Protection from fatal viral encephalomyelitis: AMPA receptor antagonists have a direct effect on the inflammatory response to infection
Protection from fatal viral encephalomyelitis: AMPA receptor antagonists have a direct effect on the inflammatory response to infection
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DOI：
10.1073/pnas.0712390105
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发表时间：
2008-03-04
影响因子：
11.1
通讯作者：
Griffin, Diane E.
中科院分区：
文献类型：
--
作者：
Greene, Ivorlyne P.;Lee, Eun-Young;Griffin, Diane E.
致命性急性病毒性脑脊髓炎期间的神经元细胞死亡可由病毒复制、谷氨酸兴奋性毒性和免疫应答引起的损伤引起。甲病毒辛德毕斯病毒（NSV）的神经毒力菌株在成年C57 BL/6小鼠中引起与运动神经元死亡相关的致死性脑脊髓炎，这可以通过用原型非竞争性α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）谷氨酸受体拮抗剂GYKI 52466治疗来预防[Nargi-Aizenman J，et al.（2004）Ann Neurol 55：541-549]。为了确定保护机制，用7-乙酰基-5-（4-氨基苯基）-8（R）-甲基-8，9-二氢-7H-1，3-二氧杂环戊烯-（4，5-h）-苯二氮卓（talampanel）治疗NSV感染的小鼠，该药物是2，3-苯二氮卓类非竞争性AMPA谷氨酸受体拮抗剂的一种有效的口服药物。Talampanel处理的小鼠受到保护，免于NSV诱导的麻痹和死亡。在感染过程中的大脑检查显示，与未治疗的小鼠相比，治疗的小鼠中单核细胞浸润显着减少，胶质细胞酸性蛋白的星形胶质细胞表达没有增加。CNS炎症的缺乏可归因于处理的小鼠未能诱导次级淋巴组织中的淋巴细胞对感染的应答活化和增殖。他仑帕奈治疗也抑制了对NSV的抗体应答，并延迟了病毒清除。这些研究揭示了AMPA受体拮抗剂对免疫应答的先前未被认识的作用，并表明除了抑制兴奋性毒性之外，预防免疫介导的损伤是这些药物保护运动神经元免受病毒感染引起的死亡的机制。
Neuronal cell death during fatal acute viral encephalomyelitis can result from damage caused by virus replication, glutamate excitotoxicity, and the immune response. A neurovirulent strain of the alphavirus Sindbis virus (NSV) causes fatal encephalomyelitis associated with motor neuron death in adult C57BL/6 mice that can be prevented by treatment with the prototypic noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor antagonist GYKI 52466 [Nargi-Aizenman J, et al. (2004) Ann Neurol 55:541-549]. To determine the mechanism of protection, NSV-infected mice were treated with 7-acetyl-5-(4-aminophenyl)-8(R)-methyl-8,9-dihydro-7H-1,3-dioxolo-(4,5-h)-benzodiazepine (talampanel), a potent, orally available member of the 2,3 benzodiazepine class of noncompetitive AMPA glutamate receptor antagonists. Talampanel-treated mice were protected from NSV-induced paralysis and death. Examination of the brain during infection showed significantly less mononuclear cell infiltration and no increase in astrocyte expression of glial fibrillary acidic protein in treated mice compared with untreated mice. Lack of CNS inflammation was attributable to failure of treated mice to induce activation and proliferation of lymphocytes in secondary lymphoid tissue in response to infection. Antibody responses to NSV were also suppressed by talampanel treatment, and virus clearance was delayed. These studies reveal a previously unrecognized effect of AMPA receptor antagonists on the immune response and suggest that prevention of immune-mediated damage, in addition to inhibition of excitotoxicity, is a mechanism by which these drugs protect from death of motor neurons caused by viral infection.