title: Elevated adiponectin prevents HIV protease inhibitor toxicity and preserves cerebrovascular homeostasis in mice.
abstract: HIV protease inhibitors are key components of HIV antiretroviral therapies, which are fundamental in the treatment of HIV infection. However, the protease inhibitors are well-known to induce metabolic dysfunction which can in turn escalate the complications of HIV, including HIV associated neurocognitive disorders. As experimental and epidemiological data support a therapeutic role for adiponectin in both metabolic and neurologic homeostasis, this study was designed to determine if increased adiponectin could prevent the detrimental effects of protease inhibitors in mice. Adult male wild type (WT) and adiponectin-overexpressing (ADTg) mice were thus subjected to a 4-week regimen of lopinavir/ritonavir, followed by comprehensive metabolic, neurobehavioral, and neurochemical analyses. Data show that lopinavir/ritonavir-induced lipodystrophy, hypoadiponectinemia, hyperglycemia, hyperinsulinemia, and hypertriglyceridemia were attenuated in ADTg mice. Furthermore, cognitive function and blood-brain barrier integrity were preserved, while loss of cerebrovascular markers and white matter injury were prevented in ADTg mice. Finally, lopinavir/ritonavir caused significant increases in expression of markers of brain inflammation and decreases in synaptic markers in WT, but not in ADTg mice. Collectively, these data reinforce the pathophysiologic link from metabolic dysfunction to loss of cerebrovascular and cognitive homeostasis; and suggest that preservation and/or replacement of adiponectin could prevent these key aspects of HIV protease inhibitor-induced toxicity in clinical settings.
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, United States.
authors.forename: Kalavathi
authors.initials: K
authors.lastname: Dasuri
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, United States; Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, United States.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Pepping
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, United States.
authors.forename: Sun-Ok
authors.initials: SO
authors.lastname: Fernandez-Kim
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, United States.
authors.forename: Sunita
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, United States.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Keller
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, United States. Electronic address: annadora.bruce-keller@pbrc.edu.
authors.forename: Annadora J
authors.initials: AJ
authors.lastname: Bruce-Keller
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D001930:Brain Injuries / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D003071:Cognition / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000009:adverse effects*; D006706:Homeostasis / Q000187:drug effects; D061466:Lopinavir / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019438:Ritonavir / Q000009:adverse effects*; D015854:Up-Regulation
chemical_list: D052242:Adiponectin; D017320:HIV Protease Inhibitors; D061466:Lopinavir; D019438:Ritonavir
keywords: Blood–brain barrier, HIV antiretroviral therapy; HIV-associated neurocognitive disorder; Lipodystrophy; Metabolic syndrome