Abstract P813: Enhanced Stress Response is Associated With Increased Inflammation and Worse Outcomes Following Ischemic Stroke in Diabetic Condition

Abstract

Introduction: Although stroke severity is increased in patients with diabetes (e.g., higher mortality, larger infarcts, and worse neurological deficits), the underlying mechanism(s) of the worse outcomes is not clear. Evidence shows that hypothalamic-pituitary-adrenal (HPA) axis is dysregulated and cortisol levels are increased in diabetes. Based on the role of HPA axis in immunity, we hypothesized that diabetes-enhanced stress response contributes to stroke injury via regulating inflammation. Methods: Diabetes was induced in C57BL/6 mice by feeding a diabetogenic diet and injecting streptozotocin. Mice were subjected to 30 min middle cerebral artery occlusion. Infarct volume and neurological scores were measured at 24h-post stroke. We measured expression of factors related to stress response, plasma corticosterone, c-Fos and corticotropin-releasing factor (CRH) in hypothalamus, and proopiomelanocortin (POMC) and corticotropin-releasing hormone receptor 1 (CRHR1) in pituitary. Inflammatory cytokine levels were also determined in the ischemic brain. Results: Diabetic mice showed hyperglycemia and delayed glucose clearance in blood. At 1d-post stroke, diabetic mice showed larger infarct and worse neurological score. Plasma corticosterone levels were significantly increased in diabetic mice. We also found increased c-Fos in hypothalamus, and CRHR1 and POMC in pituitary. These were accompanied by increased IL-1β, TNF-α, and IL-6 mRNA in the ischemic brain. Conclusion: Our results indicate that stress response is enhanced in diabetic conditions, and associated with increased inflammation in ischemic brain and worse stroke outcomes. It suggests that regulation of stress response may improve stroke outcomes in diabetic conditions.