug-resistant epilepsy (DRE). Valproic acid (VPA) is a classic anticonvulsant drug, and its resistance is a crucial predictor of DRE, but the pathogenesis remain unknown. Most patients with VPA-resistant epilepsy appear distinct inflammatory response and local hypoxia. Hypoxia-inducible factor (HIF)-1\u03b1 is an essential effector molecule of hypoxia and inflammation, and may exert therefore a significant effect on the development of VPA-resistant epilepsy. We systematically assess the significance of HIF-1\u03b1 on children and mice with VPA-resistant epilepsy, and investigated the micro (mi) RNAs that regulate HIF-1\u03b1 expression. We established models of VPA-sensitive epilepsy and VPA-resistant epilepsy in mice, and confirmed that they had significant differences in epileptic behavior and electroencephalography data. Through proteomics analysis, we identified that HIF-1\u03b1 was overexpressed in mice with VPA-resistant epilepsy, and regulated the expression of interleukin-1\u03b2 and tumor necrosis factor-\u03b1. Increased expression of HIF-1\u03b1 led to the increase of microglia and induced their polarization from the M2 phenotype to M1 phenotype, which triggered the release of proinflammatory mediators. Bioinformatics analysis of public databases demonstrated that miR-221-3p was reduced in VPA-resistant epilepsy, and negatively regulated HIF-1\u03b1 expression. Intervention using miR-221-3p mimics reduced HIF-1\u03b1 expression markedly and suppressed the activation of microglia and the release of inflammatory mediators, which relieved epileptic seizures of VPA-resistant epilepsy. These observations reveal miR-221-3p\/HIF-1\u03b1 as essential component in pathogenesis of VPA-resistant epilepsy which represent therapeutic antiseizure targets.<\/jats:p>","DOI":"10.3389\/fphar.2021.714556","type":"journal-article","created":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T03:28:22Z","timestamp":1629689302000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["MicroRNA-221-3p Suppresses the Microglia Activation and Seizures by Inhibiting of HIF-1\u03b1 in Valproic Acid-Resistant Epilepsy"],"prefix":"10.3389","volume":"12","author":[{"given":"Meng","family":"Fu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqing","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junqi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxia","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/epi.13783","article-title":"Neuroinflammatory Targets and Treatments for Epilepsy Validated in Experimental Models","volume":"58","author":"Aronica","year":"2017","journal-title":"Epilepsia"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1111\/j.1460-9568.2010.07122.x","article-title":"Expression Pattern of miR-146a, an Inflammation-Associated microRNA, in Experimental and Human Temporal Lobe Epilepsy","volume":"31","author":"Aronica","year":"2010","journal-title":"Eur. 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