👤 Benneth Ben-Azu

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. Show less

To date, the burden of alcohol-related seizures is increasing, with an unexplored etiological complex, and the psychopharmacological interplay remains significantly scarce. In this study, we developed an experimental approach to investigate the contrasting impact of alcohol on pentylenetetrazol-induced seizures and the effects of diosgenin, a phytosteroid agent with neuroprotective effects. After 7 days of binge alcoholism with ethanol (2 g/kg, oral gavage) in male mice, they were subjected to maximum and sub-convulsive pentylenetetrazol-induced seizures concomitantly with diosgenin (25 and 50 mg/kg, p.o.) or diazepam (3 mg/kg, p.o) treatments from days 8-14. The interaction between ethanol and pentylenetetrazol-induced seizures was investigated, along with behavioral comorbidities, hypothalamic-adrenal-pituitary-axis (HPA-axis), neurochemical and neurotrophic dysfunctions, oxidative stress, and neuroinflammation in the hippocampus, prefrontal cortex, and striatum. Ethanol-exacerbated pentylenetetrazol-induced seizure and frequency, characterized by rearing with myoclonic jerks, and clonic-tonic convulsions. It increased anxiety, depressive behavior and impaired spatial working memory, influenced by heightened alcohol preference and corticosterone levels, which were normalized by diosgenin. Concomitant ethanol administration exacerbated reductions in GABAergic-dependent glutamic acid decarboxylase and increased glutamate levels associated with pentylenetetrazol-induced seizures, alongside depletions of serotonin and brain-derived neurotrophic factor in the hippocampus, prefrontal cortex, and striatum. Among others, diosgenin, compared to ethanol-pentylenetetrazol exacerbation, reduced levels of myeloperoxidase, TNF-α, and IL-6, nitrite and malondialdehyde in the hippocampus, prefrontal cortex, and striatum while increasing IL-10 cytokine and antioxidant system (superoxide-dismutase, glutathione, and glutathione-transferase). These findings suggest that alcoholism exacerbates seizures across brain regions, involving neurochemical imbalance, HPA-axis dysfunction, oxidative stress, and neuroinflammation, which are reversible by diosgenin. Show less