Zinc Neurotoxicity and the Pathogenesis of Vascular-Type Dementia: Involvement of Calcium Dyshomeostasis and Carnosine

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. We found that GT1-7 cells (immortalized hypothalamic neurons) are more vulnerable to zinc-induced neurotoxicity than other cultured neuronal cells are. Further, we investigated the molecular mechanisms of Zn-induced neurotoxicity in vitro using GT1-7 cells. Pharmacological evidence based on our own results and those of numerous other studies has indicated the significance of calcium dyshomeostasis in the mechanisms of Zn-induced neuronal injury. We developed a screening system for substances, which prevent Zn-induced neurotoxicity, with the aim of identifying a treatment for vascular-type dementia. Here, we review in detail the characteristics and mechanisms of Zn-induced neuronal death in relation to calcium homeostasis. The potential role of carnosine (ß-alanyl histidine), a dipeptide present in the brain as an endogenous protective substance, in neuronal injury is also discussed. Jour n a l o f C linical T o x ic o log y

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

“…We found that GT1–7 cells, which are immortalized hypothalamic neurons, are much more sensitive to Zn than other neuronal cells are [4,5]. Figure 2 shows the viability of GT1–7 cells, PC-12 cells, B-50 cells (a neuroblastoma cell line), and primary cultured neurons derived from the rat cerebral cortex or hippocampus following exposure to Zn.…”

“…Zn caused the apoptotic death of GT1–7 cells in a dose-dependent and time-dependent manner. The degenerated GT1–7 cells are terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling (TUNEL)-positive and exhibit DNA fragmentation [4,5]. …”

“…Additionally, Zn neurotoxicity is attenuated by aspirin, which prevents Zn 2+ entry through voltage-gated Ca 2+ channels [41]. In addition to this issue, we employed a high-resolution multi-site video imaging system with fura-2 as the cytosolic-free Ca reporter fluorescent probe in order to observe the temporal changes in [Ca 2+ ] i after exposure to Zn [5]. Zn caused increased [Ca 2+ ] i among GT1–7 cells after 3–30 min of exposure [5].…”

“…In addition to this issue, we employed a high-resolution multi-site video imaging system with fura-2 as the cytosolic-free Ca reporter fluorescent probe in order to observe the temporal changes in [Ca 2+ ] i after exposure to Zn [5]. Zn caused increased [Ca 2+ ] i among GT1–7 cells after 3–30 min of exposure [5]. A detailed analysis of Zn-induced [Ca 2+ ] i revealed that the pretreatment of Al 3+ significantly blocked the Zn-induced [Ca 2+ ] i increases.…”

“…In ischemia conditions, a considerable amount of Zn (up to 300 μM) is co-related with glutamate into synaptic clefts by membrane depolarization. We have found that GT1–7 cells, which are immortalized hypothalamic neurons, are more vulnerable to Zn than other neuronal cells are [4,5]. Zn causes the apoptotic death of GT1–7 cells in a dose-dependent and time-dependent manner.…”