Elevated adiponectin prevents HIV protease inhibitor toxicity and preserves cerebrovascular homeostasis in mice

Kalavathi Dasuri, Jennifer K. Pepping, Sun OK Fernandez-Kim, Sunita Gupta, Jeffrey N. Keller, Philipp E. Scherer, Annadora J. Bruce-Keller

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1228-1235
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1862
Issue number6
DOIs
StatePublished - Jun 1 2016

Keywords

  • Blood-brain barrier
  • HIV antiretroviral therapy
  • HIV-associated neurocognitive disorder
  • Lipodystrophy
  • Metabolic syndrome

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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