Protective effects of extracellular glutathione against Zn-induced cell death in vitro and in vivo

초록

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 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 uM Zn2+ led to death of primary cortical neurons and primary astrocytes. The Zn2+ toxicity of cortical neurons was partially protected by 1 mM of glutathione (GSH). Whereas the Zn2+ toxicity of primary astrocyte cultures was completely blocked when 100 uM of GSH was applied. An excitotoxin-induced neuronal cell death model was established by i.c.v. injection of 0.2 ug KA, which produced the selective neuronal death, especially in CA1 and CA3 regions of hippocampus. The i.c.v co-injection of 0.2 ug KA and 200 pmole of GSH significantly attenuated the excitotoxin-induced neuronal cell death and the reactive gliosis in hippocampus. The results of this study suggest a potential value of GSH as a therapeutic means against Zn2+-induced pathogenesis in brain.