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

TitleAldose reductase-deficient mice are protected from iron- and transferrin-related oxidative stress and cerebral ischemic injury
Authors
Issue Date2006
PublisherSociety for Neuroscience
Citation
Neuroscience 2006, Atlanta, GA, 14-18 October 2006, Program#/Poster#: 582.3/NN72 How to Cite?
AbstractPreviously, 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.
Persistent Identifierhttp://hdl.handle.net/10722/95194

 

DC FieldValueLanguage
dc.contributor.authorLo, ACYen_HK
dc.contributor.authorHung, KLen_HK
dc.contributor.authorCheung, KHAen_HK
dc.contributor.authorHe, Qen_HK
dc.contributor.authorChiu, Jen_HK
dc.contributor.authorChung, SSMen_HK
dc.contributor.authorChung, SKen_HK
dc.date.accessioned2010-09-25T15:54:35Z-
dc.date.available2010-09-25T15:54:35Z-
dc.date.issued2006en_HK
dc.identifier.citationNeuroscience 2006, Atlanta, GA, 14-18 October 2006, Program#/Poster#: 582.3/NN72-
dc.identifier.urihttp://hdl.handle.net/10722/95194-
dc.description.abstractPreviously, 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.-
dc.languageengen_HK
dc.publisherSociety for Neuroscience-
dc.relation.ispartofSociety for Neuroscience Annual Meetingen_HK
dc.titleAldose reductase-deficient mice are protected from iron- and transferrin-related oxidative stress and cerebral ischemic injuryen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailLo, ACY: amylo@hkucc.hku.hken_HK
dc.identifier.emailHe, Q: qyhe@hkucc.hku.hken_HK
dc.identifier.emailChiu, J: jfchiu@hkucc.hku.hken_HK
dc.identifier.emailChung, SSM: smchung@hkucc.hku.hken_HK
dc.identifier.emailChung, SK: skchung@hkucc.hku.hken_HK
dc.identifier.authorityLo, ACY=rp00425en_HK
dc.identifier.authorityChung, SSM=rp00376en_HK
dc.identifier.authorityChung, SK=rp00381en_HK
dc.identifier.hkuros130344en_HK

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