Fig. 3.

Hypothetical scheme of copper (Cu)/zinc (Zn)-induced neurotoxicity. Under pathological conditions such as transient global ischemia, excess Cu‍²⁺ and Zn‍²⁺ are secreted into the synaptic cleft and co-exist in the same synapse. Zn‍²⁺ can be translocated through calcium (Ca)-permeable amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate-type glutamate receptors (Ca-A/K-R), N-methyl-d-aspartate-type glutamate receptors (NMDA-R), and voltage gated Ca‍²⁺ channels (VGCC). In general, ZnT-1 acts to maintain the intracellular Zn concentration ([Zn‍²⁺]_i) by facilitating Zn‍²⁺ efflux and inhibiting voltage-gated Ca‍²⁺ channels and NMDA-R. However, excess Zn‍²⁺ can cause the elevation of both [Zn‍²⁺]_i and [Ca‍²⁺]_i and trigger endoplasmic reticulum (ER) stress pathways, which inhibits NAD‍⁺, causes energy depletion in mitochondria, and induces neurodegeneration. Aluminum (Al‍³⁺) inhibits voltage-gated Ca‍²⁺ channels and attenuates Zn neurotoxicity. The addition of Cu‍²⁺ produces ROS, which upregulate the ER stress and stress-activated protein kinases/c-Jun amino-terminal kinases (SAPK/JNK) pathways, exacerbate neuronal death, and eventually induce the pathogenesis of vascular dementia. SP600125, an inhibitor of the SAPK/JNK signaling pathway, attenuates Cu/Zn neurotoxicity. Selenomethionine (Se-Met) and a conjugated protein consisting of thioredoxin and human serum albumin (HSA-Trx) suppress ROS production and attenuate Cu/Zn neurotoxicity. Colored circles represent Zn, Cu, Ca, and Al.