{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:40Z","timestamp":1787028580509,"version":"build-2736575974"},"reference-count":55,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001824","name":"Czech Science Foundation","doi-asserted-by":"crossref","award":["23-05746S"],"award-info":[{"award-number":["23-05746S"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004240","name":"Academy of Sciences of the Czech Republic","doi-asserted-by":"crossref","award":["RVO 61388963"],"award-info":[{"award-number":["RVO 61388963"]}],"id":[{"id":"10.13039\/501100004240","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"crossref","award":["CZ.02.1.01\/0.0\/0.0\/16_025\/0007444"],"award-info":[{"award-number":["CZ.02.1.01\/0.0\/0.0\/16_025\/0007444"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003243","name":"Ministry of Health of the Czech Republic","doi-asserted-by":"crossref","award":["RVO-VFN 64165"],"award-info":[{"award-number":["RVO-VFN 64165"]}],"id":[{"id":"10.13039\/501100003243","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Ministry of Health of the Czech Republic Institutional Support","award":["RVO 00023761"],"award-info":[{"award-number":["RVO 00023761"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pregnanolone glutamate (PG) is a synthetic neurosteroid analog showing promise for treating ischemic brain injury, yet its blood\u2013brain barrier (BBB) transport and metabolic fate remain unclear. We investigated the pharmacokinetics of PG in postnatal day 12 rats of both sexes subjected to endothelin-1 (ET-1)-induced focal hippocampal ischemia. Animals received PG (1 mg\/kg intraperitoneal (i.p.)) or vehicle; serum and hippocampal steroidomes were profiled 60 min post-administration using gas chromatography-tandem mass spectrometry (GC-MS\/MS) (hippocampus: n = 16 PG+, n = 27 PG\u2212; multi-tissue subset: n = 6 PG+, n = 21 PG\u2212). Our data revealed a \u201cdual-fate\u201d mechanism: PG undergoes systemic hydrolysis as a prodrug, as suggested by the tissue distribution pattern at 60 min post-administration, but also crosses the BBB intact, with significant parent conjugate accumulation in the hippocampus (42.3 pmol\/g). The brain functioned as a \u201cmetabolic sink\u201d, passively accumulating metabolites generated in peripheral organs\u2014such as 17-hydroxypregnanolone\u2014despite local absence of synthesizing enzymes (e.g., CYP17A1). Crucially, PG induced \u201cmetabolic segregation\u201d within the central nervous system (CNS): the pharmacological 5\u03b2-pathway was saturated (~170-fold pregnanolone increase), while endogenous neuroprotective 5\u03b1-pathway (allopregnanolone) homeostasis remained preserved, contrasting with peripheral metabolic saturation. Preferential hippocampal accumulation of 3-oxo and 3\u03b2-isomers suggests autonomous regulatory buffering via oxidative 17\u03b2-hydroxysteroid dehydrogenase (HSD17B) enzymes, protecting against excessive GABAergic inhibition. This unique pharmacokinetic profile\u2014combining metabolic segregation with active central buffering\u2014defines PG as a dual-mechanism delivery system that generates central neuroactive metabolites\u2014several with previously established GABAergic and neuroprotective activity\u2014without disrupting endogenous neurosteroidogenesis, positioning it as a promising neurotherapeutic candidate minimizing physiological steroid homeostasis disruption. Importantly, the present study characterizes the pharmacokinetic and metabolic fate of PG; the neuroprotective efficacy of PG was demonstrated in our prior functional studies using the same model.<\/jats:p>","DOI":"10.3390\/ijms27052506","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T13:27:18Z","timestamp":1773062838000},"page":"2506","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pregnanolone Glutamate: A Dual-Fate Delivery System for Neuroactive Steroids in Perinatal Focal Cerebral Ischemia"],"prefix":"10.3390","volume":"27","author":[{"given":"Grygoriy","family":"Tsenov","sequence":"first","affiliation":[{"name":"Preclinical Research Program, Division of Experimental Neurobiology, National Institute of Mental Health, 250 67 Klecany, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0189-3261","authenticated-orcid":false,"given":"Iqra","family":"Bano","sequence":"additional","affiliation":[{"name":"Preclinical Research Program, Division of Experimental Neurobiology, National Institute of Mental Health, 250 67 Klecany, Czech Republic"},{"name":"Department of Animal Physiology, Faculty of Science, Charles University, Albertov 6, 128 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Vel\u00edkov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Endocrinology, 110 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viera","family":"K\u00fatna","sequence":"additional","affiliation":[{"name":"Preclinical Research Program, Division of Experimental Neurobiology, National Institute of Mental Health, 250 67 Klecany, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hana","family":"Chodounsk\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 160 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7131-5948","authenticated-orcid":false,"given":"Eva","family":"Kudov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 160 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"Bulant","sequence":"additional","affiliation":[{"name":"Institute of Endocrinology, 110 00 Prague, Czech Republic"},{"name":"Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1705-0835","authenticated-orcid":false,"given":"Martin","family":"Hill","sequence":"additional","affiliation":[{"name":"Institute of Endocrinology, 110 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105163","DOI":"10.1016\/j.phrs.2020.105163","article-title":"Neurosteroids and their receptors in ischemic stroke: From molecular mechanisms to therapeutic opportunities","volume":"160","author":"Vahidinia","year":"2020","journal-title":"Pharmacol. 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