Mechanism of selective motor neuronal death after exposure of spinal cord to glutamate: Involvement of glutamate induced nitric oxide in motor neuron toxicity and nonmotor neuron protection
Mechanism of selective motor neuronal death after exposure of spinal cord to glutamate: Involvement of glutamate induced nitric oxide in motor neuron toxicity and nonmotor neuron protection
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DOI：
10.1002/ana.410440514
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发表时间：
1998-11-01
影响因子：
11.2
通讯作者：
Kimura, J
中科院分区：
文献类型：
--
作者：
Urushitani, M;Shimohama, S;Kimura, J
在本研究中，我们利用胚胎大鼠脊髓培养物分析了选择性运动神经元死亡（肌萎缩侧索硬化症的一个特征）的机制。当解离的培养物暴露于低水平谷氨酸（Glu）和谷氨酸转运蛋白抑制剂L-反式吡咯烷-2,4-脱羧基酯（PDC）24小时时，运动神经元通过N-甲基-D-天冬氨酸（NMDA）和α-氨基-3-羟基-5-甲基异恶唑-4-丙酸酯（AMPA）/红藻氨酸受体选择性损伤。一氧化氮合酶（NOS）抑制剂减弱了这种毒性，长效一氧化氮（NO）供体选择性地损害运动神经元。非运动神经元在暴露于低剂量 Glu/PDC 后存活，但同时使用 NO 依赖性鸟苷酸环化酶抑制剂会增强 Glu 诱导的毒性。此外，8-溴环 GMP（一种可溶性环 GMP 类似物）可以挽救暴露于高剂量 Glu/PDC 的非运动神经元，但不能挽救运动神经元。与 PDC 一起孵育 24 小时，神经元 NOS 免疫反应性神经元的数量比对照组增加了约两倍，并且使用运动神经元标记 SMI32 的双重染色研究表明，其中大多数是非运动神经元。这些发现表明，长期低水平接触 Glu 引起的选择性运动神经元死亡是由非运动神经元中 NO 的形成介导的，NO 的形成通过鸟苷酸环化酶-环 GMP 级联反向保护非运动神经元。非运动神经元中神经元NOS的诱导可能增强运动神经元的毒性和非运动神经元的保护，这可以解释肌萎缩侧索硬化症的病理学。
In this study, we analyzed the mechanism of selective motor neuronal death, a characteristic of amyotrophic lateral sclerosis, using embryonic rat spinal cord culture. When dissociated cultures were exposed to low-level glutamate (Glu) coadministered with the Glu transporter inhibitor L-trans-pyrrolidine-2,4-decarboxylate (PDC) for 24 hours, motor neurons were selectively injured through N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptors. Nitric oxide synthase (NOS) inhibitors attenuated this toxicity, and long-acting nitric oxide (NO) donors damaged motor neurons selectively. Nonmotor neurons survived after exposure to low-dose Glu/PDC, but Glu-induced toxicity was potentiated by coadministration of an NO-dependent guanylyl cyclase inhibitor. In addition, 8-bromo-cyclic GMP, a soluble cyclic GMP analogue, rescued nonmotor neurons, but not motor neurons, exposed to high-dose Glu/PDC. Twenty-four hours' incubation with PDC elevated the number of neuronal NOS-immunoreactive neurons by about twofold compared with controls, and a double-staining study, using the motor neuron marker SMI32, revealed that most of them were nonmotor neurons. These findings suggest that selective motor neuronal death caused by chronic low-level exposure to Glu is mediated by the formation of NO in nonmotor neurons, which inversely protects nonmotor neurons through the guanylyl cyclase-cyclic GMP cascade. Induction of neuronal NOS in nonmotor neurons might enhance both the toxicity of motor neurons and the protection of nonmotor neurons, which could explain the pathology of amyotrophic lateral sclerosis.