TY - JOUR
T1 - Nanoformulated Antiretroviral Therapy Attenuates Brain Metabolic Oxidative Stress
AU - Montenegro-Burke, J. Rafael
AU - Woldstad, Christopher J.
AU - Fang, Mingliang
AU - Bade, Aditya N.
AU - McMillan, Jo Ellyn
AU - Edagwa, Benson
AU - Boska, Michael D.
AU - Gendelman, Howard E.
AU - Siuzdak, Gary
N1 - Funding Information:
Funding Information This work was supported, in part, by the University of Nebraska Foundation, which includes individual donations from Dr. Carol Swarts, Frances and Louie Blumkin, and National Institutes of Health, and grants P01 MH64570, RO1 MH104147, P01 DA028555, R01 NS36126, P01 NS31492, 2R01 NS034239, P01 NS43985, P30 MH062261, R01 AG043540, and R01 GM114368. This work also received funding support from ViiV Healthcare.
Publisher Copyright:
© 2018, The Author(s).
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
KW - Antiretroviral therapy
KW - Human immunodeficiency virus (HIV)
KW - Metabolomics
KW - Nanomedicine
KW - Neuroprotection
KW - Neurotoxicity
UR - http://www.scopus.com/inward/record.url?scp=85051457253&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85051457253&partnerID=8YFLogxK
U2 - 10.1007/s12035-018-1273-8
DO - 10.1007/s12035-018-1273-8
M3 - Article
C2 - 30069830
AN - SCOPUS:85051457253
VL - 56
SP - 2896
EP - 2907
JO - Molecular Neurobiology
JF - Molecular Neurobiology
SN - 0893-7648
IS - 4
ER -