Glutamate receptor antagonists protect from virus-induced neural degeneration
Glutamate receptor antagonists protect from virus-induced neural degeneration
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DOI：
10.1002/ana.20033
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发表时间：
2004-04-01
影响因子：
11.2
通讯作者：
Griffin, DE
中科院分区：
文献类型：
--
作者：
Nargi-Aizenman, JL;Havert, MB;Griffin, DE
急性病毒性脑脊髓炎期间的神经元损伤可直接由病毒感染或间接由宿主对感染的免疫反应引起。在神经退行性疾病和中风中，神经元死亡也可由兴奋性氨基酸神经递质（如谷氨酸）的过度释放引起。为了确定谷氨酸兴奋毒性在致死性甲型病毒诱导的麻痹性脑脊髓炎中的作用，我们用n -甲基- d -天冬氨酸（NMDA）和α -氨基-3-羟基-5-甲基-4-异唑丙酸（AMPA）亚型谷氨酸受体拮抗剂治疗感染神经适应性辛德比病毒（NSV）的小鼠。用NMDA受体拮抗剂MK-801或AMPA受体拮抗剂GYKI-52466处理的动物海马中凋亡和坏死神经元均减少。然而，只有AMPA受体阻断才能阻止脊髓运动神经元的损伤，并保护小鼠免于因NSV感染而瘫痪和死亡。保护不是由改变病毒复制引起的，因为治疗不影响病毒分布，实际上延迟了病毒清除。这些结果为NSV感染激活神经毒性通路，导致谷氨酸受体异常刺激和神经元损伤提供了证据。此外，AMPA受体介导的运动神经元死亡是急性甲型病毒诱导的脑脊髓炎瘫痪和死亡的重要因素。
Neuronal damage during acute viral encephalomyelitis can result directly from virus infection or indirectly from the host immune response to infection. In neurodegenerative diseases and stroke, neuronal death also can result from excess release of excitatory amino acid neurotransmitters, such as glutamate. To determine the role of glutamate excitotoxicity in fatal alphavirus-induced paralytic encephalomyelitis, we treated mice infected with neuroadapted Sindbis virus (NSV) with antagonists of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtypes of glutamate receptors. Both apoptotic and necrotic neurons in the hippocampus were decreased in animals treated with MK-801, an NMDA receptor antagonist, or GYKI-52466, an AMPA receptor antagonist. However, only AMPA receptor blockade prevented damage to spinal cord motor neurons and protected mice from paralysis and death due to NSV infection. Protection was not caused by altered virus replication because treatment did not affect virus distribution and actually delayed virus clearance. These results provide evidence that NSV infection activates neurotoxic pathways that result in aberrant glutamate receptor stimulation and neuronal damage. Furthermore, AMPA receptor-mediated motor neuron death is an important contributor to paralysis and mortality in acute alphavirus-induced encephalomyelitis.