Centers for Neural Development and Disease, University of Rochester, Rochester, New York 14642, USA.
J Neurosci. 2013 Jun 12;33(24):9998-10010. doi: 10.1523/JNEUROSCI.0598-13.2013.
Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) is a significant source of disability in the HIV-infected population. Even with stringent adherence to anti-retroviral therapy, >50% of patients living with HIV-1 will develop HAND (Heaton et al., 2010). Because suppression of viral replication alone is not enough to stop HAND progression, there is a need for an adjunctive neuroprotective therapy in this population. To this end, we have developed a small-molecule brain-penetrant inhibitor with activity against mixed-lineage kinase 3 (MLK3), named URMC-099. MLK3 activation is associated with many of the pathologic hallmarks of HAND (Bodner et al., 2002, 2004; Sui et al., 2006) and therefore represents a prime target for adjunctive therapy based on small-molecule kinase inhibition. Here we demonstrate the anti-inflammatory and neuroprotective effects of URMC-099 in multiple murine and rodent models of HAND. In vitro, URMC-099 treatment reduced inflammatory cytokine production by HIV-1 Tat-exposed microglia and prevented destruction and phagocytosis of cultured neuronal axons by these cells. In vivo, URMC-099 treatment reduced inflammatory cytokine production, protected neuronal architecture, and altered the morphologic and ultrastructural response of microglia to HIV-1 Tat exposure. In conclusion, these data provide compelling in vitro and in vivo evidence to investigate the utility of URMC-099 in other models of HAND with the goal of advancement to an adjunctive therapeutic agent.
人类免疫缺陷病毒（HIV）相关的神经认知障碍（HAND）是 HIV 感染者致残的主要原因。即使严格遵循抗逆转录病毒治疗，仍有超过 50%的 HIV-1 感染者会发展为 HAND（Heaton 等人，2010 年）。由于单纯抑制病毒复制不足以阻止 HAND 的进展，因此需要在该人群中使用辅助神经保护疗法。为此，我们开发了一种针对混合谱系激酶 3（MLK3）的小分子脑穿透抑制剂，命名为 URMC-099。MLK3 的激活与 HAND 的许多病理特征有关（Bodner 等人，2002 年，2004 年；Sui 等人，2006 年），因此代表了基于小分子激酶抑制的辅助治疗的主要靶点。在这里，我们在多种 HAND 的鼠和啮齿动物模型中证明了 URMC-099 的抗炎和神经保护作用。在体外，URMC-099 处理可降低 HIV-1 Tat 暴露的小神经胶质细胞中炎性细胞因子的产生，并防止这些细胞破坏和吞噬培养的神经元轴突。在体内，URMC-099 处理可减少炎性细胞因子的产生，保护神经元结构，并改变 HIV-1 Tat 暴露时小神经胶质细胞的形态和超微结构反应。总之，这些数据提供了令人信服的体外和体内证据，表明有必要研究 URMC-099 在 HAND 的其他模型中的应用，以期将其作为辅助治疗药物。
