Kawahara Masahiro, Tanaka Ken-Ichiro, Kato-Negishi Midori
Department of Bio-Analytical Chemistry, Faculty of Pharmacy, Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
J Clin Biochem Nutr. 2022 Jul;71(1):7-15. doi: 10.3164/jcbn.22-40. Epub 2022 Jul 1.
Copper and zinc are essential for normal brain functions. Both are localized in presynaptic vesicles and are secreted into synaptic clefts during neuronal excitation. Despite their significance, excesses of copper and zinc are neurotoxic. In particular, excess zinc after transient global ischemia plays a central role in the ischemia-induced neurodegeneration and pathogenesis of vascular type senile dementia. We previously found that sub-lethal concentrations of copper remarkably exacerbated zinc-induced neurotoxicity, and we investigated the molecular pathways of copper-enhanced zinc-induced neurotoxicity. The endoplasmic reticulum stress pathway, the stress-activated protein kinases/c-Jun amino-terminal kinases pathway, and mitochondrial energy production failure were revealed to be involved in the neurodegenerative processes. Regarding the upstream factors of these pathways, we focused on copper-derived reactive oxygen species and the disruption of calcium homeostasis. Because excess copper and zinc may be present in the synaptic clefts during ischemia, it is possible that secreted copper and copper-induced reactive oxygen species may enhance zinc neurotoxicity and eventually contribute to the pathogenesis of vascular type senile dementia.
铜和锌对于正常的脑功能至关重要。二者均定位于突触前囊泡，并在神经元兴奋时分泌到突触间隙中。尽管它们很重要，但过量的铜和锌具有神经毒性。特别是，短暂性全脑缺血后过量的锌在缺血诱导的神经退行性变和血管型老年痴呆症的发病机制中起核心作用。我们之前发现亚致死浓度的铜会显著加剧锌诱导的神经毒性，并且我们研究了铜增强锌诱导的神经毒性的分子途径。内质网应激途径、应激激活蛋白激酶/c-Jun氨基末端激酶途径以及线粒体能量产生障碍被揭示参与了神经退行性变过程。关于这些途径的上游因素，我们聚焦于铜衍生的活性氧物种以及钙稳态的破坏。由于缺血期间突触间隙中可能存在过量的铜和锌，分泌的铜和铜诱导的活性氧物种有可能增强锌的神经毒性，并最终导致血管型老年痴呆症的发病机制。
