EXPRESSION OF INDUCIBLE NITRIC-OXIDE SYNTHASE CAUSES DELAYED NEUROTOXICITY IN PRIMARY MIXED NEURONAL-GLIAL CORTICAL CULTURES
EXPRESSION OF INDUCIBLE NITRIC-OXIDE SYNTHASE CAUSES DELAYED NEUROTOXICITY IN PRIMARY MIXED NEURONAL-GLIAL CORTICAL CULTURES
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DOI：
10.1016/0028-3908(94)90045-0
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发表时间：
1994-11-01
影响因子：
4.7
通讯作者：
DAWSON, TM
中科院分区：
文献类型：
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作者：
DAWSON, VL;BRAHMBHATT, HP;DAWSON, TM
一氧化氮（NO）是中枢神经系统（CNS）中一种有效的生物信使分子。在中枢神经系统中有几种NO产生的潜在来源，包括组成性表达NO合酶（NOS）的神经元和内皮细胞。星形胶质细胞和小胶质细胞可被细胞因子诱导表达类似于巨噬细胞NOS（mNOS）的NOS亚型。暴露于脂多糖（LPS）或LPS和γ-干扰素（INF-γ）的组合的原代混合神经胶质培养物以剂量依赖性方式产生亚硝酸盐，其为NO形成的分解产物。亚硝酸盐的产生在12小时可检测到，在48小时达到峰值，并持续至少96小时。NOS抑制剂硝基-L-精氨酸（NArg）抑制亚硝酸盐的形成，但免疫抑制剂FK 506不能。在暴露于50 ng LPS或5 ng LPS和1 μ g INF γ的混合神经胶质-神经元培养物中，神经元开始在约48小时死亡。可检测到亚硝酸盐产生后24-36小时。神经毒性被100 μ M NArg减弱。这些数据表明，诱导型mNOS的表达引起延迟的神经毒性。
Nitric oxide (NO) is a potent biological messenger molecule in the central nervous system (CNS). There are several potential sources of NO production in the CNS, including neurons and endothelial cells which express NO synthase (NOS) constitutively. Astrocytes and microglia can be induced by cytokines to express a NOS isoform similar to macrophage NOS (mNOS). Primary mixed glial cultures exposed to lipopolysaccharide (LPS) or a combination of LPS and gamma-interferon (INF-gamma) produce nitrite, a breakdown product of NO formation, in a dose-dependent manner. Nitrite production is detectable at 12 hr, peaks at 48 hr and is sustained for at least 96 hr. The NOS inhibitor, nitro-L-arginine (NArg), inhibits nitrite formation, but the immunosuppressant agent, FK506, does not. In mixed glial-neuronal cultures exposed to 50 ng LPS or 5 ng LPS and 1 mu g INF gamma, neurons begin to die at 48 hr, approx. 24-36 hr after detectable nitrite production. Neurotoxicity is attenuated by 100 mu M NArg. These data indicate that expression of inducible mNOS causes delayed neurotoxicity.