Zn2+ entry produces oxidative neuronal necrosis in cortical cell cultures

Evidence has accumulated that Zn2+ plays a central role in neurodegenerativ e processes following brain injuries including ischaemia or epilepsy. In th e present study, we examined patterns and possible mechanisms of Zn2+ neuro toxicity. Inclusion of 30-300 mu M 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, inhib itors of protein synthesis or caspase. Blockade of glutamate receptors or n itric oxide synthase showed no beneficial effect against Zn2+ neurotoxicity . Interestingly, antioxidants, trolox or SKF38393, attenuated Zn2+-induced neuronal necrosis. Pretreatment with insulin or brain-derived neurotrophic factor increased the Zn2+-induced free radical injury. Kainate or AMPA faci litated Zn2+ entry and potentiated Zn2+ neurotoxicity in a way sensitive to trolox. Reactive oxygen species and lipid peroxidation were generated in t he early phase of Zn2+ neurotoxicity. These findings indicate that entry an d accumulation of Zn2+ result in generation of toxic free radicals and then cause necrotic neuronal degeneration under certain pathological conditions in the brain.