The Role of CCR5 as a Therapeutic Target in Stroke
Introduction. Stroke disrupts normal blood flow to the central nervous system and is the second leading cause of death globally.2 Stroke can be divided into hemorrhagic or ischemic types. Hemorrhagic strokes entail bleeding into the brain tissue, while ischemic strokes cause infarctions.2 Ischemic strokes make up the vast majority of stroke cases worldwide. Age, sex, and genetic factors all play a role in stroke incidence.2 Most ischemic strokes are thromboembolic and originate from large artery atherosclerosis and cardiac diseases. Tissue plasminogen activator (tPA) is the treatment in the acute setting for ischemic stroke. However, tPA must be given within 4.5 hours of stroke onset and is commonly contraindicated due to bleeding risks.2 Even with tPA administration, 50-60% of stroke patients continue to suffer from motor deficits after recovery. Due to the lack of efficient therapeutic targets, physical rehabilitation is the only option to alleviate motor deficits. CCR5, a coreceptor first identified in cellular human immunodeficiency virus (HIV) entry, provides a possible target to fill this treatment gap.1 Methods. Fluorescence in situ hybridization (FISH) was performed to identify changes in CCR5 expression in neural cells following stroke. In another experiment, ischemic stroke was induced in a mouse model and CCR5 was knocked down (KD) by AAV-mediated gene silencing or blocked by administering maraviroc, a pharmacological CCR5 antagonist and an FDA-approved drug for HIV patients.1 Testing was done following CCR5 KD to assess for motor recovery. These groups were compared to a control group that did not receive CCR5 KD or maravoric.1 Results. An increased CCR5 expression was observed in neurons post-stroke, whereas CCR5 is normally only expressed in microglia in the healthy brain. Both viral KD and pharmacological blockade resulted in significant decrease in foot faults and forelimb bias post-stroke compared to the control group. Mice with CCR5 KD also showed increased expression of cAMP-response element binding protein (CREB) and dual leucine zipper kinase (DLK), which are vital for cognitive function and axonal regeneration, respectively.1 Conclusions. Enhanced motor recovery and improved cognitive function were observed with CCR5 KD or blockade following ischemic stroke. Signaling cascades, including DLK and CREB, have been linked to the motor and cognitive recovery following CCR5 KD or blockade via maraviroc.1 Application of such therapy in future clinical trials for stroke appears promising, as maraviroc is an FDA-approved drug currently used to antagonize CCR5 in HIV patients.
- Joy MT, Ben Assayag E, Shabashov-Stone D, et al. CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury. Cell. 2019;176(5):1143-1157.e13. doi:10.1016/j.cell.2019.01.044
- Campbell, B.C.V., De Silva, D.A., Macleod, M.R. et al. Ischaemic stroke. Nat Rev Dis Primers 5, 70 (2019). https://doi-org.srv-proxy2.library.tamu.edu/10.1038/s41572-019-0118-8