Nanoformulated Antiretroviral Therapy Attenuates Brain Metabolic Oxidative Stress

J. Rafael Montenegro-Burke, Christopher J. Woldstad, Mingliang Fang, Aditya N. Bade, Jo Ellyn McMillan, Benson Edagwa, Michael D. Boska, Howard E. Gendelman, Gary Siuzdak

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Antiretroviral therapy (ART) restricts human immunodeficiency virus type one (HIV-1) replication and by so doing, improves the quality and longevity of life for infected people. Nonetheless, treatment can also lead to adverse clinical outcomes such as drug resistance and systemic adverse events. Both could be affected by long-acting slow effective release ART. Indeed, maintenance of sustained plasma drug levels, for weeks or months, after a single high-level dosing, could improve regimen adherence but, at the same time, affect systemic toxicities. Of these, the most troubling are those that affect the central nervous system (CNS). To address this, dolutegravir (Tivicay, DTG), a potent and durable HIV integrase inhibitor used effectively in combination ART was tested. Rodents were administered parenteral 45-mg/kg doses. DTG-associated changes in CNS homeostasis were assessed by measuring brain metabolic activities. After antiretroviral treatment, brain subregions were dissected and screened by mass spectrometry-based metabolomics. Metabolic drug-related dysregulation of energy and oxidative stress were readily observed within the cerebellum and frontal cortex following native drug administrations. Each was associated with alterations in neural homeostasis and depleted canonical oxidation protection pools that included glutathione and ascorbic acid. Surprisingly, the oxidative stress-related metabolites were completely attenuated when DTG was administered as nanoformulations. These data demonstrate the importance of formulation design in control of DTG or perhaps other antiretroviral drug-associated CNS events.

Original languageEnglish (US)
Pages (from-to)2896-2907
Number of pages12
JournalMolecular Neurobiology
Volume56
Issue number4
DOIs
StatePublished - Apr 1 2019

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Keywords

  • Antiretroviral therapy
  • Human immunodeficiency virus (HIV)
  • Metabolomics
  • Nanomedicine
  • Neuroprotection
  • Neurotoxicity

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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