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Current anticonvulsants have poor efficacy, and many have been associated with upregulation of apoptosis in the developing brain. Apigenin, a natural bioactive flavonoid, is a potent inhibitor of hyaluronidase and reduces seizures in adult animal models. However, its impact on perinatal seizures is unclear. In the present study, we examined the effect of apigenin and S3, a synthetic, selective hyaluronidase inhibitor, on seizures after cerebral ischemia in preterm fetal sheep at 0.7 gestation (98\u201399 days, term ~147 days). Fetuses received sham ischemia (n = 9) or ischemia induced by bilateral carotid occlusion for 25 min. Immediately after ischemia, fetuses received either a continuous infusion of vehicle (0.036% dimethyl sulfoxide, n = 8) or apigenin (50 \u00b5M, n = 6). In a pilot study, we also tested infusion of S3 (2 \u00b5M, n = 3). Fetuses were monitored continuously for 72 h after ischemia. Infusion of apigenin or S3 were both associated with reduced numbers of animals with seizures, total seizure time, and mean seizure burden. S3 was also associated with a reduction in the total number of seizures over the 72 h recovery period. In animals that developed seizures, apigenin was associated with earlier cessation of seizures. However, apigenin or S3 treatment did not alter recovery of electroencephalographic power or spectral edge frequency. These data support that targeting brain hyaluronidase activity with apigenin or S3 may be an effective strategy to reduce perinatal seizures following ischemia. Further studies are required to determine their effects on neurohistological outcomes.<\/jats:p>","DOI":"10.3390\/ijms242316926","type":"journal-article","created":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T09:00:18Z","timestamp":1701248418000},"page":"16926","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Postischemic Infusion of Apigenin Reduces Seizure Burden in Preterm Fetal Sheep"],"prefix":"10.3390","volume":"24","author":[{"given":"Kenta H. T.","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Physiology, University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalya","family":"Hounsell","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn","family":"McClendon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Art","family":"Riddle","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8844-468X","authenticated-orcid":false,"family":"Basappa","sequence":"additional","affiliation":[{"name":"Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simerdeep K.","family":"Dhillon","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Bennet","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Back","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA"},{"name":"Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6098-6551","authenticated-orcid":false,"given":"Larry S.","family":"Sherman","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, USA"},{"name":"Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0656-7035","authenticated-orcid":false,"given":"Alistair J.","family":"Gunn","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1377-0878","authenticated-orcid":false,"given":"Justin M.","family":"Dean","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,29]]},"reference":[{"key":"ref_1","unstructured":"Behrman, R.E., and Butler, A.S. 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