Neuroprotection against reactive oxygen species-mediated injury in acute ischemic stroke

Abstract

The roles of reactive oxygen species (ROS) and oxidative stress continue to be a very active area of research in vascular biology with broad implications in both health and disease. In general, low concentrations of ROS function as mediators and modulators of cell signaling. By contrast, higher levels of ROS commonly contribute to vascular disease. Oxidative stress can be broadly defined as an imbalance between generation of ROS and degradation or metabolism of ROS by the various antioxidant defense mechanisms, leading to excessive levels of ROS. The overall effects of ROS depend on local concentrations, subcellular localization, and the proximity of ROS to other target molecules. Ischemic stroke is the consequence of the interruption or severe reduction of blood flow in cerebral arteries. Several compounds have been tested to prove their antioxidant-dependent neuroprotective role in acute ischemic stroke setting. It is currently unknown whether Rac1 GTPase plays an important role in NADPH oxidase activation, ROS generation, and oxidative stress in the hippocampus following stroke and whether inhibition of Rac GTPase activation might preserve cognitive function following cerebral ischemia. Enzyme, NADPH oxidase, contributes significantly to ROS generation following ischemic reperfusion. Activation of NADPH oxidase leads to generation of the superoxide ion (O2 2-), a ROS which can be converted to the highly reactive hydroxyl radical and to peroxynitrite, a highly damaging RNS. To date, five NADPH oxidase enzyme (NOX) isoforms have been identified (NOX 1-5), and localization studies have shown that of the five NOX enzymes, the NOX2 and NOX4 isoforms are highly localized in the hippocampus CA1, and cerebral cortex NOX2 appears particularly important in oxidative stress-induced neuronal cell death following stroke, as evidenced by a dramatic reduction in infarct size in NOX2 knockout animals. Studies in immune cells have provided evidence that the Rho GTPase, Rac1, plays an important role in NOX2 activation in immune cells. Some authors conducted a study to examine the regulatory and functional role of the Rho GTPase, Rac1 in NADPH oxidase activation, ROS generation, and neuronal cell death/cognitive dysfunction following global cerebral ischemia in the male rat. Furthermore, antioxidants have been shown to attenuate ROS formation and neuronal damage in the reperfusion period in a global ischemia model; however, there is limited data demonstrating a direct effect of antioxidants at reducing measured ROS formation during focal ischemia. Others demonstrated that high doses of melatonin given prior to ischemia inhibited production of hydroxyl radicals in the striatum of rats following MCA occlusion. Therefore, it is critical not only to restore blood flow but also to protect neurons in order to reduce brain damage following an ischemic insult. Moreover, an extension of the therapeutic window would be beneficial to treat a broader range of patients with acute brain ischemia.