Protective Effects of Apomorphine against Zinc-Induced Neurotoxicity in Cultured Cortical Neurons

Abstract

There is evidence that excessive zinc (Zn²⁺) 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 Zn²⁺ exposure. Pretreatment with Apo dose- and time-dependently ameliorated Zn²⁺ neurotoxicity. In addition, pretreatment with Apo prevented intracellular nicotinamide adenine dinucleotide (NAD⁺) and ATP depletion caused by Zn²⁺ exposure. Dopamine receptor antagonists did not influence Apo protection against Zn²⁺ 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 Zn²⁺ into neurons is thought to be a critical step of Zn²⁺ neurotoxicity. Interestingly, we found that pretreatment with Apo decreased elevation of intracellular Zn²⁺ levels after Zn²⁺ exposure and induced mRNA expression of the zinc transporter ZnT1, which transports intracellular Zn²⁺ 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 Zn²⁺ contributes to Apo protection against Zn²⁺ neurotoxicity.