The New Small-Molecule Mixed-Lineage Kinase 3 Inhibitor URMC-099 Is Neuroprotective and Anti-Inflammatory in Models of Human Immunodeficiency Virus-Associated Neurocognitive Disorders

• Type of Material: Article
• Authors: Daniel F. Marker, University of Rochester; Marie-Ève Tremblay, University of Rochester; Jenna M. Puccini, University of Rochester; Justin Barbieri, University of Rochester; Mary A. Gantz Marker, University of Rochester; Colin J. Loweth, Califia Bio; E Christopher Muly, Emory University; Shao-Ming Lu, University of Rochester; Val S. Goodfellow, Califia Bio; Stephen Dewhurst, University of Rochester; Harris A. Gelbard, University of Rochester
• Language: English
• Date: 2013-06-12
• Publisher: Society for Neuroscience
• Publication Version: Final Published Version
• Copyright Statement: © 2013 the authors
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.0598-13.2013
• Title of Journal or Parent Work: Journal of Neuroscience
• ISSN: 0270-6474
• Volume: 33
• Issue: 24
• Start Page: 9998
• End Page: 10010
• Grant/Funding Information: This work was funded by National Institutes of Health Grants PO1 MH64570 (H.A.G.), RO1 MH56838 (H.A.G.), UL1 RR024160 (H.A.G.), T32 GM07356 (D.F.M.), T32 AI049815 (D.F.M.), F30 MH095664 (D.F.M.), F32 MH099913 (J.M.P.), P51 RR000165 (E.C.M.), the Fonds de Recherche en Santé du Québec (M.-È.T.), the Canadian Institutes of Health Research (M.-È.T.), Merit Award from the Office of Research and Development, Department of Veterans Affairs (E.C.M.), and the Geoffrey Waisdorp Pediatric Neurology Fund (H.A.G.).
• Keywords: ANTIRETROVIRAL THERAPY; PROTEIN; CELLS; DELAY DISABILITY; Science & Technology; MICROGLIAL PHAGOCYTOSIS; EARLY PARKINSON-DISEASE; Life Sciences & Biomedicine; HIV; TAT; Neurosciences; Neurosciences & Neurology; CEP-1347 FAILS; SIGNALING CASCADES
• Research Categories: Health Sciences, Immunology; Biology, Virology; Biology, Neuroscience

Abstract

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.