Getts Daniel R, Matsumoto Izuru, Müller Marcus, Getts Meghann Teague, Radford Jane, Shrestha Bimmi, Campbell Iain L, King Nicholas J C
The Discipline of Pathology, The University of Sydney, Sydney, New South Wales, Australia.
J Neurochem. 2007 Nov;103(3):1019-30. doi: 10.1111/j.1471-4159.2007.04798.x. Epub 2007 Sep 5.
Seizures are a major complication of viral encephalitis. However, the mechanisms of seizure-associated neuronal dysfunction remain poorly understood. We report that intranasal inoculation with West Nile virus (WNV) (Sarafend) causes limbic seizures in C57BL/6 mice, but not in interferon (IFN)-gamma-deficient (IFN-gamma-/-) mice. Both strains showed similar levels of virus in the brain, as well as similar concentrations of the cytokines, tumor necrosis factor and interleukin-6, both of which can alter neuronal excitability. Experiments in chimeric IFN-gamma-/- mice reconstituted with IFN-gamma-producing leukocytes showed that IFN-gamma is not required during central nervous system infection for limbic seizure development, suggesting a role for IFN-gamma in the developing brain. This was supported responses to pentylenetetrazole, kainic acid (KA), and N-methyl-d-aspartate (NMDA). Both strains of mice exhibited similar behavior after pentylenetetrazole challenge. However, while NMDA and KA treatment resulted in characteristic seizures in C57BL/6 mice, these responses were diminished (NMDA treatment) or absent (KA treatment) in IFN-gamma-/- mice. Furthermore, NMDA-receptor blockade with MK-801 in WNV-infected C57BL/6 mice abrogated seizures and prolonged survival. Our data show that IFN-gamma plays an important role in the development of the excitatory seizure pathways in the brain and that these cascades become pathogenic in encephalitic WNV infection.
癫痫发作是病毒性脑炎的主要并发症。然而，癫痫发作相关的神经元功能障碍机制仍知之甚少。我们报告，经鼻接种西尼罗河病毒（WNV）（Sarafend株）可导致C57BL/6小鼠出现边缘叶癫痫发作，但在干扰素（IFN）-γ缺陷（IFN-γ-/-）小鼠中则不会。两种品系小鼠大脑中的病毒水平相似，细胞因子、肿瘤坏死因子和白细胞介素-6的浓度也相似，这两种细胞因子均可改变神经元兴奋性。在用产生IFN-γ的白细胞重建的嵌合IFN-γ-/-小鼠中进行的实验表明，在中枢神经系统感染期间，边缘叶癫痫发作的发展不需要IFN-γ，这表明IFN-γ在发育中的大脑中发挥作用。这一点得到了对戊四氮、 kainic酸（KA）和N-甲基-D-天冬氨酸（NMDA）反应的支持。两种品系的小鼠在戊四氮攻击后表现出相似的行为。然而，虽然NMDA和KA处理在C57BL/6小鼠中导致典型的癫痫发作，但这些反应在IFN-γ-/-小鼠中减弱（NMDA处理）或不存在（KA处理）。此外，在WNV感染的C57BL/6小鼠中用MK-801阻断NMDA受体可消除癫痫发作并延长生存期。我们的数据表明，IFN-γ在大脑兴奋性癫痫发作途径的发展中起重要作用，并且这些级联反应在WNV脑炎感染中变得具有致病性。
