RRC ID 34823
Author Ramkissoon A, Wells PG.
Title Methamphetamine oxidative stress, neurotoxicity, and functional deficits are modulated by nuclear factor-E2-related factor 2.
Journal Free Radic Biol Med
Abstract Activation of redox-sensitive transcription factors like nuclear factor-E2-related factor 2 (Nrf2) can enhance the transcription of cytoprotective genes during oxidative stress. We investigated whether Nrf2 is activated by methamphetamine (METH) thereby altering neurotoxicity in Nrf2 +/+ and -/- adult mouse brain. A single dose of METH can induce the mRNA levels of Nrf2-regulated antioxidant and cytoprotective proteins in mouse brain. Multiple-day dosing with METH enhanced DNA oxidation and decreased tyrosine hydroxylase and dopamine transporter staining in the striatum, indicating dopaminergic nerve terminal toxicity, which was more severe in -/- mice, as were deficits in motor coordination and olfactory discrimination. These Nrf2-dependent effects were independent of changes in METH metabolism or the induction of hyperthermia. Similarly, METH increased striatal glial fibrillary acidic protein, indicating neurotoxicity. METH neurotoxicity was also observed in the glial cells and in the GABAergic system of the olfactory bulbs and was enhanced in -/- mice, whereas dopaminergic parameters were unaffected. With one-day dosing of METH, there were no differences between +/+ and -/- mice in either basal or METH-enhanced DNA oxidation and neurotoxicity markers. Nrf2-mediated pathways accordingly may protect against the neurodegenerative effects and functional deficits initiated by METH and perhaps other reactive oxygen species-enhancing neurotoxicants, when there is time for transcriptional activation and protein induction. In human users of METH, this mechanism may be essential when differences in drug abuse patterns may alter the induction and duration of Nrf2 activation thereby modulating susceptibility to the neurotoxic effects of METH.
Volume 89
Pages 358-68
Published 2015-12-1
DOI 10.1016/j.freeradbiomed.2015.07.157
PII S0891-5849(15)00522-5
PMID 26427884
MeSH Animals Apoptosis / drug effects Behavior, Animal / drug effects* Blotting, Western Cell Proliferation / drug effects Cells, Cultured Central Nervous System Stimulants / toxicity* Corpus Striatum / drug effects Corpus Striatum / metabolism Corpus Striatum / pathology Disease Models, Animal Dopamine / metabolism Fever / chemically induced Fever / metabolism Fever / pathology Glial Fibrillary Acidic Protein / genetics Glial Fibrillary Acidic Protein / metabolism Humans Immunoenzyme Techniques Methamphetamine / toxicity* Mice Mice, Knockout NF-E2-Related Factor 2 / physiology* Neurotoxicity Syndromes / etiology* Neurotoxicity Syndromes / metabolism Neurotoxicity Syndromes / pathology Oxidative Stress / drug effects* RNA, Messenger / genetics Reactive Oxygen Species / metabolism Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Tyrosine 3-Monooxygenase / metabolism
IF 6.17
Times Cited 15
Mice RBRC00984