EXTRACELLULAR SUPEROXIDE-DISMUTASE, NITRIC-OXIDE, AND CENTRAL-NERVOUS-SYSTEM O2 TOXICITY
EXTRACELLULAR SUPEROXIDE-DISMUTASE, NITRIC-OXIDE, AND CENTRAL-NERVOUS-SYSTEM O2 TOXICITY
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DOI：
10.1073/pnas.89.20.9715
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发表时间：
1992-10-15
影响因子：
11.1
通讯作者：
CRAPO, JD
中科院分区：
文献类型：
--
作者：
OURY, TD;HO, YS;CRAPO, JD
虽然活性O2物种似乎参与中枢神经系统（CNS）的O2毒性，不同的活性O2物种的确切作用是不确定的。为了研究细胞外超氧阴离子（O2-）对CNS O2毒性的贡献，我们构建了在脑中过表达人细胞外超氧化物歧化酶（ECSOD;超氧化物：超氧化物氧化还原酶，EC 1.15.1.1）的转基因小鼠。值得注意的是，当暴露于6 atm（1 atm = 101.3 kPA）高压氧25分钟时，转基因小鼠的死亡率（83%）高于非转基因小鼠（33%; P < 0.017）。用二乙基二硫代氨基甲酸酯预处理，抑制ECSOD和Cu/Zn超氧化物歧化酶（Cu/Zn SOD）活性，增加了对CNS O2毒性的抵抗力，在存活率（转基因小鼠100%，非转基因小鼠93%）和癫痫发作抵抗力（转基因和非转基因小鼠癫痫发作潜伏期增加4倍; P < 0.05）方面。因此，O2-显然可以防止CNS O2毒性。我们假设O2-通过灭活一氧化氮（NO.）降低毒性。为了测试这一点，我们用N（ω）-硝基-L-精氨酸抑制NO合酶（EC 1.14.23），以确定NO是否有助于增强转基因小鼠的CNS O2毒性。N（ω）-硝基-L-精氨酸保护转基因和非转基因小鼠免受CNS O2毒性（100%存活率和首次癫痫发作时间延迟4倍; P < 0.05），并消除转基因和非转基因小鼠对CNS O2毒性敏感性的差异。这些结果暗示NO是CNS O2毒性的重要介质，并表明ECSOD通过抑制O2介导的NO失活而增加CNS O2毒性。
Although reactive O2 species appear to participate in central nervous system (CNS) O2 toxicity, the exact roles of different reactive O2 species are undetermined. To study the contribution of extracellular superoxide anion (O2-) to CNS O2 toxicity we constructed transgenic mice overexpressing human extracellular superoxide dismutase (ECSOD; superoxide:superoxide oxidoreductase, EC 1.15.1.1) in the brain. Remarkably, when exposed to 6 atm (1 atm = 101.3 kPA) of hyperbaric oxygen for 25 min, transgenic mice demonstrated higher mortality (83%) than nontransgenic littermates (33%; P < 0.017). Pretreatment with diethyldithiocarbamate, which inhibits both ECSOD and Cu/Zn superoxide dismutase (Cu/Zn SOD) activity, increased resistance to CNS O2 toxicity, in terms of both survival (100% in transgenics and 93% in nontransgenics) and resistance to seizures (4-fold increase in seizure latency in both transgenic and nontransgenic mice; P < 0.05). Thus, O2- apparently protects against CNS O2 toxicity. We hypothesized that O2- decreased toxicity by inactivating nitric oxide (NO.). To test this, we inhibited NO. synthase (EC 1.14.23) with N(omega)-nitro-L-arginine to determine whether NO. contributes to enhanced CNS O2 toxicity in transgenic mice. N(omega)-nitro-L-arginine protected both transgenic and nontransgenic mice against CNS O2 toxicity (100% survival and a 4-fold delay in time to first seizure; P < 0.05), as well as abolishing the difference in sensitivity to CNS O2 toxicity between transgenic and nontransgenic mice. These results implicate NO. as an important mediator in CNS O2 toxicity and suggest that ECSOD increases CNS O2 toxicity by inhibiting O2--mediated inactivation of NO..