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It has been reported that the novel ATP-sensitive potassium (K-ATP) channel opener iptakalim (IPT) decreases ischemic neuronal damage in rats. However, the mechanisms underlying neuroprotection are still to be fully elucidated. The results of this study showed that mice with ischemia induced by middle cerebral artery occlusion exhibited higher mortality and more neurological deficits, as well as larger infarct volume, compared with sham mice. Moreover, it was found that ischemia activated astrocytes surrounding CA1 neurons with an increased expression of D-serine, induced greater microglial activation accompanied by higher tumor necrosis factor alpha (TNF-α) production, and caused higher expressions of matrix metalloproteinase 9 (MMP-9) in the endothelial cells of mice. Pretreatment with IPT significantly attenuated the neurological deficits and decreased the infarct volume in mice. IPT treatment could decrease MMP-9 secretion, inhibit astrocytic activation with decreasing D-serine and elevating connexin43 expression. Microglial activation was also inhibited and TNF-αproduction was decreased by IPT. Taken together, a K-ATP channel opener may improve the function of neurovascular unit and protect against ischemic injury. These findings suggest that targeting K-ATP channels provides a promising therapeutic approach for stroke.