Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals

Kelly L. Stauch, Katy Emanuel, Benjamin G. Lamberty, Brenda Morsey, Howard S Fox

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The use of antiretroviral (ARV) drugs with central nervous system (CNS) penetration effectiveness (CPE) may be useful in the treatment of HIV-associated neurocognitive disorder (HAND) as well as targeting a CNS reservoir in strategies to achieve a functional cure for HIV. However, increased cognitive deficits are linked to at least one of these drugs (efavirenz). As mitochondrial dysfunction has been found with a number of ARVs, and as such can affect neuronal function, the objective of this study was to assess the effects of ARV with high CPE for toxicological profiles on presynaptic nerve terminal energy metabolism. This subcellular region is especially vulnerable in that a constant supply of ATP is required for the proper maintenance of neurotransmitter release and uptake supporting proper neuronal function. We evaluated the effects of acute treatment with ten different high CPE ARVs from five different drug classes on rat cortical and striatal nerve terminal bioenergetic function. While cortical nerve terminal bioenergetics were not altered, striatal nerve terminals exposed to efavirenz, nevirapine, abacavir, emtricitabine, zidovudine, darunavir, lopinavir, raltegravir, or maraviroc (but not indinavir) exhibit reduced mitochondrial spare respiratory capacity (SRC). Further examination of efavirenz and maraviroc revealed a concentration-dependent impairment of striatal nerve terminal maximal mitochondrial respiration and SRC as well as a reduction of intraterminal ATP levels. Depletion of ATP at the synapse may underlie its dysfunction and contribute to neuronal dysfunction in treated HIV infection.

Original languageEnglish (US)
Pages (from-to)795-807
Number of pages13
JournalJournal of neurovirology
Volume23
Issue number6
DOIs
StatePublished - Dec 1 2017

Fingerprint

efavirenz
Corpus Striatum
Energy Metabolism
Central Nervous System
Adenosine Triphosphate
HIV
Central Nervous System Agents
Lopinavir
Indinavir
Nevirapine
Zidovudine
Presynaptic Terminals
Pharmaceutical Preparations
Synapses
Toxicology
HIV Infections
Neurotransmitter Agents
Respiration
Maintenance

Keywords

  • Antiretrovirals
  • Bioenergetics
  • Neurotoxicity
  • Synaptic mitochondria

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Virology

Cite this

Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals. / Stauch, Kelly L.; Emanuel, Katy; Lamberty, Benjamin G.; Morsey, Brenda; Fox, Howard S.

In: Journal of neurovirology, Vol. 23, No. 6, 01.12.2017, p. 795-807.

Research output: Contribution to journalArticle

Stauch, Kelly L. ; Emanuel, Katy ; Lamberty, Benjamin G. ; Morsey, Brenda ; Fox, Howard S. / Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals. In: Journal of neurovirology. 2017 ; Vol. 23, No. 6. pp. 795-807.
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