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Prenatal Immune Activation and Intermittent Maternal Hypoxic Stress Exacerbate Ischaemic Stroke in Adult Rats: A
Faith B Friday1, Benneth Ben-Azu1, Prosper Iwhiwhu1
1DELSU Joint Canada-Israel Neuroscience and Biopsychiatry Laboratory, Department of Pharmacology, Faculty of Allied Health Sciences, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria.
Abstract:
The developmental origins of health and disease hypothesis states that prenatal immune activation (PIA) and hypoxic stress contribute to long-term susceptibility to neurological disorders, including ischaemic stroke. However, an understanding of the interplay between PIA and intermittent maternal hypoxic stress (IMHS) in animal models of ischaemic stroke vulnerability remains unknown. We developed an experimental approach to examine how PIA and IMHS together affect neurological and biochemical outcomes in a rat model of ischaemic stroke caused by bilateral common carotid artery occlusion/reperfusion (BCCAO/R). PIA was induced with lipopolysaccharide (0.1 mg/kg, ip) injection at gestational day (GD) 15, followed by IMHS exposure from GD 17 to delivery. Male and female offspring of dams from different groups were divided into the following cohorts: sham control, BCCAO/R (from naïve rats), LPS-exposed, hypoxia-exposed and LPS + hypoxia coexposed (n = 10 per sex). After monitoring behavioural, neurological phenotypes during infancy, adolescence and adulthood using various neurological test tools, we conducted BCCAO/R-induced cerebral hypoperfusion at postnatal day (PND) 90 in adult offspring (Groups 2-5) to assess ischaemic stroke vulnerability. Afterwards, neurological deficits and behavioural tests were re-conducted at 1 and 5 h postsurgery. Behavioural characterisation across infancy (PNDs 25-30), adolescence (PNDs 35-40) and adulthood (PNDs 85-88) served as developmental phenotyping of the prenatal stressor model and was not performed in the context of stroke induction. The prefrontal cortex and striatum were analysed for oxidative markers, molybdoenzymes, cholinergic function and inflammatory markers (myeloperoxidase, interleukin-1β and interleukin-4), which are implicated in the disease. Combined PIA + IMHS significantly intensified post-reperfusion neurological and motor impairments, elevated lipid peroxidation and nitrergic stress and suppressed antioxidant defences, notably in females. These prenatal stressors shifted cytokine profiles toward inflammation and increased myeloperoxidase activity. Females showed higher striatal IL-1β responses and cortical cholinergic dysfunction, worsening ischaemic vulnerability through oxidative-inflammatory mechanisms.