ArticleInternational journal of molecular sciences2026
Pregnanolone Glutamate: A Dual-Fate Delivery System for Neuroactive Steroids in Perinatal Focal Cerebral Ischemia.
Article in International journal of molecular sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Cross-tissue Mendelian randomization prioritizes RAB27B as a brain-derived candidate protein for postpartum depression.European archives of psychiatry and clinical neuroscience · 2026Article
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8 authors.
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Abstract
Pregnanolone glutamate (PG) is a synthetic neurosteroid analog showing promise for treating ischemic brain injury, yet its blood-brain 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-; multi-tissue subset: n = 6 PG+, n = 21 PG-). Our data revealed a "dual-fate" 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 "metabolic sink", passively accumulating metabolites generated in peripheral organs-such as 17-hydroxypregnanolone-despite local absence of synthesizing enzymes (e.g., CYP17A1). Crucially, PG induced "metabolic segregation" within the central nervous system (CNS): the pharmacological 5β-pathway was saturated (~170-fold pregnanolone increase), while endogenous neuroprotective 5α-pathway (allopregnanolone) homeostasis remained preserved, contrasting with peripheral metabolic saturation. Preferential hippocampal accumulation of 3-oxo and 3β-isomers suggests autonomous regulatory buffering via oxidative 17β-hydroxysteroid dehydrogenase (HSD17B) enzymes, protecting against excessive GABAergic inhibition. This unique pharmacokinetic profile-combining metabolic segregation with active central buffering-defines PG as a dual-mechanism delivery system that generates central neuroactive metabolites-several with previously established GABAergic and neuroprotective activity-without 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.
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