Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
J Immunol. 2010 Jan 15;184(2):746-56. doi: 10.4049/jimmunol.0902962. Epub 2009 Dec 4.
When the nervous system is infected with HIV-1, it commonly results in neuroinflammation leading to overt neuronal dysfunction and subsequent cognitive and behavioral impairments. The multifaceted disease process, now referred to as HIV-1-associated neurocognitive disorders (HAND), provides a range of molecular targets for adjunctive therapies. One is CEP-1347, an inhibitor of mixed lineage kinases that elicits neuroprotective and anti-inflammatory responses in models of neurodegenerative diseases. Since HAND is associated with inflammatory encephalopathy induced by virus infection and mononuclear phagocytes (perivascular macrophages and microglia) immune activation, we investigated whether CEP-1347 could ameliorate disease in laboratory models of HAND. We now demonstrate that CEP-1347 reduces the levels of secreted proinflammatory cytokines and chemokines in HIV-1-infected human macrophages and attenuates dose-dependent neurotoxicity in rodent cortical neurons. CEP-1347-treated mice readily achieve therapeutic drug levels in peripheral blood. HIV-1 encephalitis (HIVE) mice, where human virus-infected monocyte-derived macrophages are stereotactically injected into the basal ganglia of CB17 severe combined immunodeficient mice, received daily intraperitoneal injections of CEP-1347. Here, CEP-1347 treatment of HIVE mice showed a dose-dependent reduction in microgliosis. Dendritic integrity and neuronal loss were sustained and prevented, respectively. These results demonstrate that CEP-1347 elicits anti-inflammatory and neuroprotective responses in an HIVE model of human disease and as such warrants further study as an adjunctive therapy for human disease.
当神经系统感染 HIV-1 时，通常会导致神经炎症，导致明显的神经元功能障碍，随后出现认知和行为障碍。这种多方面的疾病过程，现在被称为 HIV-1 相关的神经认知障碍（HAND），为辅助治疗提供了一系列分子靶点。其中一种是 CEP-1347，它是一种混合谱系激酶抑制剂，在神经退行性疾病模型中可引发神经保护和抗炎反应。由于 HAND 与病毒感染和单核吞噬细胞（血管周巨噬细胞和小胶质细胞）免疫激活引起的炎症性脑病有关，我们研究了 CEP-1347 是否可以改善 HAND 的实验室模型中的疾病。我们现在证明，CEP-1347 可以降低 HIV-1 感染的人巨噬细胞中分泌的促炎细胞因子和趋化因子的水平，并减弱在啮齿动物皮质神经元中的剂量依赖性神经毒性。CEP-1347 治疗的小鼠在周围血液中很容易达到治疗药物水平。HIV-1 脑炎（HIVE）小鼠，其中人病毒感染的单核细胞衍生的巨噬细胞被立体定向注射到 CB17 严重联合免疫缺陷小鼠的基底神经节中，每天接受 CEP-1347 的腹腔内注射。在这里，CEP-1347 治疗 HIVE 小鼠显示出剂量依赖性的小胶质细胞增生减少。树突状完整性和神经元丢失分别得到维持和预防。这些结果表明，CEP-1347 在人类疾病的 HIVE 模型中引发抗炎和神经保护反应，因此值得进一步研究作为人类疾病的辅助治疗。
