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Pregnane steroidogenesis is altered by HIV-1 Tat and morphine: Physiological allopregnanolone is protective against neurotoxic and psychomotor effects.

Authors
  • Paris, Jason J1, 2
  • Liere, Philippe3
  • Kim, Sarah4
  • Mahdi, Fakhri1
  • Buchanan, Meagan E1
  • Nass, Sara R5
  • Qrareya, Alaa N1
  • Salahuddin, Mohammed F1
  • Pianos, Antoine3
  • Fernandez, Neïké3
  • Shariat-Madar, Zia1, 2
  • Knapp, Pamela E4, 5, 6
  • Schumacher, Michael3
  • Hauser, Kurt F4, 5, 6
  • 1 Department of BioMolecular Sciences, University of Mississippi, School of Pharmacy, University, MS, 38677-1848, USA.
  • 2 Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS, 38677, USA.
  • 3 U1195 Inserm and University Paris-Sud and University Paris-Saclay, 94276, Le Kremlin-Bicêtre, France. , (France)
  • 4 Department of Anatomy and Neurobiology, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.
  • 5 Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.
  • 6 Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, 23298-0059, USA.
Type
Published Article
Journal
Neurobiology of stress
Publication Date
May 01, 2020
Volume
12
Pages
100211–100211
Identifiers
DOI: 10.1016/j.ynstr.2020.100211
PMID: 32258256
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Pregnane steroids, particularly allopregnanolone (AlloP), are neuroprotective in response to central insult. While unexplored in vivo, AlloP may confer protection against the neurological dysfunction associated with human immunodeficiency virus type 1 (HIV-1). The HIV-1 regulatory protein, trans-activator of transcription (Tat), is neurotoxic and its expression in mice increases anxiety-like behavior; an effect that can be ameliorated by progesterone, but not when 5α-reduction is blocked. Given that Tat's neurotoxic effects involve mitochondrial dysfunction and can be worsened with opioid exposure, we hypothesized that Tat and/or combined morphine would perturb steroidogenesis in mice, promoting neuronal death, and that exogenous AlloP would rescue these effects. Like other models of neural injury, conditionally inducing HIV-1 Tat in transgenic mice significantly increased the central synthesis of pregnenolone and progesterone's 5α-reduced metabolites, including AlloP, while decreasing central deoxycorticosterone (independent of changes in plasma). Morphine significantly increased brain and plasma concentrations of several steroids (including progesterone, deoxycorticosterone, corticosterone, and their metabolites) likely via activation of the hypothalamic-pituitary-adrenal stress axis. Tat, but not morphine, caused glucocorticoid resistance in primary splenocytes. In neurons, Tat depolarized mitochondrial membrane potential and increased cell death. Physiological concentrations of AlloP (0.1, 1, or 10 nM) reversed these effects. High-concentration AlloP (100 nM) was neurotoxic in combination with morphine. Tat induction in transgenic mice potentiated the psychomotor effects of acute morphine, while exogenous AlloP (1.0 mg/kg, but not 0.5 mg/kg) was ameliorative. Data demonstrate that steroidogenesis is altered by HIV-1 Tat or morphine and that physiological AlloP attenuates resulting neurotoxic and psychomotor effects. © 2020 The Author(s).

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