Journal
JOURNAL OF NEUROSCIENCE
Volume 33, Issue 24, Pages 9998-10010Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0598-13.2013
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Funding
- National Institutes of Health [PO1 MH64570, RO1 MH56838, UL1 RR024160, T32 GM07356, T32 AI049815, F30 MH095664, F32 MH099913, P51 RR000165]
- Fonds de Recherche en Sante du Quebec
- Canadian Institutes of Health Research
- Merit Award from the Office of Research and Development, Department of Veterans Affairs
- Geoffrey Waisdorp Pediatric Neurology Fund
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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.
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