Deletion of Aldose Reductase Leads to Protection against Cerebral Ischemic Injury

Abstract

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 À/À brains showed lowered expression of transferrin and transferrin receptor with less iron deposition and nitrotyrosine accumulation. The protection against oxidative stress in AR À/À 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.

A Critical Role for the Potassium-Dependent Sodium–Calcium Exchanger NCKX2 in Protection against Focal Ischemic Brain Damage

“…Cerebral macrovascular morphology was assessed by examining the major cerebral blood vessels of the circle of Willis after transcardial perfusion of nckx2ϩ/ϩ and nckx2Ϫ/Ϫ mice with a solution containing gelatin and waterproof Pelikan Ink (9:1), according to the methodology described by Paxinos and Franklin and other authors to evaluate cerebrovascular anatomy (Huang et al, 1994;Scremin, 1995;Paxinos and Franklin, 2000;Lo et al, 2007).…”

Upregulation of Aldose Reductase During Foam Cell Formation as Possible Link Among Diabetes, Hyperlipidemia, and Atherosclerosis

“…7 By contrast, AR activity has also been related to greater oxidative stress and increased damage during brain ischemia in mice. 8 In keeping with a proinflammatory role of AR, AR null mice exhibit reduced oxidative stress and are protected from ischemic injury. 8 The main physiological substrates of the polyol pathway are aldehydes, but sugars like glucose or galactose have also been shown to be metabolized by AR.…”

“…8 In keeping with a proinflammatory role of AR, AR null mice exhibit reduced oxidative stress and are protected from ischemic injury. 8 The main physiological substrates of the polyol pathway are aldehydes, but sugars like glucose or galactose have also been shown to be metabolized by AR. 9 With rising intracellular glucose levels as seen in diabetics, glucose can be shunted into the polyol pathway resulting in sorbitol production, which is subsequently metabolized by sorbitol dehydrogenase to fructose.…”

Nuclear Factor of Activated T Cells 5 Deficiency Increases the Severity of Neuronal Cell Death in Ischemic Injury

“…This is in line with the increased expression of AR in NFAT5 –/– neurons under H/I condition. Also, increased AR activity contributes to oxidative stress in the pathogenesis of cerebral ischemia [15,47]. The level of AR acts as an indicator of oxidative stress; therefore, the upregulation of AR is associated with a significant increase of ROS in NFAT5 +/– and NFAT5 –/– neurons in H/I condition.…”

“…An antiapoptotic protein, HSP70, has been reported to protect the brains from H/I injury [14]. Besides, AR is an enzyme in the polyol pathway and is upregulated during cerebral ischemia, AR deletion protects the brains from ischemic injury [15]. Moreover, the expression of SMIT mRNA increases significantly in the ischemic core after focal cerebral ischemia [16].…”