Abstract:The relative roles of the superoxide and hydroxyl rad icals in oxidative stress-induced neuronal damage were investigated using organotypic hippocampal slice cultures. Cultures exposed to 100 ftM duroquinone, a superoxide-generating compound, for 3 h developed CAl -selective lesions over a period of 24 h. The damage accounted for '-64% of the CAl subfield, whereas CA3 showed just 6% damage, a pattern of damage comparable to that observed following hypoxia!ischaemia. Duroquinone-induced damage was attenuated by a spin-trap agent. In contrast, hydroxyl radical-mediated damage, generated by exposure to 30 jiM ferrous sulphate for 1 h, resulted in a CA3-dominant lesion. The damage developed over 24 h, similar to that observed with duroquinone, but with -45% damage in CA3 compared with only 7% in CAl. These data demonstrate a selective vulnerability of the CAl pyramidal neurones to superoxide-induced damage and suggest that of the free radicals generated following hypoxia/ischaemia, superoxide, rather than hydroxyl radical, is instrumental in producing neuronal damage.
Responses to G protein-coupled receptor stimulation may be mediated by paracrine factors. We have developed a coculture system to study paracrine regulation of migration of gastric epithelial (AGS) cells after stimulation of gastrin-CCK(B) receptors. In cells expressing this receptor, G-17 stimulated migration by activation of protein kinase C. However, G-17 also stimulated the migration of cells expressing green fluorescent protein, but not the receptor, when they were cocultured with receptor-expressing cells consistent with activation of paracrine signals. The use of various pharmacological inhibitors indicated that gastrin stimulated migration via activation of the EGF receptor (EGR-R), the erbB-2 receptor tyrosine kinase, and the MAP kinase pathway. However, gastrin also released fibroblast growth factor (FGF)-1, and migration was inhibited by the FGF receptor tyrosine kinase inhibitor SU-5402. Flow cytometry indicated that in both cell types, gastrin increased MAP kinase via activation of EGF-R but not FGF-R1 or erbB-2. We conclude that gastrin-CCK(B) receptors stimulate epithelial cell migration partly via paracrine mechanisms; transactivation of EGF-R is only one component of the paracrine pathway.
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