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This study investigates the cortical expression pattern of neuroserpin during postnatal brain development and evaluates its neuroprotective potential in hypoxia\u2013ischaemia (HI)-induced brain damage using a modified Rice\u2013Vannucci model. Experiments were conducted in both male and female neuroserpin knockout (KO) mice and through administration of exogenous neuroserpin into the brain. Between postnatal day 4 to 14 (P4\u2013P14), neuroserpin-immunoreactive cell density peaked at P8\u2013P10 in cortical layers 5 and 6b, with a gradual increase in layers 2\/3 and minimal changes in layers 4 and 6a. Despite comparable levels of ischaemic brain damage between the KO and wild-type (WT) mice, exogenous neuroserpin administration suppressed the HI-induced oxidative stress. Additionally, it reduced microglial activation and reactive astrogliosis in the cortex in mild HIE, mitigating cortical thinning and preserving neuronal distribution. These findings suggest that endogenous neuroserpin alone is insufficient for neuroprotection against HI-induced damage, but exogenous neuroserpin shows promise as a pharmacological intervention for mild neonatal HIE.<\/jats:p>","DOI":"10.3390\/cells14231840","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T11:04:31Z","timestamp":1763723071000},"page":"1840","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuroserpin: A Potential Neuroprotective Agent in Mild Neonatal Hypoxic\u2013Ischaemic Encephalopathy"],"prefix":"10.3390","volume":"14","author":[{"given":"Eri","family":"Kawashita","sequence":"first","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Sherrington Rd, Oxford OX1 3PT, UK"},{"name":"Laboratory of Pathological Biochemistry, Kyoto Pharmaceutical University, Misasagi Nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumi","family":"Fukuzaki","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Sherrington Rd, Oxford OX1 3PT, UK"},{"name":"Department of Neurology, University of California, San Francisco, Sandler Neuroscience Building, 675 Nelson Rising Lane, San Francisco, CA 94158, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Sherrington Rd, Oxford OX1 3PT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Sherrington Rd, Oxford OX1 3PT, UK"},{"name":"JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumei","family":"Liao","sequence":"additional","affiliation":[{"name":"JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lancelot Jamie","family":"Millar","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Sherrington Rd, Oxford OX1 3PT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7984-7068","authenticated-orcid":false,"given":"Peiyun","family":"Zhong","sequence":"additional","affiliation":[{"name":"JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1953-7871","authenticated-orcid":false,"given":"Anna","family":"Hoerder-Suabedissen","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Sherrington Rd, Oxford OX1 3PT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9127-7061","authenticated-orcid":false,"given":"Luana Campos","family":"Soares","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Sherrington Rd, Oxford OX1 3PT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6852-6004","authenticated-orcid":false,"given":"Zolt\u00e1n","family":"Moln\u00e1r","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Sherrington Rd, Oxford OX1 3PT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1002\/1098-2779(200102)7:1<56::AID-MRDD1008>3.0.CO;2-A","article-title":"Perinatal brain injury: From pathogenesis to neuroprotection","volume":"7","author":"Volpe","year":"2001","journal-title":"Ment. 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