Abstract
Introduction: Stroke remains a leading cause of disability in the United States. Despite recent advances, interventions to reduce damage and enhance recovery after stroke is lacking. Therefore, validating new drug targets is critical for stroke treatment. P2X4, a receptor for adenosine triphosphate ATP, regulate activation of myeloid immune cells (both infiltrating monocytes/macrophages and brain-resident microglia) after stroke injury. Over-stimulation of P2X4Rs, due to excessive ATP release from the dying or damaged neuronal cells, contributes to ischemic injury. In this study, we pharmacologically targeted P2X4R to control immune response of myeloid cells during acute stroke phase and studied recovery at acute or chronic time point after stroke. Methods: We subjected 8-12 weeks old wild type mice of both sexes to 60 min right middle cerebral artery occlusion (MCAo) followed by 3 (acute) or 30 (chronic) days of reperfusion. We performed histological, behavioral (sensorimotor, anxiety and depressive), and flow cytometric analyses to determine the acute and chronic outcomes after P2X4R inhibitor 5-BDBD (1mg/kg P.O daily x3 days started after 4 hrs. of MCAo) treatment. Results: Treatment with 5-BDBD for 3 days not only significantly (*P<0.05) reduced infarct volume (40.94 ± 7.512 N=7 vs 21.21 ± 7.372 N=11, unpaired t-test) and neurological deficit (ND) score at 3 days post-stroke but also showed a progressive recovery on motor and balance coordination using rotarod test (*P<0.05) during chronic recovery at 30 days. 5-BDBD treatments also improved (*P<0.01) anxiety like behavior during the chronic recovery. We did not see any effect on depression like behavior. Flow cytometric analysis reveals that 5-BDBD treatment significantly reduced (*P<0.05) total number of infiltrated leukocytes. Subsequent analysis revealed that among those infiltrated leukocytes the number of Ly6C +hi pro-inflammatory monocytes was reduced in 5-BDBD vs. vehicle treated mice. Conclusions: Acute P2X4R inhibition protects against ischemic injury at both acute and chronic time point after stroke. Reduced number of infiltrated Ly6C +hi proinflammatory monocyte in 5-BDBD treated mice suggests its potential mechanism of neuroprotection after stroke.
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