Oxidative stress and inflammation are two critical pathological processes of cerebral ischemia-reperfusion injury. Myeloperoxidase (MPO) is a critical inflammatory enzyme and therapeutic target triggering both oxidative stress and neuroinflammation in the pathological process of cerebral ischemia-reperfusion injury. MPO is presented in infiltrated neutrophils, activated microglial cells, neurons, and astrocytes in the ischemic brain. Activation of MPO can catalyze the reaction of chloride and H₂O₂ to produce HOCl. MPO also mediates oxidative stress by promoting the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), modulating the polarization and inflammation-related signaling pathways in microglia and neutrophils. MPO can be a therapeutic target for attenuating oxidative damage and neuroinflammation in ischemic stroke. Targeting MPO with inhibitors or gene deficiency significantly reduced brain infarction and improved neurological outcomes. This article discusses the important roles of MPO in mediating oxidative stress and neuroinflammation during cerebral ischemia-reperfusion injury and reviews the current understanding of the underlying mechanisms. Furthermore, we summarize the active compounds from medicinal herbs with potential as MPO inhibitors for anti-oxidative stress and anti-inflammation to attenuate cerebral ischemia-reperfusion injury, and as adjunct therapeutic agents for extending the window of thrombolytic treatment. We highlight that targeting MPO could be a promising strategy for alleviating ischemic brain injury, which merits further translational study.

J. Neurochem.(2012)120, 147–156. The roles of caveolin‐1 (cav‐1) in regulating blood–brain barrier (BBB) permeability are unclear yet. We previously reported that cav‐1 was down‐regulated and the production of nitric oxide (NO) induced the loss of cav‐1 in focal cerebral ischemia and reperfusion injury. The present study aims to address whether the loss of cav‐1 impacts on BBB permeability and matrix metalloproteinases (MMPs) activity during cerebral ischemia‐reperfusion injury. We found that focal cerebral ischemia‐reperfusion down‐regulated the expression of cav‐1 in isolated cortex microvessels, hippocampus, and cortex of ischemic brain. The down‐regulation of cav‐1 was correlated with the increased MMP‐2 and ‐9 activities, decreased tight junction (TJ) protein zonula occludens (ZO)‐1 expression and enhanced BBB permeability. Treatment ofN^G‐nitro‐l‐arginine methyl ester [l‐NAME, a non‐selective nitric oxide synthase (NOS) inhibitor] reserved the expression of cav‐1, inhibited MMPs activity, and reduced BBB permeability. To elucidate the roles of cav‐1 in regulating MMPs and BBB permeability, we used two approaches including cav‐1 knockdown in cultured brain microvascular endothelial cells (BMECs)in vitroand cav‐1 knockout (KO) micein vivo. Cav‐1 knockdown remarkably increased MMPs activity in BMECs. Meanwhile, with focal cerebral ischemia‐reperfusion, cav‐1 deficiency mice displayed higher MMPs activities and BBB permeability than wild‐type mice. Interestingly, the effects ofl‐NAME on MMPs activity and BBB permeability was partly reversed in cav‐1 deficiency mice. These results, when taken together, suggest that cav‐1 plays important roles in regulating MMPs activity and BBB permeability in focal cerebral ischemia and reperfusion injury. The effects ofl‐NAME on MMPs activity and BBB permeability are partly mediated by preservation of cav‐1.