title: 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.
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.
authors.affiliation: Centers for Neural Development and Disease, University of Rochester, Rochester, New York 14642, USA. Daniel_marker@urmc.rochester.edu
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Marker
authors.forename: Marie-Ève
authors.initials: MÈ
authors.lastname: Tremblay
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Puccini
authors.forename: Justin
authors.initials: J
authors.lastname: Barbieri
authors.forename: Mary A
authors.initials: MA
authors.lastname: Gantz Marker
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Loweth
authors.forename: E Chris
authors.initials: EC
authors.lastname: Muly
authors.forename: Shao-Ming
authors.initials: SM
authors.lastname: Lu
authors.forename: Val S
authors.initials: VS
authors.lastname: Goodfellow
authors.forename: Stephen
authors.initials: S
authors.lastname: Dewhurst
authors.forename: Harris A
authors.initials: HA
authors.lastname: Gelbard
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D000073883:CX3C Chemokine Receptor 1; D002461:Cell Line, Transformed / Q000187:drug effects / Q000821:virology; D002478:Cells, Cultured; D016207:Cytokines; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D015696:Gene Products, tat / Q000276:immunology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000502:physiology; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D018709:Statistics, Nonparametric; D013997:Time Factors; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D000073883:CX3C Chemokine Receptor 1; D016207:Cytokines; D015696:Gene Products, tat; D049452:Green Fluorescent Proteins; D020930:MAP Kinase Kinase Kinases; D018696:Neuroprotective Agents; D011725:Pyridines; D011758:Pyrroles; D019707:Receptors, Chemokine; D054322:tat Gene Products, Human Immunodeficiency Virus; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C095235:CX3CR1 protein, human; C583037:URMC-099