Kim E Y, Koh J Y, Kim Y H, Sohn S, Joe E, Gwag B J
Department of Pharmacology, School of Medicine, Ajou University, Suwon, Kyungkido, Korea.
Eur J Neurosci. 1999 Jan;11(1):327-34. doi: 10.1046/j.1460-9568.1999.00437.x.
Evidence has accumulated that Zn2+ plays a central role in neurodegenerative processes following brain injuries including ischaemia or epilepsy. In the present study, we examined patterns and possible mechanisms of Zn2+ neurotoxicity. Inclusion of 30-300 microM Zn2+ for 30 min caused neuronal necrosis apparent by cell body and mitochondrial swelling in cortical cell cultures. This Zn2+ neurotoxicity was not attenuated by antiapoptosis agents, inhibitors of protein synthesis or caspase. Blockade of glutamate receptors or nitric oxide synthase showed no beneficial effect against Zn2+ neurotoxicity. Interestingly, antioxidants, trolox or SKF38393, attenuated Zn(2+)-induced neuronal necrosis. Pretreatment with insulin or brain-derived neurotrophic factor increased the Zn(2+)-induced free radical injury. Kainate or AMPA facilitated Zn2+ entry and potentiated Zn2+ neurotoxicity in a way sensitive to trolox. Reactive oxygen species and lipid peroxidation were generated in the early phase of Zn2+ neurotoxicity. These findings indicate that entry and accumulation of Zn2+ result in generation of toxic free radicals and then cause necrotic neuronal degeneration under certain pathological conditions in the brain.
已有证据表明，锌离子（Zn2+）在包括缺血或癫痫在内的脑损伤后的神经退行性过程中起核心作用。在本研究中，我们研究了Zn2+神经毒性的模式及可能机制。在皮质细胞培养物中加入30 - 300微摩尔Zn2+ 30分钟，可导致神经元坏死，表现为细胞体和线粒体肿胀。这种Zn2+神经毒性不会因抗凋亡剂、蛋白质合成抑制剂或半胱天冬酶而减弱。阻断谷氨酸受体或一氧化氮合酶对Zn2+神经毒性没有有益作用。有趣的是，抗氧化剂、生育三烯酚（trolox）或SKF38393可减轻Zn2+诱导的神经元坏死。胰岛素或脑源性神经营养因子预处理会增加Zn2+诱导的自由基损伤。海人酸或α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）促进Zn2+进入并增强Zn2+神经毒性，其方式对生育三烯酚敏感。在Zn2+神经毒性的早期会产生活性氧和脂质过氧化。这些发现表明，在大脑的某些病理条件下，Zn2+的进入和积累会导致有毒自由基的产生，进而引起坏死性神经元变性。
