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Abstract
A disabling consequence of stroke is cognitive impairment, occurring in up to 48% of patients, for which there is NO therapy. A critical barrier is the lack of understanding of how post- stroke cognitive impairment (PSCI) develops. While 70% of stroke victims present with comorbid diseases such as diabetes & hypertension, the limited use of comorbid disease models in preclinical research further contributes to this lack of progress. Since otherwise healthy rats recover motor and cognitive function almost fully post-stroke, deficits that develop overtime in the comorbid environment, as in stroke patients, go unrecognized and remain understudied. To this end, we used a translational model of diabetes to study the development of PSCI. We then investigated whether the chronic inflammatory state of diabetes contributed the development of PSCI. Stimulation of angiotensin II type 2 receptor (AT2R) has emerged as a novel therapeutic strategy in vascular and nervous system diseases by virtue of its anti-inflammatory, anti- proliferative and tissue regenerating properties. To this end, we evaluated the application of compound 21 (C21), for the treatment of PSCI in vivo in a double blinded manner, with a strict inclusion criteria and a delayed administration time-point. Lastly, we employed a global knockdown with intracerebroventricular (ICV) instillation of lentiviral shRNA for colony - stimulating factor 1 receptor (CSF1R), to silence microglia and investigate its therapeutic potential while deciphering underlying mechanisms of cognitive decline. We discovered that diabetes drastically exacerbated cognitive decline after a stroke and this was mediated by the elevated inflammatory state within these animals. When microglia activation was polarized toward an anti-inflammatory state with C21 or reduced by global knockdown the decline in cognition post-stroke was reduced. This highly translational study demonstrated that 1) the progressive nature of PSCI offers an opportunity to prevent cognitive decline; 2) AT2R agonism is a promising therapeutic tactic in the prevention of PSCI; and 3) microglia activation is a contributing mechanism. Evaluating the therapeutic potential in our comorbid model may pave the road for a move toward more translational preclinical studies that may lead to a higher number of successful clinical trials and FDA approved stroke therapies.