The new small-molecule mixed-lineage kinase 3 inhibitor URMC-099 is neuroprotective and anti-inflammatory in models of human immunodeficiency virus-associated …

DF Marker, MÈ Tremblay, JM Puccini… - Journal of …, 2013 - Soc Neuroscience
DF Marker, MÈ Tremblay, JM Puccini, J Barbieri, MAG Marker, CJ Loweth, EC Muly, SM Lu…
Journal of Neuroscience, 2013Soc Neuroscience
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. 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 …
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 . 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 (, ; ) 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.
Soc Neuroscience