title: The role of mitochondrial alterations in the combined toxic effects of human immunodeficiency virus Tat protein and methamphetamine on calbindin positive-neurons.
abstract: The use of methamphetamine (METH) continues to increase the risk of human immunodeficiency virus (HIV) transmission within both homosexual and heterosexual drug abuser groups. Neurological studies indicate that the progression of HIV encephalitis is also enhanced by illicit drug use. Recently, the authors' studies in the postmortem brains of HIV-positive METH users have shown that the combined effects of HIV and METH selectively damage calbindin (CB)-immunoreactive nonpyramidal neurons, which may contribute to the behavioral alterations observed in these patients. To better understand the mechanisms of toxicity associated with exposure to HIV and METH, neuronal survival, phenotypic markers, levels of oxidative stress, and mitochondrial potential were assessed in vitro in the hippocampal neuronal cell line, HT22, and in primary human neurons exposed to the HIV Tat protein and/or METH. Both Tat and METH were toxic to neurons in a time- and dose-dependent fashion. Neurons exposed to a combination of Tat and METH displayed early evidence of neuronal damage at 6 h, characterized by a decrease in CB and microtubule-associated protein 2 (MAP2) immunoreactivity followed by more extensive cell death at 24 h. Loss of CB immunoreactivity associated with the combined exposure to Tat and METH was accompanied by mitochondrial damage with increased levels of oxidative stress. The toxic effects of Tat and METH were inhibited by blocking mitochondrial uptake of intracellular calcium, whereas blocking calcium flux in the endoplasmic reticulum or from the extracellular environment had no effect on Tat and METH toxicity. These studies indicate that in vitro, when combined, the HIV protein Tat and METH damage CB-immunoreactive nonpyramidal neurons by dysregulating the mitochondrial calcium potential. In combination, Tat and METH may increase cell injury and death, thereby enhancing brain metabolic disturbances observed in HIV-positive METH users in clinical populations.
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California 92093-0624, USA.
authors.forename: Dianne
authors.initials: D
authors.lastname: Langford
authors.forename: Aline
authors.initials: A
authors.lastname: Grigorian
authors.forename: Rosemary
authors.initials: R
authors.lastname: Hurford
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Leslie
authors.initials: L
authors.lastname: Crews
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D064026:Calbindins; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015696:Gene Products, tat / Q000494:pharmacology*; D006678:HIV; D006801:Humans; D007150:Immunohistochemistry; D008694:Methamphetamine / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013997:Time Factors; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D064026:Calbindins; D000697:Central Nervous System Stimulants; D015696:Gene Products, tat; D008869:Microtubule-Associated Proteins; D064030:S100 Calcium Binding Protein G; D054322:tat Gene Products, Human Immunodeficiency Virus; D008694:Methamphetamine; D002118:Calcium