{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:02:03Z","timestamp":1789189323126,"version":"build-2803163510"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T00:00:00Z","timestamp":1675900800000},"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:p>Neonatal hypoxic-ischemic encephalopathy (HIE) is considered a major cause of death and long-term neurological injury in newborns. Studies have demonstrated that oxidative stress and apoptosis play a major role in the progression of neonatal HIE. Echinocystic acid (EA), a natural plant extract, shows great antioxidant and antiapoptotic activities in various diseases. However, it has not yet been reported whether EA exerts a neuroprotective effect against neonatal HIE. Therefore, this study was undertaken to explore the neuroprotective effects and potential mechanisms of EA in neonatal HIE using <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> experiments. In the <jats:italic>in vivo<\/jats:italic> study, a hypoxic-ischemic brain damage (HIBD) model was established in neonatal mice, and EA was administered immediately after HIBD. Cerebral infarction, brain atrophy and long-term neurobehavioral deficits were measured. Hematoxylin and eosin (H&amp;amp;E), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and dihydroethidium (DHE) staining were performed, and the contents of malondialdehyde (MDA) and glutathione (GSH) were detected. In the <jats:italic>in vitro<\/jats:italic> study, an oxygen-glucose deprivation\/reperfusion (OGD\/R) model was employed in primary cortical neurons, and EA was introduced during OGD\/R. Cell death and cellular ROS levels were determined. To illustrate the mechanism, the PI3K inhibitor LY294002 and Nrf2 inhibitor ML385 were used. The protein expression levels of p-PI3K, PI3K, p-Akt, Akt, Nrf2, NQO1, and HO-1 were measured by western blotting. The results showed that EA treatment significantly reduced cerebral infarction, attenuated neuronal injury, and improved brain atrophy and long-term neurobehavioral deficits in neonatal mice subjected to HIBD. Meanwhile, EA effectively increased the survival rate in neurons exposed to OGD\/R and inhibited oxidative stress and apoptosis in both <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> studies. Moreover, EA activated the PI3K\/Akt\/Nrf2 pathway in neonatal mice following HIBD and in neurons after OGD\/R. In conclusion, these results suggested that EA alleviated HIBD by ameliorating oxidative stress and apoptosis <jats:italic>via<\/jats:italic> activation of the PI3K\/Akt\/Nrf2 signaling pathway.<\/jats:p>","DOI":"10.3389\/fphar.2023.1103265","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T10:51:01Z","timestamp":1675939861000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Echinocystic acid alleviated hypoxic-ischemic brain damage in neonatal mice by activating the PI3K\/Akt\/Nrf2 signaling pathway"],"prefix":"10.3389","volume":"14","author":[{"given":"Yuan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Xia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shao-Hua","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng-Chao","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Fei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Wei","family":"Min","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1177\/0963689718766362","article-title":"Inflammatory responses are sex specific in chronic hypoxic-ischemic encephalopathy","volume":"27","author":"Al Mamun","year":"2018","journal-title":"Cell Transpl."},{"key":"B2","doi-asserted-by":"publisher","first-page":"265","DOI":"10.3390\/ijms18020265","article-title":"Role of antioxidants in neonatal hypoxic-ischemic brain injury: New therapeutic approaches","volume":"18","author":"Arteaga","year":"2017","journal-title":"Int. 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