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Purpose: Inflammatory responses after ischemic stroke contribute to worsening of ischemic brain injury. Calcium release-activated calcium (CRAC) channels are known to be involved in the activation of immune responses in microglia, and have been studied indirectly through non-specific calcineurin inhibitors such as cyclosporine and FK506. Since these compounds have many off-target effects and unacceptable side effects, we studied a novel CRAC channel inhibitor which is specific to the CRAC channel and appears safe in preclinical studies in anticipation of human clinical trials for other indications. We explored whether this inhibitor might improve outcome in experimental stroke by inhibiting microglial activation.Subjects and Methods: 2-3 month old C57/BL6 male mice, were exposed to transient middle cerebral artery occlusion (tMCAO, filament model) for 2h followed by reperfusion. Some were treated with the CRAC channel inhibitor (CM-EX-137, 5mg/kg IP; tMCAO-CM) or vehicle control (tMCAO) daily beginning immediately after occlusion and the following two days. Brains were collected 3d post-stroke. Neurological function was evaluated using a Bederson score, elevated body swing test, adhesive removal test, and corner test at baseline, at 3, 24 and 72 h. Relative cerebral blood flow (rCBF) was studied in some mice using laser Doppler flowmetry. Ischemic lesion size was evaluated by 2,3,5-triphenyl tetrazolium chloride (TTC) staining. Microglial/monocyte activation was assessed by isolectin B4 histochemistry.Results: A total of 18 mice were studied (tMCAO-CM: 8; tMCAO: 8, sham:2). rCBF was no different between experimental groups, and is consistent with the notion that the compound should not alter blood flow. Neurological function at 1 & 3d after ischemia was significantly improved in tMCAO-CM group compared to tMCAO (p<0.001). The CM compound also significantly reduced infarct volume by ~60% (p<0.05). Isolectin B4 staining was markedly reduced in the tMCAO-CM group compared to tMCAO 3d post ischemia (p<0.01).Conclusion: CRAC channel inhibition protects against experimental stroke by decreasing lesion size, improving neurological outcomes and decreasing microglial activation.