Zinc Neurotoxicity and its Role in Neurodegenerative Diseases

Zinc is the second most abundant transition metal in the body. It is essential for most living beings. The human body contains approximately 2 g of zinc. It is mainly distributed in the blood, kidney, liver, bone, and brain. Zinc is a co-factor of more than 300 enzymes or metalloproteins. These zinc-related proteins play biologically important roles in mitotic cell division, protein synthesis, DNA and RNA synthesis etc. Therefore, zinc is essential for the normal growth and development. In 1961, Prasad et al. firstly reported that zinc deficiency caused the dwarfism with the retardation of physical and sexual development in human. Nowadays, zinc deficiency is widely known to impair the overall immunological system, cause adverse effects of the body growth and the sexual development, and lead to olfactory and gustatory dysfunction. A considerable amount of zinc is accumulated in the brain, particularly in the hippocampus, amygdala, cerebral cortex, and olfactory cortex. The total amount of zinc in the hippocampus is estimated as 70–90 ppm (dry weight). Although some zinc in the brain firmly binds to metalloproteins or enzymes, a substantial amount of zinc (approximately 10% or more) forms free zinc ions (Zn) or is loosely bound and detectable by the staining using chelating reagents. Chelatable zinc is stored in the presynaptic vesicles of particular excitatory neurons, and is secreted from vesicles to synaptic clefts with excitatory neurotransmitter glutamate during the neuronal excitation. Its concentration is estimated to be approximately 300 μM. Despite its abundance, the physiological role of synaptically released zinc has not yet been defined precisely. It has been reported that zinc alters the behavior of various receptors or ion channels, including N-methyl-D-aspartate (NMDA)-type glutamate receptor, γ-aminobutyric acid A (GABAA) receptor, glycine receptor, acetylcholine receptor, ATP channel, voltage-gated Ca channel, and K Zinc Neurotoxicity and its Role in Neurodegenerative Diseases