Cu/Zn- and Mn-superoxide dismutases are specifically up-regulated in neurons after focal brain injury.
In previous studies, we have demonstrated that damaged neurons within a boundary area around necrosis fall into delayed cell death due to the cytotoxic effect of microglial nitric oxide (NO), and are finally eliminated by activated microglia. In contrast, neurons in a narrow surrounding region nearby this boundary area remain alive even though they may encounter cytotoxic NO. To investigate the mechanism by which neurons tolerate this oxidative stress, we examined the in vitro and in vivo expression levels of superoxide dismutase (SOD) under pathological conditions. Results from our in situ hybridization and immunohistochemical studies showed up-regulation of Cu/Zn-SOD only in neurons outside the boundary area, whereas up-regulation of Mn-SOD was detected in both neurons and glial cells in the same region. In vitro experiments using rat PC12 pheochromocytoma and C6 glioma cell lines showed that induction of both Cu/Zn- and Mn-SOD mRNA could only be detected in PC12 cells after treatment with NO donors, while a slight induction of Mn-SOD mRNA alone could be seen in C6 glioma cells. The mechanism of resistance toward oxidative stress therefore appears to be quite different between neuronal and glial cells. It is assumed that these two types of SOD might play a critical role in protecting neurons from NO cytotoxicity in vivo, and the inability of SOD induction in damaged neurons seems to cause their selective elimination after focal brain injury.
Takeuchi
A
A
Department of Basic Gerontology, National Institute for Longevity Sciences, 36-3 Gengo, Morioka-cho, Oobu 474-8522, Japan.
Miyaishi
O
O
Kiuchi
K
K
Isobe
K
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001930:Brain Injuries / Q000378:metabolism*; D002492:Central Nervous System Depressants; D003342:Corpus Striatum / Q000293:injuries; D004790:Enzyme Induction; D000431:Ethanol; D005910:Glioma / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D016716:PC12 Cells; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation
D002492:Central Nervous System Depressants; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D000431:Ethanol; D013482:Superoxide Dismutase; D010396:Penicillamine