title: Impairment of adult hippocampal neural progenitor proliferation by methamphetamine: role for nitrotyrosination.
abstract: Methamphetamine (METH) abuse has reached epidemic proportions, and it has become increasingly recognized that abusers suffer from a wide range of neurocognitive deficits. Much previous work has focused on the deleterious effects of METH on mature neurons, but little is known about the effects of METH on neural progenitor cells (NPCs). It is now well established that new neurons are continuously generated from NPCs in the adult hippocampus, and accumulating evidence suggests important roles for these neurons in hippocampal-dependent cognitive functions. In a rat hippocampal NPC culture system, we find that METH results in a dose-dependent reduction of NPC proliferation, and higher concentrations of METH impair NPC survival. NPC differentiation, however, is not affected by METH, suggesting cell-stage specificity of the effects of METH. We demonstrate that the effects of METH on NPCs are, in part, mediated through oxidative and nitrosative stress. Further, we identify seventeen NPC proteins that are post-translationally modified via 3-nitrotyrosination in response to METH, using mass spectrometric approaches. One such protein was pyruvate kinase isoform M2 (PKM2), an important mediator of cellular energetics and proliferation. We identify sites of PKM2 that undergo nitrotyrosination, and demonstrate that nitration of the protein impairs its activity. Thus, METH abuse may result in impaired adult hippocampal neurogenesis, and effects on NPCs may be mediated by protein nitration. Our study has implications for the development of novel therapeutic approaches for METH-abusing individuals with neurologic dysfunction and may be applicable to other neurodegenerative diseases in which hippocampal neurogenesis is impaired.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA. avenkat2@jhmi.edu
authors.forename: Arun
authors.initials: A
authors.lastname: Venkatesan
authors.forename: Lerna
authors.initials: L
authors.lastname: Uzasci
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Chen
authors.forename: Labchan
authors.initials: L
authors.lastname: Rajbhandari
authors.forename: Carol
authors.initials: C
authors.lastname: Anderson
authors.forename: Myoung-Hwa
authors.initials: MH
authors.lastname: Lee
authors.forename: Mario A
authors.initials: MA
authors.lastname: Bianchet
authors.forename: Robert
authors.initials: R
authors.lastname: Cotter
authors.forename: Hongjun
authors.initials: H
authors.lastname: Song
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D008694:Methamphetamine / Q000494:pharmacology*; D008958:Models, Molecular; D058953:Neural Stem Cells / Q000187:drug effects* / Q000502:physiology*; D018384:Oxidative Stress; D011487:Protein Conformation; D011770:Pyruvate Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D019966:Substance-Related Disorders; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002839:Chromans; D015259:Dopamine Agents; C002744:3-nitrotyrosine; D014443:Tyrosine; D008694:Methamphetamine; D011770:Pyruvate Kinase; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid