Cysteinyl leukotrienes (CysLTs) induce inflammatory responses by activating their receptors, CysLT1R and CysLT2R.We have reported that CysLT2R is involved in neuronal injury, astrocytosis and microgliosis, and intracerebroventricular injection of the selective CysLT2R antagonist HAMI 3379 protects against acute brain injury after focal cerebral ischemia in rats.In the present study, we administrated HAMI 3379 to rats by intraperitoneal injection to determine its effect on ischemic brain injury after middle cerebral artery occlusion (MCAO).We found that the protective effect of HAMI 3379 against acute brain injury 24 h after MCAO with effective dose range of 0.1-0.4 mg · kg-1 and a therapeutic window of 1 h.It attenuated neurological deficits, and reduced infarct volume, brain edema, neuron loss and degeneration 24 and 72 h after MCAO.Also, it inhibited the release of the cytokines IL-1 β, IFN-γ and TNF-α in the serum and spinal cerebral fluid 24 h after MCAO.Moreover, HAMI 3379 ameliorated the microglial activation and neutrophil accumulation in the ischemic regions, but did not affect astrocyte proliferation 72 h after MCAO.In comparison, the CysLT1R antagonist pranlukast did not affect microglial activation and IFN-γ release, but inhibited astrocyte proliferation and serum IL-4.From these results, we conclude that HAMI 3379 has a protective effect on acute and subacute brain ischemic injury, and attenuates microglia-related inflammation.Thus, the CysLT2R antagonist(s) or combination with CysLT 1R antagonists may be a novel class of therapeutic candidates in the treatment of ischemic of stroke.