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. © 2011 Wiley‐Liss, Inc.

Melatonin Protects Methamphetamine-Induced Neuroinflammation Through NF-κB and Nrf2 Pathways in Glioma Cell Line

“…The present study showed that METH significantly increased the degradation of IjBa and increased the translocation of the p65 protein into the nucleus in glioma cells after exposure for different lengths of time and was associated with a remarkable increased in iNOS expression and NO production indicating that METH-induced inflammation mediated by NF-jB signaling. These results correlated well with earlier studies demonstrating significant activation of NF-jB signaling following METH treatment in both neuronal and glial cells [33,41]. In addition, we further observed the suppression of Nrf2 signaling pathway by METH in glioma cells.…”

“…We next evaluated whether METH-reduced the activity of the Nrf2 pathway in glial cells, which is a typical mechanism of phase II enzymes that scavenge ROS [41]. It is well known that antioxidant genes, including HO-1, NQO-1, and c-GCLC, are transcribed by Nrf2, a major transcription factor regulating antioxidant response element (ARE)-driven phase II gene expression.…”

Methamphetamine Causes Degeneration of Dopamine Cell Bodies and Terminals of the Nigrostriatal Pathway Evidenced by Silver Staining

“…A large body of evidence indicates that the molecular mechanisms of terminal degeneration are separate and distinct from those of neuron somatic degeneration (Burke and O'Malley, 2012;Coleman, 2005;Raff et al, 2002;Ries et al, 2008). This idea is further supported by the fact that genetic inactivation of Nrf2 potentiates dopamine terminal loss without affecting survival of dopamine neurons in the SNpc (Granado et al, 2011b). In line with this, we observe no significant differences between the effects of single high dose and multiple lower doses on methamphetamineinduced dopaminergic neuronal loss, despite the clear dose dependence of dopamine terminal loss in the striatum.…”

Diphenyl Diselenide Modulates Gene Expression of Antioxidant Enzymes in the Cerebral Cortex, Hippocampus and Striatum of Female Hypothyroid Rats

“…Here, the striatal Nrf-2 expression was not modified by MTZ exposure. We did not expect this result since several studies, mainly related to Parkinson disease models, have demonstrated that this transcription factor in the striatum and/or dopaminergic neurons can be modulated by different drugs, including methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium (MPTP) [81,82]. The results obtained here indicate that the pattern of gene expression in response to hypothyroidism is complex and depends on the brain region considered.…”