Bromocriptine activates NQO1 via Nrf2-PI3K/Akt signaling: novel cytoprotective mechanism against oxidative damage.
Parkinson's disease (PD) is a neurodegenerative disorder associated with selective loss of dopaminergic neurons in the substantia nigra. Because oxidative stress caused by dopamine oxidation to dopamine quinone is suggested as a major factor contributing to the pathogenesis of PD, the induction of the enzyme that catalyzes the reduction of quinones, NAD(P)H quinone oxidoreductase1 (NQO1), could be a desirable therapeutic strategy to protect cells from oxidative damage. The dopamine agonist bromocriptine is used clinically for PD therapy. In addition to ameliorating the motor deficit via dopamine D2 receptor activation, bromocriptine also has neuroprotective and antioxidative activity. In the present study, we show that bromocriptine upregulates the expression and activity of NQO1, attenuates the increase in the protein-bound quinone in H(2)O(2)-treated PC12 cells, and protects PC12 cells against oxidative damage. Bromocriptine increases the expression and nuclear translocation of a basic leucine zipper transcription factor, nuclear factor-E2-related factor-2 (Nrf2), which is known to be involved in the regulation of numerous antioxidant enzymes via the antioxidant response element. The Nrf2-related cytoprotective and antioxidative effects of bromocriptine are PI3K/Akt pathway-dependent, and are independent of dopamine receptor activation. The cytoprotective effect of bromocriptine in PC12 cells is not affected by the presence of dopamine D2 antagonist, and the bromocriptine-induced Nrf2-ARE activation and cytoprotection against oxidative stress are observed in both dopamine D2 receptor-expressing A7-D2 and non-expressing A7 cells. Taken together, we investigate the novel cytoprotective effect of bromocriptine involving PI3K- and Nrf2-mediated upregulation of the antioxidant enzyme NQO1.
Lim
Ju Hee
JH
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, 300 Yongbong-dong, Buk-gu, Gwangju 500-757, South Korea.
Kim
Kyeong-Man
KM
Kim
Seong Who
SW
Hwang
Onyou
O
Choi
Hyun Jin
HJ
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001971:Bromocriptine / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000633:toxicity; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D017448:Receptors, Dopamine D2; D001971:Bromocriptine; D006861:Hydrogen Peroxide; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt