Deletion of aldose reductase leads to protection against cerebral ischemic injury.
Previously, we reported that transgenic mice overexpressing endothelin-1 in astrocytes showed more severe neurological deficits and increased infarct after transient focal ischemia. In those studies, we also observed increased level of aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, which has been implicated in osmotic and oxidative stress. To further understand the involvement of the polyol pathway, the mice with deletion of enzymes in the polyol pathway, AR, and sorbitol dehydrogenase (SD), which is the second enzyme in this pathway, were challenged with similar cerebral ischemic injury. Deletion of AR-protected animals from severe neurological deficits and large infarct, whereas similar protection was not observed in mice with SD deficiency. Most interestingly, AR(-/-) brains showed lowered expression of transferrin and transferrin receptor with less iron deposition and nitrotyrosine accumulation. The protection against oxidative stress in AR(-/-) brain was also associated with less poly(adenosine diphosphate-ribose) polymerase (PARP) and caspase-3 activation. Pharmacological inhibition of AR by Fidarestat also protected animals against cerebral ischemic injury. These findings are the first to show that AR contributes to iron- and transferrin-related oxidative stress associated with cerebral ischemic injury, suggesting that inhibition of AR but not SD may have therapeutic potential against cerebral ischemic injury.
Lo
Amy C Y
AC
Department of Anatomy, The University of Hong Kong, Hong Kong SAR, China.
Cheung
Alvin K H
AK
Hung
Victor K L
VK
Yeung
Chung-Man
CM
He
Qing-Yu
QY
Chiu
Jen-Fu
JF
Chung
Stephen S M
SS
Chung
Sookja K
SK
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000098:blood supply / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D053148:Caspase 3 / Q000378:metabolism; D017353:Gene Deletion; D048289:Imidazolidines / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery; D007501:Iron / Q000378:metabolism; D007064:L-Iditol 2-Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018384:Oxidative Stress; D011990:Receptors, Transferrin / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D048289:Imidazolidines; D011990:Receptors, Transferrin; D014168:Transferrin; C002744:3-nitrotyrosine; D014443:Tyrosine; C077139:fidarestat; D007501:Iron; D007064:L-Iditol 2-Dehydrogenase; D000449:Aldehyde Reductase; D053148:Caspase 3