Protective effects of extracellular glutathione against Zn2+-induced cell death in vitro and in vivo.
The central nervous system reserves high concentrations of free Zn(2+) in certain excitatory synaptic vesicles. In pathological conditions such as transient cerebral ischemia, traumatic brain injury, and kainic acid (KA)-induced seizure, free Zn(2+) 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 Zn(2+)-induced cell death in vitro and in vivo. Chronic treatment with 35 microM Zn(2+) led to death of primary cortical neurons and primary astrocytes. The Zn(2+) toxicity of cortical neurons was partially protected by 1 mM of GSH, whereas the Zn(2+) toxicity of primary astrocyte cultures was blocked completely by 100 microM 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 microg) 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 Zn(2+) in the excitotoxin-induced neural cell death model and a potential value of GSH as a therapeutic means against Zn(2+)-induced pathogenesis in brain.
Cho
Ik Hyun
IH
Department of Neuroscience, Ewha Institute of Neuroscience and Medical Research Center, Ewha Womans University School of Medicine, Seoul, Korea.
Im
Joo-Young
JY
Kim
Doyeun
D
Kim
Kyoung-Shim
KS
Lee
Ja-Kyeong
JK
Han
Pyung-Lim
PL
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology; D045604:Extracellular Fluid / Q000737:chemistry; D005978:Glutathione / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007276:Injections, Intraventricular; D007608:Kainic Acid / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015032:Zinc / Q000633:toxicity*
D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D005978:Glutathione; D015032:Zinc; D007608:Kainic Acid