Dopamine as a Potent Inducer of Cellular Glutathio

Authors: Zhenquan Jia Hong Zhu Bhaba R Misra Yunbo Li Hara P Misra

Publish Date: 2008/03/27

Volume: 33, Issue: 11, Pages: 2197-2205

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Abstract

Dopamine autooxidation and the consequent formation of reactive oxygen species and electrophilic quinone molecules have been implicated in dopaminergic neuronal cell death in Parkinson’s disease We reported here that in PC12 dopaminergic neuronal cells dopamine at noncytotoxic concentrations 50–150 μM potently induced cellular glutathione GSH and the phase 2 enzyme NADPHquinone oxidoreductase 1 NQO1 two critical cellular defenses in detoxification of ROS and electrophilic quinone molecules Incubation of PC12 cells with dopamine also led to a marked increase in the mRNA levels for γglutamylcysteine ligase catalytic subunit GCLC and NQO1 In addition treatment of PC12 cells with dopamine resulted in a significant elevation of GSH content in the mitochondrial compartment To determine whether treatment with dopamine at noncytotoxic concentrations which upregulated the cellular defenses could protect the neuronal cells against subsequent lethal oxidative and electrophilic injury PC12 cells were pretreated with dopamine 150 μM for 24 h and then exposed to various cytotoxic concentrations of dopamine or 6hydroxydopamine 6OHDA We found that pretreatment of PC12 cells with dopamine at a noncytotoxic concentration led to a remarkable protection against cytotoxicity caused by dopamine or 6OHDA at lethal concentrations as detected by 345dimethylthiazol2yl25diphenyltetrazolium reduction assay In view of the critical roles of GSH and NQO1 in protecting against dopaminergic neuron degeneration the above findings implicate that upregulation of both GSH and NQO1 by dopamine at noncytotoxic concentrations may serve as an important adaptive mechanism for dopaminergic neuroprotection

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