Zinc toxicity on neonatal cortical neurons: involvement of glutathione chelation.
Several mechanisms have been implicated in pathological neuronal death including zinc neurotoxicity, calcium excitotoxicity and oxidative injury. Glutathione (GSH) serves to provide reducing equivalents for the maintenance of oxidant homeostasis, and also plays roles in intracellular and intercellular signaling in the brain. We investigated the role of GSH homeostasis in the neurotoxic action of zinc using both mixed cortical cultures containing neurons and glia, and cortical neurons prepared from 1-day-old rats. Zinc caused neuronal cell death in a concentration-dependent manner. In parallel, a high concentration of zinc depleted GSH, in a time-dependent manner, preceding the onset of neuronal damage. Depletion of GSH by diethylmaleate injured neurons and exacerbated zinc-induced death. In contrast, replenishment of GSH attenuated zinc neurotoxicity. The thiol-containing compounds N-acetylcysteine and GSH chemically chelated zinc leading to decreases in the influx of zinc, the fall in GSH level and neuronal death. Interestingly, the glycolytic substrate pyruvate, but not lactate, chelated zinc concentration dependently and prevented its toxicity. On the other hand, pyrrolidine dithiocarbamate, serving as a zinc chaperon, enhanced its entry and toxicity. The results suggest that zinc non-enzymatically depleted GSH, an intrinsic factor for neuron survival, leading to activation of the cellular death signal and eventually neuronal death.
Chen
Chun-Jung
CJ
Department of Education and Research, Taichung Veterans General Hospital, Taiwan, Republic of China. cjchen@vghtc.gov.tw
Liao
Su-Lan
SL
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000378:metabolism* / Q000494:pharmacology; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D008298:Maleates / Q000633:toxicity; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D019289:Pyruvic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013859:Thiocarbamates / Q000494:pharmacology; D015032:Zinc / Q000037:antagonists & inhibitors / Q000633:toxicity*
D000975:Antioxidants; D002614:Chelating Agents; D008298:Maleates; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D019289:Pyruvic Acid; C014476:diethyl maleate; D005978:Glutathione; D015032:Zinc; D000111:Acetylcysteine