HUMAN COPPER-ZINC SUPEROXIDE-DISMUTASE TRANSGENIC MICE ARE HIGHLY RESISTANT TO REPERFUSION INJURY AFTER FOCAL CEREBRAL-ISCHEMIA

Background and Purpose We have demonstrated in a previous study that s uperoxide radicals play a role in the pathogenesis of cerebral infarct ion, using a transgenic mouse model of distal middle cerebral artery o cclusion, permanent ipsilateral cerebral carotid artery occlusion, and 1-hour contralateral cerebral carotid artery occlusion that produced infarction only in the cortex. However, the role of superoxide radical s in reperfusion injury in transgenic mice overexpressing superoxide d ismutase (SOD) is unknown. Using a mouse model of intraluminal blockad e of middle cerebral artery that produced both cortical and striatal i nfarction, we now further examined the role of superoxide radicals in ischemic cerebral infarction after reperfusion in transgenic mice over expressing human CuZn-SOD activity. Methods Transgenic mice of strain Tg HS/SF-218, carrying human SOD-1 genes, and nontransgenic littermate s were anesthetized with chloral hydrate (350 mg/kg IP) and xylazine ( 4 mg/kg IP). Physiological parameters were maintained at a normal rang e using a 30% O2/70% N2O gas mixture inserted via an inhalation mask. Body temperature was maintained at 37+/-0.5-degrees-C by using a heati ng pad throughout the studies. The middle cerebral artery occlusion wa s achieved with a 5-0 rounded nylon suture placed within the internal cerebral artery for 3 hours followed by the removal of the suture to a llow reperfusion for another 3 hours. Cerebral infarct size in brain s lices and infarct volume, neurological deficit, cortical blood flow, a nd glutathione levels were measured in both transgenic and nontransgen ic mice. Results Compared with the nontransgenic mice, the infarcted a reas were significantly decreased in coronal slices from transgenic mi ce. The infarct volume (in cubic millimeters) was reduced by 26% in tr ansgenic mice after ischemia and reperfusion. This decrease in the inf arct volume in transgenic mice closely paralleled the reduced neurolog ical deficits. Introduction of the suture to block blood supply to the middle cerebral artery territory produced a rapid decrease in the rel ative surface blood flow in the ipsilateral core and the peri-ischemic (penumbra) areas. There were no significant differences in the local cerebral blood flow in the ischemic core or the penumbra areas between the transgenic and nontransgenic groups. However, the level of reduce d glutathione in the penumbra area was significantly higher in transge nic mice than in nontransgenic mice, whereas there was no difference i n the reduced glutathione levels in the ischemic core between these tw o groups. Conclusions Our study demonstrated that superoxide radicals play a major role in the pathogenesis of cerebral infarction in reperf usion injury after a focal stroke. The reduction in infarct volume and neurological deficits is not dependent on the changes in cerebral blo od flow but rather correlate with reduced oxidative stress in the isch emic brain tissue, which was indicated by the relatively high levels o f endogenous reduced glutathione in transgenic mice.