Kiran Sankarappan

Introduction. Stroke is the fifth leading cause of death and a leading cause of disability in the United States, affecting 800,000 individuals annually.² The brain is a notable utilizer of oxygen and stroke occurs when an obstruction of an artery prevents blood and oxygen from reaching a certain part of the brain.² Stroke can cause an array of symptoms including facial droop, dysarthria, or complete paralysis.² The risk factors associated with stroke include age, sex, hypertension, and hyperlipidemia.² Stroke is most often diagnosed using nonconstrast computed tomography (CT).² If detected within 4.5 hours of symptom onset, stroke is treated with tisue plasminogen activator (tPA).² If detected within 24 hours of symptom onset, it is treated with dual antiplatelet therapy.² Even with treatment, 50-60% of stroke patients continue to suffer from motor deficits. CCR5, a coreceptor first identified on macrophages for the entry of human immunodeficiency virus (HIV), provides a possible therapeutic target on neurons for treating stroke by upregulating CREB and DLK signaling cascades.¹ CREB, known for its role in memory formation, modulates cognition through transcription factors and DLK regulates forms of neural development including dendritic morphogenesis.⁹ Methods. Fluorescence in situ hybridization (FISH) was performed to identify CCR5 expression changes in post-stroke neurons.¹ Furthermore, CREB and DLK signaling activation was measured using fluorescence activated cell sorting (FACS).¹ Finally, stroke was induced in mice and CCR5 was knocked down (KD) using short hairpin adeno-associated virus gene silencing or by administering Maraviroc, an FDA-approved pharmacological CCR5 antagonist used for HIV.¹ Results. Inhibition of CCR5 on neurons in the post-stroke mice brains enhanced motor recovery and cognition by activating CREB and DLK signaling pathways.¹ Motor recovery in mice was measured using gridwalk and cylinder tests.¹ In these tests, both viral KD and pharmacological blockade resulted in significant decreases in foot faults and forelimb bias post-stroke compared to the control group.¹ Conclusion. CCR5 KD following stroke improved motor and cognitive recovery in mice through the upregulation of CREB and DLK signaling cascades.¹ Such findings implied that CCR5 blockade has the potential to be translated into therapeutics to combat stroke-induced motor and cognitive deficits. From this perspective, CCR5 antagonist Maraviroc, an FDA-approved drug for HIV, could be tested in clinical trials to ease the complications of a stroke, the leading cause of death and disability in the United States.

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