title: Methamphetamine potentiates HIV-1 gp120-mediated autophagy via Beclin-1 and Atg5/7 as a pro-survival response in astrocytes.
abstract: Methamphetamine (METH), a commonly used controlled substance, is known to exacerbate neuropathological dysfunction in HIV-infected individuals. The neuropathological manifestation results from cell death or dysfunction in the central nervous system (CNS) wherein autophagy is expected to have an important role. Autophagy is generally considered protective during deprivation/stress. However, excessive autophagy can be destructive, leading to autophagic cell death. This study was designed to investigate if METH and HIV-1 gp120 interact to induce autophagy in SVGA astrocytes, and whether autophagy is epiphenomenal or it has a role in METH- and gp120-induced cytotoxicity. We found that METH and gp120 IIIb caused an increase in LC3II level in astrocytes in a dose- and time-dependent manner, and the level of LC3II was further increased when the cells were treated with METH and gp120 IIIb in combination. Next, we sought to explore the mechanism by which METH and gp120 induce the autophagic response. We found that METH induces autophagy via opioid and metabotropic glutamate receptor type 5 (mGluR5) receptors. Other than that, signaling proteins Akt, mammalian target of rapamycin (mTOR), Beclin-1, Atg5 and Atg7 were involved in METH and gp120-mediated autophagy. In addition, long-term treatment of METH and gp120 IIIb resulted in cell death, which was exacerbated by inhibition of autophagy. This suggests that autophagy functions as a protective response against apoptosis caused by METH and gp120. This study is novel and clinically relevant because METH abuse among HIV-infected populations is highly prevalent and is known to cause exacerbated neuroAIDS.
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.
authors.forename: Mingui
authors.initials: M
authors.lastname: Fu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
mesh_terms: D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism*; D000071193:Autophagy-Related Protein 7 / Q000378:metabolism*; D000071186:Beclin-1 / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008694:Methamphetamine / Q000494:pharmacology*; D008954:Models, Biological; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D015699:HIV Envelope Protein gp120; D064529:Receptor, Metabotropic Glutamate 5; D011957:Receptors, Opioid; D008694:Methamphetamine; D058570:TOR Serine-Threonine Kinases; D000071193:Autophagy-Related Protein 7