Mol Neurobiol. 2026 Apr 13;63(1):560. doi: 10.1007/s12035-026-05791-2.
ABSTRACT
Ischemic stroke is a leading cause of death and disability among youth, with sex-specific differences in risk and outcomes, including post-stroke cognitive impairment. However, the neurodevelopmental factors underlying these pathological states are unclear. This study examined hypoxia-inducible factor-1 alpha (HIF-1α) and brain-derived neurotrophic factor (BDNF) levels in bilateral common carotid artery occlusion/reperfusion (BCCAO/R)-induced ischemic stroke in rats. It focused on post-stroke cognitive decline in male and female adult offspring following BCCAO/R-induced ischemic stroke, after prenatal immune activation (PIA) and late-trimester intermittent maternal hypoxic stress (IMHS). PIA was induced by lipopolysaccharide (0.1 mg/kg, i.p.) injection at gestational day (GD) 15, followed by IMHS exposure from GDs 17 until delivery. Thereafter, offspring (n = 10, male and females) from sham control, LPS-exposed, hypoxia-exposed, and combined LPS + hypoxia group were exposed to BCCAO/R-induced ischemic stroke at postnatal day 90. Neurological deficits and post-stroke cognitive function were assessed using Y-maze and novel-object recognition tests at 1-day and 5-days post-surgery. The prefrontal cortex and striatum, where structural and functional alterations have primarily been described in stroke patients, were isolated for BDNF and HIF-1α ELISA quantification. In female rats, non-spatial working memory was acutely reduced after BCCAO/R-induced stroke following PIA-IMHS exposures, but males were unaffected. Rats co-exposed to LPS + hypoxia show decreased HIF-1α in the male striatum compared to sham or LPS/hypoxia groups. The two-hit factor increased striatal BDNF levels compared with LPS alone. In females' prefrontal cortex, LPS + hypoxia versus controls, but LPS + hypoxia reduces BDNF more than LPS alone, indicating a synergistic and sex-dependent role of PIA and IMHS in stroke vulnerability at adulthood.
PMID:41973183 | DOI:10.1007/s12035-026-05791-2