HIV-1 Tat and methamphetamine co-induced oxidative cellular injury is mitigated by N-acetylcysteine amide (NACA) through rectifying mTOR signaling. (15th December 2018)

• Record Type: Journal Article
• Authors: Zeng, Xiao-Feng; Li, Qi; Li, Juan; Wong, Naikei; Li, Zhen; Huang, Jian; Yang, Genmeng; Sham, Pak C.; Li, Sheng-Bin; Lu, Gang
• Is Part Of: Toxicology letters. Volume 299(2018)
• Page Start: 159
• Page End: 171
• Publication Date: 2018-12-15
• Subjects: METH methamphetamine -- HAND HIV-associated neurocognitive disorders -- NACA N-acetylcysteine amide -- mTOR mammalian target of rapamycin -- 3-MA 3-methyladenine -- Rapa rapamycin; HIV-1Tat -- Methamphetamine -- Autophagy -- Oxidative stress -- mTOR -- NACA; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2018.09.009
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: Meth and Tat synergistically increased cell death in dose- and time-dependent manners. Meth and Tat-induced autophagy and apoptosis in vitro and in vivo . NACA confers protection against Tat- and/or Meth-induced and/or autophagy through mTOR signaling in vitro and in vivo . Abstract: Methamphetamine (Meth) is an addictive psychostimulant whose abuse is intimately linked to increased risks for HIV-1 infection. Converging lines of evidence indicate that Meth also aggravates the symptoms of HIV-associated neurocognitive disorders (HAND), though the underlying mechanisms remain poorly understood. By using the lipophilic antioxidant N -acetylcysteine amide (NACA) as an interventional agent, we examined the roles of oxidative stress in autophagy and apoptosis induced by HIV-Tat (the transactivator of transcription), Meth or their combined treatment in human SH-SY5Y neuroblastoma cells and in the rat striatum. Oxidative stress was monitored in terms of the production of intracellular reactive oxygen species (ROS) and antioxidant reserves including glutathione peroxidase (GPx) and Cu, Zn- superoxide dismutase (SOD). NACA significantly reduced the level of ROS and restored GPx and SOD to levels comparable to that of normal control, implying a cytoprotective effect of NACA against oxidative stress elicited by Tat- and/or Meth. Protein expression of mammalian target of rapamycin (mTOR) was measured in SH-SY5Y cells and in the rat striatum to further explore the underlying mechanism of NACA protect against oxidative stress. The results support a beneficial effect of NACA in vivo and in vitro through rectification of the mTOR signaling pathway. Collectively, our study shows that NACA protects against Meth and/or Tat-induced cellular injury in vitro and in the rat striatum in vivo by attenuating oxidative stress, apoptosis and autophagy, at least in part, via modulation of mTOR signaling.