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: Reduction of cerebral blood flow results in several acute metabolic disturbances, including a reduction in Na,K-ATPase activity. The relation between this reduction and the onset of edema is unknown, as is the effect of restoration of blood flow. Therefore, we investigated the role of decreased Na,K-ATPase activity in the pathogenesis and time course of ischemic brain edema and reperfusion.Methods: The middle cerebral arteries of rats were occluded by cannulation with a nylon suture for 30, 60, 120, or 240 minutes. The animals were then decapitated (permanent occlusion) or the suture was withdrawn to allow 24 hours of reperfusion before decapitation (temporary occlusion). Na,K-ATPase activity and Na + , K + and water contents were measured at various intervals. Results: In the ischemic hemisphere, Na,K-ATPase activity was significantly decreased at 30, 60,120, and 240 minutes of permanent occlusion (p<0.05). There was also a significant decrease in rats subjected to 60 or 120 minutes of temporary occlusion followed by 24 hours of reperfusion. Water content increased after 60, 120, or 240 minutes of permanent occlusion (p<0.01); after 24 hours of reperfusion, water content remained elevated (p<0.01). The Na + content increased after both permanent and temporary occlusion, and the K + content decreased only after permanent occlusion. Increases in water content correlated with decreases in Na,K-ATPase activity after temporary occlusion and with the Na + : K + ratio after permanent occlusion.Conclusion: Reduction in Na,K-ATPase activity resulting in disruption of cellular ionic homeostasis may account for early development of cytotoxic brain edema after permanent occlusion of the middle cerebral artery. Such edema is also present 24 hours after 60 and 120 but not 30 minutes of temporary occlusion. -2 which may be exacerbated rather than reversed even if ischemia is followed by reperfusion.3 The temporal sequence of these disturbances is not precisely known; however, interruption of cerebral blood flow is generally believed to result first in depletion of energy stores and next in disruption of ion homeostasis, release of neurotransmitter amino acids, and release of free fatty acids. 4 These physiological and biochemical alterations are the primary determinants of cell survival or death.Decreased energy metabolism results in dysfunction of all adenosine triphosphate (ATP)-dependent enzymes. One such enzyme is Na,K-ATPase, a catalyst for the Na + pump, which normally maintains intracellularFrom the Departments of Neurological Surgery
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