Zinc Neurotoxicity and its Role in Neurodegenerative Diseases

Abstract

Zinc is an extremely most abundant trace element in the brain. Substantial amounts of zinc exist in the presynaptic vesicles, and are released with glutamate during the neuronal excitation. Synaptically-released zinc is believed to play crucial roles in normal brain functions. Therefore, zinc deficiency impairs brain development and capabilities of learning and memory. Notwithstanding, recent studies have indicated that excess zinc is linked with several neurodegenerative diseases and has a causative role in delayed neuronal death after transient global ischemia. We have developed the sensitive assay system for zinc neurotoxicity in vitro using GT1-7 cells (immortalized hypothalamic neurons) to elucidate the functions of zinc in neurodegenerative diseases. Pharmacological experiments have exhibited the involvement of energy failure, metal-metal interaction, and disruption of calcium homeostasis in zinc-induced neurotoxicity. It is inferred that zinc might play its part in brain functions as Janus, an ancient Roman god with two faces, and that zinc homeostasis is essential for the neuronal survival. Our assay system provides a good method for screening the protective substances of zinc neurotoxicity as a therapeutic target of the global ischemia.