Abstract
Introduction: We have recently shown that the angiotensin type 2 receptor (AT2R) agonist, compound 21 (C21), provides sustained functional recovery after ischemic stroke. This was associated with upregulation of the AT2R and the neurotrophin, brain derived neurotrophic factor (BDNF), in the contralesional brain hemisphere. Here, we aimed to study the contribution of this hemisphere in C21 mediated functional recovery after stroke through localized knockdown of the AT2R. Methods: male wistar rats (34) received two intrastriatal injections of short hairpin RNA (shRNA) lentiviral particles against AT2R, or non-targeting control vector (NTC) into the left brain hemisphere to achieve localized AT2R knockdown. After 14 days, rats were subjected to 90 minutes right middle cerebral artery occlusion (MCAO) and received either C21 (0.03 mg/kg) or saline at reperfusion (IV) then daily (IP) for 7 days. Rats were blindly assessed for behavioral outcome up to 10 days as well as molecular analysis. Results (table): PCR and Western blotting confirmed successful knockdown of the AT2R in the left (contralesional) hemisphere by about 50%. All groups showed worsened outcome on days 1 to 3 then recovered on days 7 to 10. The C21/NTC group showed better behavioral outcome compared to other groups at days 7 and 10, while the saline/shRNA group was associated with the least recovery. Using Western blotting, C21/NTC group showed higher BDNF and lower proBDNF (pro-form) levels in the ischemic and contralesional hemispheres respectively. Expression of the pro-apoptotic P75NTR receptor of proBDNF was decreased with C21 treatment irrespective of AT2R knockdown. Conclusion: Contralesional AT2R could be involved in C21 mediated functional recovery after stroke.
Published Version
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