Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase.

Abstract

Oxygen-derived free radicals have been implicated in the pathogenesis of vasogenic edema and infarction caused by ischeria and reperfusion injury. In earlier studies, exogenously supplied liposome-entrapped CuZn superoxide dismutase (CuZn-SOD) ameliorated ischemic brain edema and infarction in rats following focal cerebral ischemla. To ascertain directly the role of SOD in the protection against superoxide radical-induced injury, we measured infarct size and water content 24 hr following focal cerebral ischemia in nontransgenic mice and in transgeic mice bearing the human SODI gene. These transgenic mice have 3.1-fold higher cellular CuZn-SOD activity in the brain than do their nontransgenic littermates. We also'measured antioxidant levels (reduced glutathione and reduced ascorbate) of contralateral cortex, infarct cortex, surrounding cortex, and striatum. Infarct size and brain edema were s ntly decreased in trenic mice compared with nontransgenic mice. Reduced glutathione and reduced ascorbate levels decreased in the ischemlc hemisphere, -but levels-in surrounding cortex and striaturm were gficantly higher in trasgenic'mice than in nontransgenic mice. These rEsults indicate that increased endogenous SOD activity in brain reduces the level of ischemic damage and support the concept that superoxide radicals play an important role in the-pathogenesis of infarction and edema following focal cerebral ischemia.The role of oxygen free radicals in the pathogenesis of infarction and edema following cerebral ischemia has been intensively investigated since the report of Flamm et al. (1).Because of technical 4ffficulties in the measurement of free radicals'in brain tissues the part played by free radicals in the pathogenesis of cerebral ischemia still remains unclear (2, 3). However, reports of decreased levels of lipid-soluble and water-soluble endogenous antioxidants and of increased levels ofconjugated dienes and lipid peroxidation (4-10) support the notion that free radicals are involved in ischemic brain injury.Indirect methods using specific antioxidants [e.g., superoxide dismutase (SOD) and catalase] have traditionally been used to implicate oxygen free radicals in physiological or pathological processes. Unfortunately, the half-life of CuZn-SOD in circulating blood is extremely short (6 min), and it is unable to pass the blood-brain barrier. Therefore, use has been made of chemically modified enzymes for work on cerebral injury (11), and it has been found that polyethylene glycol-conjugated CuZn-SOD (PEG-SOD) and PEG-catalase reduce the degree of cortical infarction resulting from focal cerebral ischemia (12). Similarly, CuZn-SOD conjugated with divinyl ether/maleic acid copolymer ameliorated delayed hippocampal neuronal death after global cerebral ischemia in the gerbil brain (13). Liposome-entrapped CuZn-SOD, which has a half life of 4.2 hr (11), reduces the severity of traumatic and ischemic injuries (14,15).Although these studies provide potential therapeutic precedents for the management of brain in...

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Global Cerebral Ischemia in the Rat: Online Monitoring of Oxygen Free Radical Production Using Chemiluminescence in vivo

“…Indirect strategies to study the role of ROS for ischemic damage have used compounds that inter act with ROS production (particularly ROS scaven gers; for overview see Traystman et al , 1991), and more recently transgenic approaches were used [i. e. , Cu-Zn-SOD overexpressing mice (Kinouchi et al , 1991;Halliwell et al , 1992)]. With very few exceptions, these studies have shown in a number of different ischemia models and species that exper imentally induced increases in the capacity of the brain to cope with oxidative stress are neuroprotec tive.…”

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“…36 It is significant that focal cerebral ischemic injury is attenuated in transgenic mice constitutively overexpressing superoxide dismutase. 115 The complex relation between ROS-induced events and anoxia is illustrated by the finding that morphological damage to the penumbra region around an ischemic region is generally more severe than at the core. 107 The presence of excess oxygen free radicals in post-ischemic tissue has been directly demonstrated.…”