Protective effects of extracellular glutathione against Zn2+‐induced cell death in vitro and in vivo

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Abstract
The central nervous system reserves high concentrations of free Zn2+ in certain excitatory synaptic vesicles. In pathological conditions such as transient cerebral ischemia, traumatic brain injury, and kainic acid (KA)‐induced seizure, free Zn2+ is released in excess at synapses, which causes neuronal and glial death. We report here that glutathione (GSH) can be used as an effective means for protection of neural cells from Zn2+‐induced cell death in vitro and in vivo. Chronic treatment with 35 μM Zn2+ led to death of primary cortical neurons and primary astrocytes. The Zn2+ toxicity of cortical neurons was partially protected by 1 mM of GSH, whereas the Zn2+ toxicity of primary astrocyte cultures was blocked completely by 100 μM of GSH. To evaluate the beneficial effects of GSH in vivo, an excitotoxin‐induced neural cell death model was established by intracerebroventricular (i.c.v.) injection of 0.94 nmol (0.2 μg) KA, which produced selective neuronal death, especially in CA1 and CA3 hippocampal regions. The i.c.v. co‐injection of 200 pmol of GSH significantly attenuated KA‐induced neuronal cell death and reactive gliosis in hippocampus. The results of this study suggest the contribution of Zn2+ in the excitotoxin‐induced neural cell death model and a potential value of GSH as a therapeutic means against Zn2+‐induced pathogenesis in brain.