{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T10:59:05Z","timestamp":1787828345958,"version":"build-2784847793"},"reference-count":72,"publisher":"Society for Neuroscience","issue":"41","license":[{"start":{"date-parts":[[2017,4,12]],"date-time":"2017-04-12T00:00:00Z","timestamp":1491955200000},"content-version":"vor","delay-in-days":182,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2016,10,12]]},"abstract":"<jats:p>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<jats:italic>ex vivo<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>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<jats:italic>CXCL10<\/jats:italic>and<jats:italic>IL-6<\/jats:italic>transcript levels, and induced peroxisome proliferator-activated receptor gamma (<jats:italic>PPAR<\/jats:italic>-\u03b3) 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 \u03bcl for 6 weeks) reduced CXCL10, IL-6, and FIV RNA detection in brain, although PPAR-\u03b3 in glia was increased compared with PBS-treated FIV<jats:sup>+<\/jats:sup>control animals. These molecular changes were accompanied by diminished glial activation in cerebral cortex and white matter of insulin-treated FIV<jats:sup>+<\/jats:sup>animals, with associated preservation of cortical neurons. Neuronal counts in parietal cortex, striatum, and hippocampus were higher in the FIV<jats:sup>+<\/jats:sup>\/insulin-treated group compared with the FIV<jats:sup>+<\/jats:sup>\/PBS-treated group. Moreover, intranasal insulin treatment improved neurobehavioral performance, including both memory and motor functions, in FIV<jats:sup>+<\/jats:sup>animals. Therefore, insulin exerted<jats:italic>ex vivo<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>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.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>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-\u03b3), 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.<\/jats:p>","DOI":"10.1523\/jneurosci.1287-16.2016","type":"journal-article","created":{"date-parts":[[2016,10,12]],"date-time":"2016-10-12T16:58:13Z","timestamp":1476291493000},"page":"10683-10695","source":"Crossref","is-referenced-by-count":77,"title":["Insulin Treatment Prevents Neuroinflammation and Neuronal Injury with Restored Neurobehavioral Function in Models of HIV\/AIDS Neurodegeneration"],"prefix":"10.1523","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7212-5430","authenticated-orcid":false,"given":"Manmeet K.","family":"Mamik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene 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