Academic Journal
Pregnane steroidogenesis is altered by HIV-1 Tat and morphine: Physiological allopregnanolone is protective against neurotoxic and psychomotor effects
| العنوان: | Pregnane steroidogenesis is altered by HIV-1 Tat and morphine: Physiological allopregnanolone is protective against neurotoxic and psychomotor effects |
|---|---|
| المؤلفون: | Jason J. Paris, Philippe Liere, Sarah Kim, Fakhri Mahdi, Meagan E. Buchanan, Sara R. Nass, Alaa N. Qrareya, Mohammed F. Salahuddin, Antoine Pianos, Neïké Fernandez, Zia Shariat-Madar, Pamela E. Knapp, Michael Schumacher, Kurt F. Hauser |
| المصدر: | Neurobiology of Stress, Vol 12, Iss , Pp - (2020) |
| بيانات النشر: | Elsevier, 2020. |
| سنة النشر: | 2020 |
| المجموعة: | LCC:Neurosciences. Biological psychiatry. Neuropsychiatry LCC:Neurology. Diseases of the nervous system LCC:Neurophysiology and neuropsychology |
| مصطلحات موضوعية: | 5α-pregnan-3α-ol-20-one, Glucocorticoid resistance, HIV/AIDS, Opioid, Neurosteroid, Stress, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429, Neurophysiology and neuropsychology, QP351-495 |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2352-2895 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S2352289520300011; https://doaj.org/toc/2352-2895 |
| DOI: | 10.1016/j.ynstr.2020.100211 |
| URL الوصول: | https://doaj.org/article/1eae79c386794b818bb6eb4c7ba81e75 |
| رقم الانضمام: | edsdoj.1eae79c386794b818bb6eb4c7ba81e75 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 23522895 |
|---|---|
| DOI: | 10.1016/j.ynstr.2020.100211 |