title: HIV-1 Tat and Cocaine Impair Survival of Cultured Primary Neuronal Cells via a Mitochondrial Pathway.
abstract: Addictive stimulant drugs, such as cocaine, are known to increase the risk of exposure to HIV-1 infection and hence predispose towards the development of AIDS. Previous findings suggested that the combined effect of chronic cocaine administration and HIV-1 infection enhances cell death. Neuronal survival is highly dependent on the health of mitochondria providing a rationale for assessing mitochondrial integrity and functionality following cocaine treatment, either alone or in combination with the HIV-1 viral protein Tat, by monitoring ATP release and mitochondrial membrane potential (ΔΨm). Our results indicate that exposing human and rat primary hippocampal neurons to cocaine and HIV-1 Tat synergistically decreased both mitochondrial membrane potential and ATP production. Additionally, since previous studies suggested HIV-1 infection alters autophagy in the CNS, we investigated how HIV-1 Tat and cocaine affect autophagy in neurons. The results indicated that Tat induces an increase in LC3-II levels and the formation of Parkin-ring-like structures surrounding damaged mitochondria, indicating the possible involvement of the Parkin/PINK1/DJ-1 (PPD) complex in neuronal degeneration. The importance of mitochondrial damage is also indicated by reductions in mitochondrial membrane potential and ATP content induced by HIV-1 Tat and cocaine.
authors.affiliation: Department of Neuroscience, Center for Neurovirology and Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.|Shriners Hospitals Pediatric Research Center, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
authors.forename: Francesca Isabella
authors.initials: FI
authors.lastname: De Simone
authors.affiliation: Department of Neuroscience, Center for Neurovirology and Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.|Shriners Hospitals Pediatric Research Center, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
authors.forename: Nune
authors.initials: N
authors.lastname: Darbinian
authors.affiliation: Department of Neuroscience, Center for Neurovirology and Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.|Department of Biology, College of Science and Technology, Temple University, 1803 N. Broad Street, Philadelphia, PA, 19122, USA.
authors.forename: Shohreh
authors.initials: S
authors.lastname: Amini
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
authors.forename: Madesh
authors.initials: M
authors.lastname: Muniswamy
authors.affiliation: Department of Neuroscience, Center for Neurovirology and Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
authors.forename: Martyn K
authors.initials: MK
authors.lastname: White
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Elrod
authors.affiliation: Department of Neuroscience, Center for Neurovirology and Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
authors.forename: Prasun K
authors.initials: PK
authors.lastname: Datta
authors.affiliation: Department of Neuroscience, Center for Neurovirology and Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
authors.forename: Dianne
authors.initials: D
authors.lastname: Langford
authors.affiliation: Department of Neuroscience, Center for Neurovirology and Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA. kamel.khalili@temple.edu.
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003042:Cocaine / Q000633:toxicity*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000633:toxicity*
chemical_list: D054322:tat Gene Products, Human Immunodeficiency Virus; D003042:Cocaine
keywords: Autophagy; Cocaine; HIV-1 Tat; Mitochondria; Mitophagy; Neurodegeneration; Neuronal Cells; ROS