The opioid receptor antagonist, naloxone, protects spinal motor neurons in a murine model of alphavirus encephalomyelitis.
The opioid receptor antagonist, naloxone, protects spinal motor neurons in a murine model of alphavirus encephalomyelitis.
复制标题
阿片受体拮抗剂纳洛酮可保护甲病毒脑脊髓炎小鼠模型中的脊髓运动神经元。
DOI：
10.1016/j.expneurol.2007.03.013
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发表时间：
2007
影响因子：
5.3
通讯作者：
Irani,DavidN
中科院分区：
文献类型：
--
作者：
Prow,NatalieA;Irani,DavidN
神经适应性辛德毕斯病毒（NSV）传播到脊髓（SC）的运动神经元（MN），导致C57 BL/6小鼠严重的后肢无力，并模拟人类甲病毒和黄病毒脑脊髓炎可能伴随的瘫痪。脊髓MN的命运决定了NSV诱导的瘫痪的严重程度，最近的数据表明，MN损伤可以通过激活的小胶质细胞的作用间接发生。由于阿片受体拮抗剂纳洛酮（NAL）在其他模型中阻断了小胶质细胞介导的神经变性，因此我们研究了其在NSV感染期间的作用。药物治疗预防了麻痹，提高了MN的存活率，而不改变NSV的嗜性、复制或从SC组织中清除。进一步的研究表明，NAL在NSV攻击后72小时的窗口内最有效地抑制麻痹，表明该药物抑制了SC发病机制中的早期事件。组织化学研究表明，NAL阻断了SC组织切片中早期小胶质细胞的活化，蛋白质测定显示，SC匀浆中致病性IL-1β的早期诱导减弱。最后，谷氨酸转运蛋白-1（GLT-1）表达的损失，在SC，星形胶质细胞谷氨酸再摄取蛋白负责降低毒性细胞外谷氨酸水平和防止MN损伤，被逆转NAL治疗。这种GLT-1损失被证明是高度IL-1β依赖性的。综上所述，这些数据表明NAL通过抑制小胶质细胞活化而在SC中具有神经保护作用，从而维持正常的星形胶质细胞谷氨酸稳态。我们认为，针对这种小胶质细胞反应的药物可能对相关病毒感染的人类有治疗益处。
Spread of neuroadapted Sindbis virus (NSV) to motor neurons (MN) of the spinal cord (SC) causes severe hind limb weakness in C57BL/6 mice and models the paralysis that can accompany alphavirus and flavivirus encephalomyelitis in humans. The fate of spinal MN dictates the severity of NSV-induced paralysis, and recent data suggest that MN damage can occur indirectly via the actions of activated microglial cells. Because the opioid receptor antagonist, naloxone (NAL), blocks microglial-mediated neurodegeneration in other models, we examined its effects during NSV infection. Drug treatment prevented paralysis and enhanced the survival of MN without altering NSV tropism, replication, or clearance from SC tissue. Further studies showed that NAL most effectively inhibited paralysis in a 72-h window after NSV challenge, suggesting that the drug inhibits an early event in SC pathogenesis. Histochemical studies demonstrated that NAL blocked early microglial activation in SC tissue sections, and protein assays showed that the early induction of pathogenic IL-1β was blunted in SC homogenates. Finally, loss of glutamate transporter-1 (GLT-1) expression in SC, an astrocyte glutamate reuptake protein responsible for lowering toxic extracellular levels of glutamate and preventing MN damage, was reversed by NAL treatment. This GLT-1 loss proved to be highly IL-1β-dependent. Taken together, these data suggest that NAL is neuroprotective in the SC by inhibiting microglial activation that, in turn, maintains normal astrocyte glutamate homeostasis. We propose that drugs targeting such microglial responses may have therapeutic benefit in humans with related viral infections.