Delayed Administration of Angiotensin Receptor (AT2R) Agonist C21 Improves Survival and Preserves Sensorimotor Outcomes in Female Diabetic Rats Post-Stroke through Modulation of Microglial Activation.

Ladonya Jackson-Cowan,Guangkuo Dong,Wael Eldahshan,Selin Dumanli,Susan C Fagan,Babak Baban,Adviye Ergul,Waleed Althomali,Yasir Abdul,Sarah Jamil

doi:10.3390/ijms22031356

Abstract

About 70% of stroke victims present with comorbid diseases such as diabetes and hypertension. The integration of comorbidities in pre-clinical experimental design is important in understanding the mechanisms involved in the development of stroke injury and recovery. We recently showed that administration of compound C21, an angiotensin II type 2 receptor agonist, at day 3 post-stroke improved sensorimotor outcomes by lowering neuroinflammation in diabetic male animals. In the current study, we hypothesized that a delayed administration of C21 would also lower chronic inflammation post-stroke in diabetic female animals. Young female diabetic rats were subjected to 1 h of middle cerebral artery occlusion (MCAO). Three 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 impact of C21 on microglial polarization was analyzed by flow cytometry in vivo and in vitro. Compound 21 treatment improved fine motor skills after MCAO through modulation of the microglia/macrophage inflammatory properties. In addition, C21 increased M2 polarization and reduced the M1:M2 ratio in vitro. In conclusion, delayed administration of C21 downregulates post-stroke inflammation in female diabetic animals. C21 may be a useful therapeutic option to lower neuro-inflammation and improve the post-stroke recovery in diabetes.

Highlights

Licensee MDPI, Basel, Switzerland.Stroke is a leading cause of death and disability both in the U.S and worldwide.A vast dichotomy of stroke outcomes exists between men and women
We have shown a tendency toward improvement of survival at 14 days in female Wistar rats [8]
The objectives of the current study werewere to determine whether delayed administration

Summary

Introduction

Stroke is a leading cause of death and disability both in the U.S and worldwide. A vast dichotomy of stroke outcomes exists between men and women. In younger and middle-aged groups, stroke incidence rates are lower in women compared to men, whereas in the higher age groups the incidence rates in women are equal to or higher than those in men [1]. Younger age can be protective in women, interestingly this protection is negated in the presence of diabetes [2].

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