Zn²⁺ entry produces oxidative neuronal necrosis in cortical cell cultures

TLDR

Zn²⁺ is implicated in neurodegeneration after brain injury such as ischemia or epilepsy. The study investigated the patterns and mechanisms underlying Zn²⁺ neurotoxicity. Zn²⁺ exposure induced necrotic neuronal death through early reactive oxygen species and lipid peroxidation, a process unaltered by anti‑apoptotic or glutamate‑receptor blockade but mitigated by antioxidants, while insulin or BDNF amplified the oxidative injury and kainate/AMPA enhanced Zn²⁺ entry.

Abstract

Abstract Evidence has accumulated that Zn 2+ 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 Zn 2+ neurotoxicity. Inclusion of 30–300 μ m Zn 2+ for 30 min caused neuronal necrosis apparent by cell body and mitochondrial swelling in cortical cell cultures. This Zn 2+ 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 Zn 2+ 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 Zn 2+ entry and potentiated Zn 2+ neurotoxicity in a way sensitive to trolox. Reactive oxygen species and lipid peroxidation were generated in the early phase of Zn 2+ neurotoxicity. These findings indicate that entry and accumulation of Zn 2+ result in generation of toxic free radicals and then cause necrotic neuronal degeneration under certain pathological conditions in the brain.