Nanoformulated Antiretroviral Therapy Attenuates Brain Metabolic Oxidative Stress

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

doi:10.1007/s12035-018-1273-8

J. Rafael Montenegro-Burke, Aditya N. Bade + Show 7 more

Open Access

https://doi.org/10.1007/s12035-018-1273-8

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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.

Highlights

Human immunodeficiency virus type one (HIV-1) infection is associated with a spectrum of comorbid conditions that includes the central nervous system (CNS) [1,2,3]
Following free and nanoformulated DTG mouse injections, global metabolomics were performed on five dissected brain subregions including the frontal cortex (FC), ventral cortex (VC), dorsal cortex (DC), H, and CR (Fig. 1)
Among the many dysregulated metabolites seen in brain subregions in the free DTG-treated group, the most affected were identified as energy-related pathways, including glycolysis and the tricarboxylic acid (TCA) cycle (Fig. 3)

Summary

Introduction

Human immunodeficiency virus type one (HIV-1) infection is associated with a spectrum of comorbid conditions that includes the central nervous system (CNS) [1,2,3]. Many of these conditions have been either reduced or eliminated following the widespread use of antiretroviral therapy (ART). Malignancies, depression, and immune dysfunctions are linked to cognitive and behavioral abnormalities as are antiretroviral drugs (ARVs) themselves The latter plays a role in direct neurotoxicity and consequent neuropsychiatric compromise [6, 7].

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