Radical Scavengers for Brain Ischemia Reperfusion injury

DESCRIPTION (provided by applicant): The goal of this proposal is to determine the potential of two MFH free radical scavenging compounds, Didox and Imidate, to protect brain tissue from stroke injury due to the deleterious effects of ischemia and reperfusion. Free radical generation is strongly associated with exacerbation of cerebral ischemia upon reperfusion. Didox and Imidate have exhibited biochemical properties that indicate that they are good candidates to protect against brain ischemia reperfusion injury. These compounds are very effective free radical scavengers. They have been shown to reduce inflammatory injury, to lower the level of deleterious cytokines, to inhibit NF(B activation, to down regulate neutrophil activation, and most importantly to protect against cardiac reperfusion injury in three animal models. In preliminary experiments we have been able to detect both Didox and Imidate in brain tissue after systemic administration. In this project, these compounds will be tested for efficacy in protecting brain tissue using an in vivo rat model of cerebral ischemia and reperfusion employing middle cerebral artery occlusion. The effect of the drugs on infarct size will be assessed histologically. Behavioral impairment will also be monitored as an indication of brain damage. The ability of systemic administration of Didox and Imidate to affect generation of free radicals during cerebral ischemia and reperfusion will be monitored by EPR imaging in the brain. Microdialysis will also be used to follow the presence of the OH radical by monitoring the production of 3,4-dihydroxybenzoic acid. Similarly, EPR imaging employing infused nitroxides to monitor the redox status of the tissue will be used to determine whether MFH compounds are able to maintain normal brain tissue redox status. These data will provide important information regarding the efficacy of these compounds as therapeutic drugs to prevent or ameliorate brain ischemia reperfusion injury.