title: Activation of glutathione peroxidase and inhibition of p53-related apoptosis by apomorphine.
abstract: Apomorphine hydrochloride (APO) is known to be a dopamine receptor agonist, and has recently been found to be a novel drug for Alzheimer's disease (AD). We found that APO treatment ameliorated oxidative stress in an AD mouse model and specifically attenuated the hydrogen peroxide-induced p53-related apoptosis in the SH-SY5Y neuroblastoma cell line. To further understand the mechanism behind this action, we investigated the actions of APO on intracellular redox systems, such as the glutathione cycle and catalase. We studied the effects of specific inhibitors for glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (BCNU, MCS, and ATZ, respectively) on the effects of APO. Treatments with MCS or BCNU, but not ATZ, significantly attenuated the protective effects of APO. Interestingly, APO treatment elevated GPx activity, but did not increase the expression of the GPx1 protein. Although BCNU treatment attenuated APO effects, GR activity was not elevated by APO treatment. The same effects were observed in primary neuronal cultures. In addition, treatment with dopamine D1, D2, D3 and D4 receptor antagonists did not counteract the protective action of APO. Thus, APO may enhance GPx activity through dopamine receptor-independent pathways.
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Linqing
authors.initials: L
authors.lastname: Ma
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ohyagi
authors.forename: Norimichi
authors.initials: N
authors.lastname: Nakamura
authors.forename: Kyoko M
authors.initials: KM
authors.lastname: Iinuma
authors.forename: Katsue
authors.initials: K
authors.lastname: Miyoshi
authors.forename: Eri
authors.initials: E
authors.lastname: Himeno
authors.forename: Naoko
authors.initials: N
authors.lastname: Soejima
authors.forename: Yuki T
authors.initials: YT
authors.lastname: Yanagihara
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Sakae
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamasaki
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kira
mesh_terms: D001058:Apomorphine / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism*; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D013722:Teprotide / Q000494:pharmacology; D000094765:Glutathione Peroxidase GPX1
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; C485896:PIDD1 protein, human; D006861:Hydrogen Peroxide; D013722:Teprotide; D002374:Catalase; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005978:Glutathione; D001058:Apomorphine; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human