Abstract WP155: Delayed Administration of Angiotensin Receptor (AT2-R) Agonist C21 Downregulates Diabetes Induced Pro-Inflammatory Microglia Activation Post-Stroke in Female Rats: Therapeutic Indications for Vascular Cognitive Impairment & Dementia

Abstract

Post-stroke cognitive impairment (PSCI) occurs in up to 48% of patients, for which there is no therapy. Although 70% of stroke victims present with comorbid diseases such as diabetes and hypertension, the inadequate integration of these comorbidities into experimental studies limited our understanding of the mechanisms involved in the development of PSCI. Based on our recent findings that 1) the increased prevalence of PSCI in male diabetic animals is linked to heightened chronic inflammation and 2) even delayed administration of compound 21 (C21), an angiotensin II Type 2 receptor agonist, effectively reduces PSCI by lowering inflammation in male animals, we hypothesized that a delayed administration of C21 would also lower chronic inflammation post-stroke in female animals. Methods: Diabetes was induced by a high fat diet (HFD) and low dose streptozotocin (STZ) combination. Rats were subjected to 1 h middle cerebral artery occlusion (MCAO) or sham surgery. 3 days post-stroke, rats were administered C21 or vehicle in drinking water at a dose of 0.12 mg/kg/day for 4 weeks. The direct effect of C21 on microglia polarization was determined in mouse cells (C8B4) and the mature:pro BDNF ratio was evaluated through western blot. Samples from freshly harvested brains (B-D slice containing the prefrontal cortex through the hippocampus), and from cell culture were analyzed by flow cytometry. Results: Delayed administration of C21 starting 3 days post-stroke improved inflammation through modulation of the M1/M2 ratio. Cell culture results indicated that along with decreasing the M1/M2 ratio, it also increased the mature/pro-BDNF ratio. Conclusion: Delayed administration of C21 downregulates post-stroke inflammation in both male and female diabetic animals. This study emphasizes the importance of translational disease modeling and suggests that C21 may be a useful therapeutic option to lower inflammation and prevent PSCI in comorbid diseases.