Background and Purpose We have demonstrated in a previous study that superoxide radicals play a role in the pathogenesis of cerebral infarction, using a transgenic mouse model of distal middle cerebral artery occlusion, 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 radicals in reperfusion injury in transgenic mice overexpressing superoxide dismutase (SOD) is unknown. Using a mouse model of intraluminal blockade of middle cerebral artery that produced both cortical and striatal infarction, we now further examined the role of superoxide radicals in ischemic cerebral infarction after reperfusion in transgenic mice overexpressing human CuZn-SOD activity.Methods Transgenic mice of strain Tg HS/SF-218, carrying human SOD-1 genes, and nontransgenic littermates were anesthetized with chloral hydrate (350 mg/kg IP) and xylazine (4 mg/kg IP). Physiological parameters were maintained at a normal range using a 30% O 2 /70% N 2 O gas mixture inserted via an inhalation mask. Body temperature was maintained at 37±0.5°C by using a heating pad throughout the studies. The middle cerebral artery occlusion was 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 allow reperfusion for another 3 hours. Cerebral infarct size in brain slices and infarct volume, neurological deficit, cortical blood flow, and glutathione levels were measured in both transgenic and nontransgenic mice.

Background and Purpose-To clarify the effect of superoxide dismutase (SOD) on vasospasm after subarachnoid hemorrhage (SAH), we investigated sequential changes in arterial diameter after SAH in transgenic mice overexpressing CuZn-SOD (SOD-1). Methods-SOD-transgenic mice and nontransgenic littermates (35 to 40 g) were subjected to SAH produced by endovascular perforation of left anterior cerebral artery. At 4 hours and 1, 3, 7, and 14 days after SAH, the mice were perfused with 10% formalin and consequently with a mixture of carbon black and 10% gelatin to cast all vessels. Vasospasm was evaluated by measuring the diameter of the left middle cerebral artery (MCA) with a microscope. Results-In nontransgenic mice, the diameter of the MCA on day 3 after SAH (110.5Ϯ20.5 m [meanϮSD]; nϭ16) was significantly reduced compared with that without SAH (138.5Ϯ14.5 m; nϭ12) (PϽ0.01). Moreover, on day 3 after SAH, the diameter of the MCA in SOD-transgenic mice (127.9Ϯ20.2 m; nϭ20) was significantly larger than that in nontransgenic mice (110.5Ϯ20.5 m; nϭ16) (PϽ0.05). Conclusions-These results suggest that SOD is effective on the amelioration of vasospasm after SAH and that oxygen free radicals, particularly superoxide, play an important role in the pathogenesis of vasospasm after SAH. (Stroke. 1999;30:867-872.)Key Words: free radicals Ⅲ mice, transgenic Ⅲ subarachnoid hemorrhage Ⅲ superoxide dismutase Ⅲ vasospasm E rythrocytes are essential for causing vasospasm, and oxyhemoglobin released from erythrocytes in the subarachnoid clot is believed to be a most potent trigger of vasospasm. 1,2 However, the pathophysiology of cerebral vasospasm after subarachnoid hemorrhage (SAH) still remains unclear. Recently, 2 major derangements in the cerebral artery have been indicated as a cause for cerebral vasospasm after SAH. One is augmentation of contraction, which is protein kinase C (PKC) dependent, and the other is suppression of dilation, which is mediated by endothelium-derived relaxing factor/nitric oxide (NO). 3 Oxygen free radicals are involved in both systems; active oxygens can activate the PKC system and lead to lipid peroxidation through activation of phospholipase A 2 , 4 and superoxide (O 2 Ϫ ) is known to inactivate NO, 5 resulting in the occurrence of vasospasm after SAH. Therefore, superoxide dismutase (SOD), an enzyme converting O 2 Ϫ to hydrogen peroxide (H 2 O 2 ), could prevent contraction of the cerebral artery after SAH. Experiments in vivo, however, have not always proven the efficacy of SOD in preventing vasospasm after SAH. Kamiyama et al 6 See Editorial Comment, page 872initially showed that SOD is effective against vasospasm induced by oxyhemoglobin in cats. In addition, intracisternal injection of SOD reduced endothelial injury and prevented the occurrence of vasospasm in a rabbit SAH model. 7 However, intrathecal administration of both SOD and catalase failed to protect against oxyhemoglobin-induced vasospasm in monkeys. 8 The discrepancy in the effect of SOD on vasospasm after SAH may result from difference...

To elucidate the role of oxygen-derived free radicals and superoxide dismutase in traumatic brain injury (TBI), blood-brain barrier (BBB) permeability, brain edema, behavioral function, and necrotic cavity volume (CV) were evaluated after TBI using nontransgenic (nTg) mice and heterozygous and homozygous transgenic (Tg) mice with a 1.5- (Tg 1.5x), 3.1-(Tg3.1x) and five- (Tg5x) fold increase in human copper, zinc-superoxide dismutase (CuZn-SOD) activity. Traumatic brain injury was produced by the weight-drop method. Evans blue dye leakage 4 hours after injury was attenuated in a CuZn-SOD dose-dependent manner with decreases of 18.6%, 40.9%, and 48.8%, in the Tg1.5x, Tg3.1x, and Tg5x groups, respectively. The water content 6 hours after injury in the Tg3.1x (79.64%) and Tg5x (79.45%) groups was significantly lower than in nTg mice (81.37%). There was an initial decrease in body weight and in motor performance, as measured by beam walk and beam balance tasks undertaken 1 day after TBI. However, the average reduction in beam balance and beam walk performance deficits and changes in body weight postinjury were significantly ameliorated in Tg mice. The CV was significantly smaller in Tg mice than in nTg mice (p < 0.01). These results indicate that superoxide radicals play a deleterious role following TBI. Furthermore, Tg mice provide a useful model for demonstrating the beneficial role of an antioxidant enzyme in TBI without the confounding effect of pharmacokinetics, toxicity, and BBB permeability associated with exogenous agents.