Beckham J David, Goody Robin J, Clarke Penny, Bonny Christophe, Tyler Kenneth L
Department of Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.
J Virol. 2007 Jul;81(13):6984-92. doi: 10.1128/JVI.00467-07. Epub 2007 May 2.
Viral encephalitis is a major cause of morbidity and mortality worldwide, yet there is no proven efficacious therapy for most viral infections of the central nervous system (CNS). Many of the viruses that cause encephalitis induce apoptosis and activate c-Jun N-terminal kinase (JNK) following infection. We have previously shown that reovirus infection of epithelial cell lines activates JNK-dependent apoptosis. We now show that reovirus infection resulted in activation of JNK and caspase-3 in the CNS. Treatment of reovirus-infected mice with a cell-permeating peptide that competitively inhibits JNK activity resulted in significantly prolonged survival of intracerebrally infected mice following an otherwise lethal challenge with T3D (100 x 50% lethal dose). Protection correlated with reduced CNS injury, reduced neuronal apoptosis, and reduced c-Jun activation without altering the viral titer or viral antigen distribution. Given the efficacy of the inhibitor in protecting mice from viral encephalitis, JNK inhibition represents a promising and novel treatment strategy for viral encephalitis.
病毒性脑炎是全球发病和死亡的主要原因，但对于大多数中枢神经系统（CNS）病毒感染，尚无经证实有效的治疗方法。许多引起脑炎的病毒在感染后会诱导细胞凋亡并激活c-Jun氨基末端激酶（JNK）。我们之前已表明，呼肠孤病毒感染上皮细胞系可激活JNK依赖性细胞凋亡。我们现在发现，呼肠孤病毒感染会导致中枢神经系统中JNK和caspase-3的激活。用一种竞争性抑制JNK活性的细胞穿透肽治疗呼肠孤病毒感染的小鼠，在用T3D（100×50%致死剂量）进行致命攻击后，脑内感染小鼠的存活时间显著延长。保护作用与中枢神经系统损伤减轻、神经元凋亡减少以及c-Jun激活减少相关，而病毒滴度或病毒抗原分布未改变。鉴于该抑制剂在保护小鼠免受病毒性脑炎侵害方面的功效，抑制JNK代表了一种有前景的新型病毒性脑炎治疗策略。
