Upregulation of mitochondrial base-excision repair capability within rat brain after brief ischemia.
The mechanism by which brief episodes of cerebral ischemia confer protection (tolerance) against subsequent prolonged ischemic challenges remains unclear, but may involve upregulation of cell injury repair capability. The mitochondrion is a key site for the regulation of cell death pathways, and damage to mitochondrial genes has been linked to a number of neurologic diseases and aging. Therefore, the authors examined the response of the DNA base excision repair (BER) pathway in rat brain mitochondria after either brief (tolerance-inducing) or prolonged (injury-producing) focal cerebral ischemia. Brief (30-minute) middle cerebral artery occlusion (MCAO) induced mild oxidative mitochondrial DNA damage and initiated a prolonged (up to 72-hour) activation above control levels of the principal enzymes of the mitochondrial BER pathway, including uracil DNA glycosylase, apurinic/apyrimidinic (AP) endonuclease, DNA polymerase-gamma, and DNA ligase. In contrast, prolonged (100-minute MCAO) ischemia induced more substantial mitochondrial oxidative DNA damage whereas elevation of BER activity was transient (approximately 1 hour), declining to less than control levels over the course of 4 to 72 hours. These data reveal the differences in BER capacity after brief or prolonged ischemia, which may contribute to the neuron's ability to resist subsequent ischemic insults.
Chen
Dexi
D
Robert S. Dow Neurobiology Laboratories, Legacy Research, Oregon Health Sciences University, Portland 97232, USA.
Minami
Manabu
M
Henshall
David C
DC
Meller
Robert
R
Kisby
Glen
G
Simon
Roger P
RP
D000818:Animals; D001921:Brain / Q000503:physiopathology*; D002545:Brain Ischemia / Q000201:enzymology / Q000235:genetics; D045647:DNA Glycosylases; D011088:DNA Ligases / Q000378:metabolism; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000502:physiology*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051981:Uracil-DNA Glycosidase
D004272:DNA, Mitochondrial; D004259:DNA-Directed DNA Polymerase; D004706:Endodeoxyribonucleases; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D051981:Uracil-DNA Glycosidase; D011088:DNA Ligases