Chronic intermittent oxygen deprivation alters hippocampal cholinergic and glutamatergic system via oxido-inflammatory burden and HIF-1a/Bcl-2 activity in hypothyroid mice: Ameliorative role of Ginkgo biloba supplement

Background: Several investigations in recent years have reported a relationship between hypothyroidism or ischemia and central nervous system (CNS) beginning from fetal to adult life, but the effect of ischemia and hypothyroidism comorbidity on CNS and whether phytotherapeutic approach would attenuate this pathology remains unknown. Thus, the study investigated the role of ginkgo biloba supplement (GBS), a potent anti-oxido-inflammatory and neurorestorative plant-based product on hypoxic stress-induced neurobehavioral and neurophysiological alterations in hypothyroid mice, and the underpinning molecular mechanisms Methodology: Mice were orally pre-treated with Carbimazole (1.2 mg/kg) for 14 days to develop hypothyroidism. Post-hypothyroid induction, mice were treated orally with GBS (20 mg/kg) and levothyroxine (10 µg/kg) 1 hr before 20 min exposure to hypoxia (5 times daily) for 14 consecutive days. Symptoms of behavioral deficit and neuropsychiatry were evaluated in using different models. Thereafter, brain hippocampi were sectioned for biochemical assays, immunohistochemistry and histoarchitectural studies. Results: Herein, treatment with GBS suppressed spatial memory deficit and neuropsychiatric phenotypes and attenuated hippocampal cholinergic excitotoxicity by enhancing acetylcholinesterase enzyme and glutamatergic release in the hypothyroid mice following hypoxic stress exposure. The hippocampal endogenous antioxidant system was also upregulated with concomitant downregulation of inflammatory mediators. GBS treatment consequently regulated the hypothalamic-pituitary-adrenal axis to reduce corticosterone release. Additionally, our data showed that the suppressive impact of GBS on oxido-inflammatory mainstream decreases immunoexpression of hypoxic inducible factor-1alpha (HIF-1α) and loss of hippocampal pyramidal neurons in the CA3 region with marked increase in viable neuronal cells and upregulated immunoexpression of B-cell lymphoma-2 (Bcl-2) anti-apoptotic marker. Conclusion: Herein, we deduced that prolonged intermittent exposure to hypoxia in hypothyroidism may provoke further the psychological and physiological status in the hippocampal brain region. Meanwhile, reversal of these provocative effects by the GBS treatment might be playing an important effect to suppress the hypoxic/ischemic triggered neurobehavioral and neurophysiological alterations.