title: Insulin Treatment Prevents Neuroinflammation and Neuronal Injury with Restored Neurobehavioral Function in Models of HIV/AIDS Neurodegeneration.
abstract: HIV-1 infection of the brain causes the neurodegenerative syndrome HIV-associated neurocognitive disorders (HAND), for which there is no specific treatment. Herein, we investigated the actions of insulin using ex vivo and in vivo models of HAND. Increased neuroinflammatory gene expression was observed in brains from patients with HIV/AIDS. The insulin receptor was detected on both neurons and glia, but its expression was unaffected by HIV-1 infection. Insulin treatment of HIV-infected primary human microglia suppressed supernatant HIV-1 p24 levels, reduced CXCL10 and IL-6 transcript levels, and induced peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. Insulin treatment of primary human neurons prevented HIV-1 Vpr-mediated cell process retraction and death. In feline immunodeficiency virus (FIV) infected cats, daily intranasal insulin treatment (20.0 IU/200 μl for 6 weeks) reduced CXCL10, IL-6, and FIV RNA detection in brain, although PPAR-γ in glia was increased compared with PBS-treated FIV+control animals. These molecular changes were accompanied by diminished glial activation in cerebral cortex and white matter of insulin-treated FIV+animals, with associated preservation of cortical neurons. Neuronal counts in parietal cortex, striatum, and hippocampus were higher in the FIV+/insulin-treated group compared with the FIV+/PBS-treated group. Moreover, intranasal insulin treatment improved neurobehavioral performance, including both memory and motor functions, in FIV+animals. Therefore, insulin exerted ex vivo and in vivo antiviral, anti-inflammatory, and neuroprotective effects in models of HAND, representing a new therapeutic option for patients with inflammatory or infectious neurodegenerative disorders including HAND.
  
  
  
  HIV-associated neurocognitive disorders (HAND) represent a spectrum disorder of neurocognitive dysfunctions resulting from HIV-1 infection. Although the exact mechanisms causing HAND are unknown, productive HIV-1 infection in the brain with associated neuroinflammation is a potential pathogenic mechanism resulting in neuronal damage and death. We report that, in HIV-infected microglia cultures, insulin treatment led to reduced viral replication and inflammatory gene expression. In addition, intranasal insulin treatment of experimentally feline immunodeficiency virus-infected animals resulted in improved motor and memory performances. We show that insulin restored expression of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ), which is suppressed by HIV-1 replication. Our findings indicate a unique function for insulin in improving neurological outcomes in lentiviral infections, implicating insulin as a therapeutic intervention for HAND.
authors.affiliation: Department of Medicine.
authors.forename: Manmeet K
authors.identifier: 0000-0002-7212-5430
authors.initials: MK
authors.lastname: Mamik
authors.affiliation: Department of Medicine.
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Asahchop
authors.affiliation: Department of Medicine.
authors.forename: Wing F
authors.identifier: 0000-0002-8719-7787
authors.initials: WF
authors.lastname: Chan
authors.affiliation: Department of Medicine.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Medicine.
authors.forename: William G
authors.initials: WG
authors.lastname: Branton
authors.affiliation: Department of Medical Microbiology and Immunology, and.
authors.forename: Brienne A
authors.initials: BA
authors.lastname: McKenzie
authors.affiliation: Institut de Recherches Cliniques de Montréal and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada H3T 1J4.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Cohen
authors.affiliation: Department of Medicine, Department of Medical Microbiology and Immunology, and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada T6G 2S2, and cp9@ualberta.ca.
authors.forename: Christopher
authors.identifier: 0000-0002-5131-9711
authors.initials: C
authors.lastname: Power
mesh_terms: D015526:AIDS Dementia Complex / Q000517:prevention & control*; D000281:Administration, Intranasal; D000818:Animals; D002415:Cats; D016923:Cell Death / Q000187:drug effects; D005260:Female; D015497:HIV-1; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016089:Immunodeficiency Virus, Feline; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use*; D016180:Lentivirus Infections / Q000378:metabolism; D009443:Neuritis / Q000517:prevention & control*; D019636:Neurodegenerative Diseases / Q000517:prevention & control*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011247:Pregnancy; D011972:Receptor, Insulin / Q000187:drug effects
chemical_list: D054298:Human Immunodeficiency Virus Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D018696:Neuroprotective Agents; D011972:Receptor, Insulin
keywords: FIV; HIV-1; insulin; microglia; neuropathology; neurotoxicity