Nargi-Aizenman Jennifer L, Havert Michael B, Zhang Ming, Irani David N, Rothstein Jeffrey D, Griffin Diane E
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Ann Neurol. 2004 Apr;55(4):541-9. doi: 10.1002/ana.20033.
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.
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导致，也可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，神经元死亡也可能由兴奋性氨基酸神经递质（如谷氨酸）的过度释放所致。为了确定谷氨酸兴奋性毒性在致命性甲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-异恶唑丙酸（AMPA）亚型谷氨酸受体拮抗剂治疗感染了神经适应型辛德毕斯病毒（NSV）的小鼠。用NMDA受体拮抗剂MK-801或AMPA受体拮抗剂GYKI-52,466治疗的动物，海马体中的凋亡神经元和坏死神经元均减少。然而，只有AMPA受体阻断可防止脊髓运动神经元受损，并保护小鼠免受NSV感染导致的麻痹和死亡。保护作用并非由病毒复制改变引起，因为治疗并未影响病毒分布，实际上还延迟了病毒清除。这些结果表明，NSV感染激活了神经毒性途径，导致谷氨酸受体异常刺激和神经元损伤。此外，AMPA受体介导的运动神经元死亡是急性甲病毒诱导的脑脊髓炎中麻痹和死亡的重要原因。
