Abstract
Zinc (Zn), an essential trace element, is secreted by synaptic vesicles during neuronal excitation and plays several critical roles in neuronal information processing. However, excess Zn ion (Zn2+) is neurotoxic and has a causative role in the pathogenesis of vascular dementia. Here, we investigated the molecular mechanism of Zn2+-induced neurotoxicity by using immortalized hypothalamic neurons (GT1-7 cells), which are more vulnerable than other neuronal cells to Zn2+. We examined the effects of other metal ions on the Zn2+-induced neurotoxicity in these cells and found that sub-lethal concentrations of copper ion (Cu2+) markedly exacerbated Zn2+-induced neurotoxicity. The co-administration of Cu2+ and Zn2+ also significantly increased the expression of genes related to the endoplasmic reticulum's stress response, including CHOP, GADD34, and ATF4. Similar to Zn2+, Cu2+ is stored in presynaptic vesicles and secreted during neuronal excitation. Thus, based on our results, we hypothesize here that Cu2+ interacts with Zn2+ in the synapse to synergistically promote neuronal death and significantly influence the pathogenesis of vascular dementia.
Highlights
Zinc (Zn) is essential for most organisms, and plays important roles in various physiological activities, including mitotic cell division, immune system functioning, protein, and DNA synthesis
Zn2+ significantly decreased the viability of GT1-7 cells in a concentrationdependent manner
Application of Mn2+ and Cu2+ decreased cell viability, the toxicity induced by these metals was less than that observed with Zn2+ (Figures 1B,C)
Summary
Zinc (Zn) is essential for most organisms, and plays important roles in various physiological activities, including mitotic cell division, immune system functioning, protein, and DNA synthesis. Zn deficiency in human causes dwarfism, mental and physical development retardation, immune system dysfunction, learning disabilities, and taste and olfaction disorders (Prasad, 2009; Takeda and Tamano, 2012). Some Zn binds firmly to metalloproteins or enzymes, a substantial fraction (10% or more) either forms free Zn ions (Zn2+) or is loosely bound and is histochemically detectable by chelating agent staining. This chelatable Zn2+ is mainly stored in the presynaptic vesicles of specific excitatory glutamatergic neurons and is secreted into synaptic clefts along with glutamate during neuronal excitation (Frederickson et al, 1983)
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