Alterations in metabolism associated with complete ischemia in the brain
AbstractThis study was undertaken to test the hypothesis that alterations in the composition and function of cerebral cellular membranes may represent the 'critical event' underlying the irreversibility of ischemic brain injury. Complete cerebral ischemia was produced in Mongolian gerbils by bilateral carotid artery occlusion. The cortical levels of individual phospholipids and cortical Na('+),K('+)-ATPase activity were measured after varying intervals of ischemia and post-ischemic recirculation. Several other parameters potentially related to membrane structure and function were also examined, including superoxide dismutase activity and cortical levels of calcium, nucleotides, cyclic nucleotides and lipid peroxides After up to four hours of complete cerebral ischemia, the cortical content of total phospholipids varied only slightly. However, the levels of individual phospholipids fluctuated profoundly and nonuniformly during ischemia. These fluctuations could be grouped into three phases: (1) an early phase (to 15 min ischemia) marked by decreased levels of select phospholipids; (2) a 'rebound phase' (15 to 60 min), during which many phospholipid levels returned to pre-ischemic values or higher; (3) a third phase (beyond 60 min) of broader but less pronounced decreases in the levels of individual phospholipids. During recirculation following one hour of ischemia, dramatic and nonuniform changes in cortical phospholipid levels were observed which did not appear to be simple reversals of those observed during ischemia The in vitro activity of cortical Na('+),K('+)-ATPase was significantly reduced (by 18%) after 30 minutes of ischemia compared to controls. However, after intervals of post-ischemic recirculation, the in vitro cortical Na('+),K('+)-ATPase activity was significantly higher (by 20-34%) than that measured after corresponding ischemic intervals The effects of isoproterenol, amphetamine, trimethadione, chlorpromazine and aminooxyacetic acid on cortical phospholipid composition during post-ischemic recirculation were also examined. Each of these drugs, which can modify post-ischemic mortality in this model, attenuated some of the changes in the cortical phospholipid composition observed during recirculation in untreated animals, though to varying extents These results document severe alterations in the composition and function of cerebral cellular membranes during irreversible ischemic brain injury, which can be modified by post-ischemic drug treatment
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