Treadmill exercise activates Nrf2 antioxidant system to protect the nigrostriatal dopaminergic neurons from MPP+ toxicity

Exercise induces oxidative stress, which may activate adaptive antioxidant responses. Nuclear factor erythroid 2related factor 2 (Nrf2) plays an important role in the defense of oxidative stress by regulating the expression of antioxidant enzymes, gamma-glutamylcysteine ligase (gamma GCL) and heme oxygenase-1 (HO-1). We investigated whether treadmill exercise protects dopaminergic neurons by regulating the Nrf2 antioxidant system in a 1-methy1-4-phenylpyridine (MPP+)-induced parkinsonian rat model. We found that MPP+, induced early decreases in total glutathione level and Nrf2/gamma GCLC (catalytic subunit of gamma GCL) expression, but late upregulation of HO-1 expression in association with loss of nigral dopaminergic neurons and downregulation of tyrosine hydroxylase and dopamine transporter expression in the striatum. Treadmill exercise for 4 weeks induced upregulation of Nrf2 and gamma GCLC expression, and also prevented the MPP -induced downregulation of Nrf2/gamma GCLC/glutathione, HO-1 upregulation, and nigrostriatal dopaminergic neurodegeneration. Moreover, the protective effect of exercise was blocked by the knockdown of Nrf2 using a lentivirus-carried shNrf2 delivery system. These results demonstrate an essential role of Nrf2 in the exercise-mediated protective effect that exercise enhances the nigrostriatal Nrf2 antioxidant defense capacity to protect dopaminergic neurons against the MPP+-induced toxicity. (C) 2014 Elsevier Inc All rights reserved.