Journal of neuroscience research
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Comparative Study
Unusual topographical pattern of proximal astrogliosis around a cortical devascularizing lesion.
Class II vessels were disrupted on the cortical surface of adult rats within a circular 5-mm-diameter area. This consistently resulted in the formation of a conical lesion by day 1, with a cystic cavity forming by day 21. Four markers were used to identify the glial response surrounding the lesion. ⋯ Thus, we find three immunohistochemically distinct populations of reactive astrocytes surrounding the focal ischemic lesion. In contrast to the case for stab-wound traumatic injury, the response closest to and surrounding the lesion did not up-regulate GFAP or VIM by day 6. The proximal response was, instead, more remote and only at the base of the lesion, extending partly into the corpus callosum.
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We reported previously that low levels of nitric oxide (NO) induced cell death with properties of apoptosis, including chromatin fragmentation and condensation in undifferentiated PC12 pheochromocytoma cells. The present study demonstrates that cytotoxicity of low concentrations of NO is mediated by inhibition of mitochondrial cytochrome c oxidase and generation of reactive oxygen species (ROS). An NO donor, (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3) induced cell death even at low concentrations (10-100 microM), whereas peroxynitrite and a peroxynitrite generator, 3-(4-morpholinyl)-sydnonimine (SIN-1), did not have a significant effect on cell viability up to a concentration of 0.5 mM. ⋯ Furthermore, we observed that several antioxidants, such as ascorbate, glutathione (GSH), cysteine, tetrahydrobiopterin, and dithiothreitol (DTT), all effectively prevented the NOR3-induced cell death. NOR3 treatment decreased the level of total intracellular GSH, but did not affect the activities of antioxidant enzymes SOD, GSH-peroxidase (GPX), and catalase. These results suggest that cell death induced at physiologically low concentrations of NO is mediated by ROS production in mitochondria, most likely resulting from the inhibition of cytochrome c oxidase, with ROS acting as an initiator of caspase-independent cell death.