title: D-histidine and L-histidine attenuate zinc-induced neuronal death in GT1-7 cells.
abstract: Although zinc (Zn) is an essential trace element, excess Zn causes neuronal death following transient global ischemia and plays a central role in the pathogenesis of vascular-type dementia. In this study, we developed a rapid and convenient screening system for substances that prevent Zn-induced neurotoxicity by using GT1-7 cells (immortalized hypothalamic neurons), with the aim of identifying a treatment for vascular-type dementia. Among tested, we found a protective substance in the extract of round herring (Etrumeus teres), and determined its structure as l-histidine. Analysis of the structure-activity relationship by using histidine analogues revealed that both l-histidine and d-histidine exhibit the same neuroprotective activity. Furthermore, we investigated the molecular mechanisms underlying the protective effect of histidine on Zn-induced neurotoxicity using Zn imaging and gene expression analysis, and found that histidine protects against Zn-induced neurotoxicity not by inhibiting Zn chelation, thereby preventing increases in intracellular Zn(2+). Moreover, it is also suggested that endoplasmic reticulum (ER) stress and activity-regulated cytoskeleton associated protein (Arc) are implicated in Zn-induced degeneration of neurons.
authors.affiliation: Laboratory of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan. makawa@musashino-u.ac.jp
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kawahara
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sadakane
authors.forename: Hironari
authors.initials: H
authors.lastname: Koyama
authors.forename: Keiko
authors.initials: K
authors.lastname: Konoha
authors.forename: Susumu
authors.initials: S
authors.lastname: Ohkawara
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D003470:Culture Media / Q000494:pharmacology; D005399:Fishes; D005786:Gene Expression Regulation / Q000187:drug effects; D006639:Histidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D013329:Structure-Activity Relationship; D013997:Time Factors; D015032:Zinc / Q000633:toxicity*
chemical_list: D003470:Culture Media; D018696:Neuroprotective Agents; D009498:Neurotoxins; D006639:Histidine; D015032:Zinc