Methamphetamine and HIV-1 Tat proteins synergistically induce microglial autophagy via activation of the Nrf2/NQO1/HO-1 signal pathway. (1st December 2022)

• Record Type: Journal Article
• Authors: Yang, Genmeng; Li, Juan; Leung, Chi-Kwan; Shen, Baoyu; Wang, Chan; Xu, Yue; Lin, Shucheng; Zhang, Shuwei; Tan, Yi; Zhang, Huijie; Zeng, Xiaofeng; Hong, Shijun; Li, Lihua
• Is Part Of: Neuropharmacology. Volume 220(2022)
• Publication Date: 2022-12-01
• Subjects: Methamphetamine -- HIV-1Tat protein -- Nrf2 pathway -- Microglia -- Autophagy; DMEM Dulbecco modified Eagle medium -- DAPI 4 6-diamidino-2-phenylindole -- FBS fetal bovine serum -- HIV-1 Tat Human immunodeficiency virus-1 transactivator of transcription -- HAND HIV-1-associated neurocognitive disorders -- HO-1 Heme oxygenase 1 -- IBA1 ionized calcium binding adapter molecule 1 -- KEAP1 kelch-like ECH associated protein 1 -- KO knock out -- LC3 microtubule-associated protein 1 light chain 3 -- METH Methamphetamine -- NQO1 NAD(P)H quinone dehydrogenase 1 -- mPM mouse primary microglial cells (s) -- NFE2L2/Nrf2 nuclear factor erythroid derived2 like 2 -- PBS phosphate-buffered saline -- TBS Tris base-buffered saline -- TBST Tris-HCl buffered saline-tween 20; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2022.109256
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Methamphetamine (METH) is a psychostimulant that is abused throughout the world. METH is a highly addictive drug commonly used by persons living with HIV, and its use can result in cognitive impairment and memory deficits. METH and human immunodeficiency virus-1 transactivator of transcription (HIV-1Tat) have toxic and synergistic effects on the nervous system; however, the mechanism of their synergistic effects has not been clarified. We used BV2 cells, primary microglia, Nrf2-KO C57BL/6J mice, and autopsied brain tissues of METH-abusing, HIV infection, and METH-abusing individuals comorbid with HIV to explore the regulatory role of Nrf2/NQO1/HO-1 signal pathway on microglia autophagy. Our results showed that microglia were significantly activated by METH and HIV-1Tat protein. METH and HIV-1Tat protein combination significantly increase the autophagy-related proteins (LC3-II, Beclin-1, ATG5, and ATG7) expression in microglia and striatum of C57BL/6J mice. After silencing or knocking out the Nrf2 gene, the expression levels of autophagy-related proteins were significantly increased. In human brain tissue, microglia were activated, Nrf2, LC3-II, and Beclin-1 expression levels were raised, and the p62 expression level was decreased. Our results suggested that METH and HIV or HIV-1Tat synergistically affect autophagy. And the Nrf2 pathway plays a vital role in regulating the synergistic induction of microglial autophagy by METH and HIV-1Tat protein. This study may provide a theoretical basis and new ideas for effective targets for pharmacological intervention in HIV-infected patients with drug abuse. Highlights: METH and HIV-1Tat protein synergistically induced higher levels of autophagy-related proteins expression in microglia. Activation of Nrf2 decreased the autophagy levels of METH and HIV-1 Tat protein synergistically induced in microglia. Silencing of Nrf2 synergistically induced microglial autophagy by METH and HIV-1 Tat protein. Modulation of METH- and HIV-1 Tat protein-induced oxidative stress in microglia by Nrf2.