title: Protective effects of apomorphine against zinc-induced neurotoxicity in cultured cortical neurons.
abstract: There is evidence that excessive zinc (Zn(2+)) release from presynaptic terminals following brain injuries such as ischemia and severe epileptic seizures induces neuronal cell death. Apomorphine (Apo), a dopamine receptor agonist, has been shown to have pleiotropic biological functions. In this study, we investigated whether Apo protects cultured cortical neurons from neurotoxicity provoked by excessive Zn(2+) exposure. Pretreatment with Apo dose- and time-dependently ameliorated Zn(2+) neurotoxicity. In addition, pretreatment with Apo prevented intracellular nicotinamide adenine dinucleotide (NAD(+)) and ATP depletion caused by Zn(2+) exposure. Dopamine receptor antagonists did not influence Apo protection against Zn(2+) neurotoxicity. Apo is shown to be autoxidized to produce oxidized products such as reactive oxygen species and quinones. N-Acetylcysteine, a thiol compound, partially reduced Apo protection. Entry of Zn(2+) into neurons is thought to be a critical step of Zn(2+) neurotoxicity. Interestingly, we found that pretreatment with Apo decreased elevation of intracellular Zn(2+) levels after Zn(2+) exposure and induced mRNA expression of the zinc transporter ZnT1, which transports intracellular Zn(2+) out of cells, and metallothionein. Taken together, these results suggest that the protective effects of Apo are regulated, at least in part, by its oxidized products, and preventing intracellular accumulation of Zn(2+) contributes to Apo protection against Zn(2+) neurotoxicity.
authors.affiliation: Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. harah@gifu-pu.ac.jp
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hara
authors.forename: Asuka
authors.initials: A
authors.lastname: Maeda
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kamiya
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Adachi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D015032:Zinc / Q000633:toxicity*
chemical_list: D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D011954:Receptors, Dopamine; D009243:NAD; D000255:Adenosine Triphosphate; D015032:Zinc; D001058:Apomorphine