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.
Highlights
The prevalence of senile dementia, which is a serious problem in a rapidly aging world, increases with age
Among the various food products or agricultural products we tested, we found that carnosine (β-alanyl histidine) is markedly effective in preventing the neuronal death induced by Zn [12]
The coexposure of GT1-7 cells to carnosine and His with Zn inhibited the expression of GADD34, GADD45, p8 and Arc induced by Zn exposure (Figure 5)
Summary
The prevalence of senile dementia, which is a serious problem in a rapidly aging world, increases with age. Following transient global ischemia or stroke, the interruption of blood flow and the resulting oxygen-glucose deprivation induces long-lasting membrane depolarization and an excessive release of glutamate into synaptic clefts. Increasing evidence has suggested that zinc (Zn) is central to ischemia-induced neuronal death and, to the pathogenesis of VD [3]. GT1-7 cells either lack, or possess low levels of, ionotropic glutamate receptors and do not exhibit glutamate toxicity [7]. These properties make the GT1-7 cell line an excellent model system for the investigation of Zn-induced neurotoxicity.
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