Inhibition of C-C Chemokine Receptor 5 (CCR5) Can Increase Synaptic Plasticity, Enhancing Motor Recovery and Brain Function After Stroke
Introduction. A stroke is an interruption of the blood supply to the brain and kills about 140,000 Americans every year1; it is the leading cause of long-term disability in the United States.1 The identification of a specific process that governs the ability of the brain to recover from hypoxic injury remains one of the biggest unknowns in stroke medicine. Studies have shown that C-C chemokine receptor 5 (CCR5) is upregulated in the CNS following a stroke and CCR5 inhibition leads to better motor recovery and increased synaptic plasticity. Maraviroc, an FDA approved drug for HIV treatment that acts as a noncompetitive antagonist of CCR5, presents a commercially available therapeutic to target this mechanism.2 Methods. The photo-thrombotic stroke model was utilized. Fluorescence in-situ hybridization (FISH) involved detection of CCR5 transcripts in sections of mouse cortex and checking for co-localization with either TUBB3 positive (neuronal marker) or CX3CR1 positive (microglial marker) under normal conditions and at various conditions after stroke.2 Freezing time during fear conditioning tests was used to measure contextual learning in mice. The time spent in the target quadrant Morris Water Maze test was used to analyze spatial learning.3 The number of right limb foot faults during the grid walk test were used study motor function.4 Results. Under normal conditions, CCR5 is expressed only in microglia, but it’s expression is induced in neurons for up to 28 days while gradually declining in microglia/macrophages post-stroke.2 CCR5 knockdown (kd) leads to motor recovery after stroke in mice, demonstrated via fewer deficits in the grid walk and cylinder tests.2 Both CCR5 +/- and CCR5 -/- displayed enhanced contextual fear conditioning.CCR5+/- mice were able to find and spend significantly more time in the target quadrant than, whereas the WT mice did not search for the platform at all.3 CCR5Kd and stroke neurons had large significant increases in DLK, CREB, and pCREB when compared to stroke and control AAV.2 Mice treated with Maraviroc at various time points after stroke display better performance in the grid-walk test.2 NCT03172026 is an on-going clinical trial that aims to determine the efficacy of 8 weeks of daily Maraviroc administration alongside traditional rehabilitation.4 Conclusion. CCR5 inhibition leads to activation of several pathways that function to increase synaptic plasticity, neuronal regeneration, and motor recovery through key molecules such as CREB and DLK.2 Maraviroc offers a readily available drug to quickly leverage this mechanism to drive functional recovery in stroke patients.2
- Ringer, Andrew, Jimenez, Lincoln. Stroke. https://mayfieldclinic.com/pe-stroke.htm. April, 2018. Accessed February 26, 2020.
- Joy M, Assayag E, Shabashov-Stone D, Silva A, Shohami E, Carmichael T. CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury. Cell.com. https://www.cell.com/cell/pdf/S0092-8674(19)30107-2.pdf. Published 2019. Accessed February 27, 2020
- Miou Z, Start G, Shan H, et al. CCR5 is a suppressor for cortical plasticity and hippocampal learning and memory. 2016, eLIFE. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5213777/. Accessed April 3, 2020.
- Bruce D. Maraviroc to Augment Rehabilitation Outcomes After Stroke (MAROS). 2017. U.S. National Library of Medicine. Accessed March 30, 2020.