Aldose reductase-deficient mice are protected from iron- and transferrin-related oxidative stress and cerebral ischemic injury

Abstract

Previously, we reported that over-expression of endothelin-1 in astrocytes leads to more severe neurological deficits, increased infarct, and more cerebral edema with more up-regulation of AQP-4 after transient ischemia. In this transgenic model we also observed increased level of aldose reductase (AR), an osmoregulatory protein whose expression is regulated by osmotic responsive element binding protein (TonEBP/NFAT5/OREBP). Actually, AR has already been implicated in generation of osmotic and oxidative stress in diabetic complications, which may be a consequence of ischemic injury. Indeed, our data showed that AR expression was increased after transient middle cerebral artery occlusion (MCAO). To further understand the involvement of the polyol pathway, which consists of 2 enzymes, AR that is the rate-limiting enzyme and converts glucose to sorbitol as well as sorbitol dehydrogenase (SD) that converts sorbitol to fructose, in cerebral ischemic injury involving osmotic and oxidative stress, we first challenged AR knockout (AR-/-) mice to MCAO. AR-/- mice were less susceptible to transient focal cerebral ischemic damage, showing less severe neurological deficits and smaller infarct size compared with that observed in AR+/+ mice. Most interestingly, up-regulation of transferrin and transferrin receptor levels observed in AR+/+ brains after MCAO was less in AR-/- brains were decreased. The expression of oxidative stress markers, such as nitrotyrosine and PAR was also significantly less in AR-/- brains. Similar results were obtained with pharmacological inhibition of AR by Fidarestat 1 hr and 45 min after induction of ischemia. Inhibition of SD also reduced infarct size and hemispheric swelling. These results suggest that inhibition of AR and SD is beneficial in cerebral ischemic injury and indicated that blocking AR may alleviate oxidative stress by blocking the involvement of iron-and transferrin-related pathway.