title: Nrf2 deficiency potentiates methamphetamine-induced dopaminergic axonal damage and gliosis in the striatum.
abstract: Oxidative stress that correlates with damage to nigrostriatal dopaminergic neurons and reactive gliosis in the basal ganglia is a hallmark of methamphetamine (METH) toxicity. In this study, we analyzed the protective role of the transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2), a master regulator of redox homeostasis, in METH-induced neurotoxicity. We found that Nrf2 deficiency exacerbated METH-induced damage to dopamine neurons, shown by an increase in loss of tyrosine hydroxylase (TH)- and dopamine transporter (DAT)-containing fibers in striatum. Consistent with these effects, Nrf2 deficiency potentiated glial activation, indicated by increased striatal expression of markers for microglia (Mac-1 and Iba-1) and astroglia (GFAP) one day after METH administration. At the same time, Nrf2 inactivation dramatically potentiated the increase in TNFα mRNA and IL-15 protein expression in GFAP+ cells in the striatum. In sharp contrast to the potentiation of striatal damage, Nrf2 deficiency did not affect METH-induced dopaminergic neuron death or expression of glial markers or proinflammatory molecules in the substantia nigra. This study uncovers a new role for Nrf2 in protection against METH-induced inflammatory and oxidative stress and striatal degeneration.
authors: Instituto Cajal, CSIC, Madrid, Spain.
authors: Noelia
authors: N
authors: Granado
authors: Isabel
authors: I
authors: Lastres-Becker
authors: Sara
authors: S
authors: Ares-Santos
authors: Idaira
authors: I
authors: Oliva
authors: Eduardo
authors: E
authors: Martin
authors: Antonio
authors: A
authors: Cuadrado
authors: Rosario
authors: R
authors: Moratalla
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology*; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000633:toxicity; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics; D014855:Wallerian Degeneration / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D018836:Inflammation Mediators; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D008694:Methamphetamine; D004298:Dopamine