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.

Protective activity of carnosine and anserine against zinc-induced neurotoxicity: a possible treatment for vascular dementia

“…25 Here, GT1-7 cells were simultaneously treated with Zn and carnosine, His, or anserine. 25 Here, GT1-7 cells were simultaneously treated with Zn and carnosine, His, or anserine.…”

“…Mellon et al originally developed GT1-7 cells by genetically targeting tumorigenesis in mouse hypothalamic neurons. 25 As the disruption of Ca 2+ homeostasis may be involved in Zn-induced neurotoxicity, we focused on the implications of these factors in the protective activity of carnosine. In addition, GT1-7 cells either lack or express low levels of ionotropic glutamate receptors and do not show glutamate toxicity.…”

The Molecular Mechanisms of Zinc Neurotoxicity and the Pathogenesis of Vascular Type Senile Dementia

“…Moreover, we investigated the alterations in gene expression during Zn-induced neurotoxicity with a DNA microarray and RT-PCR [42]. The expression of several genes, including metal-related genes, such as metallothionein ( MT ) -1 , MT-2 , and the Zn transporter 1 ( ZnT-1 ) were induced by Zn exposure.…”

“…(see Zn in Figure 5). Furthermore, our investigation into the changes in gene expression during Zn-induced neuronal death revealed an upregulation of several genes, including ER stress-related genes [growth-arrest DNA damage ( GADD ) 34 , GADD45 , and p8 ) and the Ca 2+ -related gene Arc (activity-related cytoskeleton protein) [42]. These findings are important considering the involvement of Ca 2+ homeostasis in Zn-induced neurotoxicity.…”

Carnosine: A Possible Drug for Vascular Dementia

“…We recently suggested that Ca dyshomeostasis may be involved in the mechanisms underlying Zn-induced neurotoxicity [51]. Zn-induced neuronal death revealed an upregulation of several genes, including metalrelated genes (metallothionein (MT)-1,MT-2, and the Zn transporter 1 (ZnT-1)), ER stress-related genes (growth-arrest DNA damage (GADD)34, GADD45, and p8), and the Ca 2+ -related gene Arc(activity-related cytoskeleton protein) [70]. These findings are significant, given the involvement of Ca 2+ homeostasis in Zn-induced neurotoxicity.…”