title: The molecular mechanisms of zinc neurotoxicity and the pathogenesis of vascular type senile dementia.
abstract: Zinc (Zn) is an essential trace element that is abundantly present in the brain. Despite its importance in normal brain functions, excess Zn is neurotoxic and causes neurodegeneration following transient global ischemia and plays a crucial role in the pathogenesis of vascular-type dementia (VD). We have investigated the molecular mechanisms of Zn-induced neurotoxicity using immortalized hypothalamic neurons (GT1-7 cells) and found that carnosine (β-alanyl histidine) and histidine (His) inhibited Zn2+-induced neuronal death. A DNA microarray analysis revealed that the expression of several genes, including metal-related genes (metallothionein and Zn transporter 1), endoplasmic reticulum (ER)-stress related genes (GADD34, GADD45, and p8), and the calcium (Ca)-related gene Arc (activity-related cytoskeleton protein), were affected after Zn exposure. The co-existence of carnosine or His inhibited the expression of GADD34, p8, and Arc, although they did not influence the expression of the metal-related genes. Therefore, ER-stress and the disruption of Ca homeostasis may underlie the mechanisms of Zn-induced neurotoxicity, and carnosine might be a possible drug candidate for the treatment of VD.
authors.affiliation: Department of Bio Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Musashino University, Nishitokyo-shi, Tokyo 202-8585, Japan. d_mizuno@musashino-u.ac.jp.
authors.forename: Dai
authors.initials: D
authors.lastname: Mizuno
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kawahara
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D002336:Carnosine / Q000008:administration & dosage; D015140:Dementia, Vascular / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D006639:Histidine / Q000008:administration & dosage; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000473:pathology; D015032:Zinc / Q000378:metabolism / Q000633:toxicity*
chemical_list: D006639:Histidine; D002336:Carnosine; D015032:Zinc