NITRIC-OXIDE MEDIATES GLUTAMATE NEUROTOXICITY IN PRIMARY CORTICAL CULTURES
NITRIC-OXIDE MEDIATES GLUTAMATE NEUROTOXICITY IN PRIMARY CORTICAL CULTURES
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DOI：
10.1073/pnas.88.14.6368
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发表时间：
1991-07-01
影响因子：
11.1
通讯作者：
SNYDER, SH
中科院分区：
文献类型：
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作者：
DAWSON, VL;DAWSON, TM;SNYDER, SH
一氧化氮（NO）介导多种生物学作用，包括血管舒张、活化的巨噬细胞的细胞毒性和通过激活小脑切片中的谷氨酸受体形成cGMP。一氧化氮合酶（EC 1.14.23.-）免疫反应性与烟酰胺腺嘌呤二核苷酸磷酸黄递酶共定位于对毒性损伤具有独特抗性的神经元中。我们表明，一氧化氮合酶抑制剂，N-ω-硝基-L-精氨酸（EC 50 = 20 μ M）和N-ω-单甲基-L-精氨酸（EC 50 = 170 μ M），防止神经毒性引起的N-甲基-D-天冬氨酸和相关的兴奋性氨基酸。这种作用被L-精氨酸竞争性逆转。通过精氨酸酶或无精氨酸的生长培养基耗尽精氨酸的培养基完全减弱N-甲基-D-天冬氨酸的毒性。硝普钠自发释放NO，产生与cGMP形成平行的剂量依赖性细胞死亡。血红蛋白，复合NO，防止N-甲基-D-天冬氨酸和硝普钠的神经毒性作用。这些数据证实NO介导谷氨酸的神经毒性。
Nitric oxide (NO) mediates several biological actions, including relaxation of blood vessels, cytotoxicity of activated macrophages, and formation of cGMP by activation of glutamate receptors in cerebellar slices. Nitric oxide synthase (EC 1.14.23.-) immunoreactivity is colocalized with nicotinamide adenine di-nucleotide phosphate diaphorase in neurons that are uniquely resistant to toxic insults. We show that the nitric oxide synthase inhibitors, N-omega-nitro-L-arginine (EC50 = 20 mu-M) and N-omega-monomethyl-L-arginine (EC50 = 170-mu-M), prevent neurotoxicity elicited by N-methyl-D-aspartate and related excitatory amino acids. This effect is competitively reversed by L-arginine. Depletion of the culture medium of arginine by arginase or arginine-free growth medium completely attenuates N-methyl-D-aspartate toxicity. Sodium nitroprusside, which spontaneously releases NO, produces dose-dependent cell death that parallels cGMP formation. Hemoglobin, which complexes NO, prevents neurotoxic effects of both N-methyl-D-aspartate and sodium nitroprusside. These data establish that NO mediates the neurotoxicity of glutamate.