New Indication for Aldose Reductase Inhibitors?

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crystal structure of aldose reductaseThe physiological role of aldose reductase (AR) is still incompletely understood, although it has long been associated with the pathogenesis of diabetes-associated diseases such as cataract and neuropathy. In the last twenty years a number of AR inhibitors have entered clinical trials for the potential treatment of diabetic neuropathy. Whilst the compounds have generally been well tolerated, efficacy has not been clearly established (although one compound, Epalrestat, is approved in Japan for treatment of subjective neuropathy symptoms associated with diabetic peripheral neuropathy).

The rationale for use of AR inhibitors in diabetic complications is based on the ability of AR to reduce glucose to sorbitol, levels of which are elevated in tissues of diabetic patients. Although glucose does not have high affinity for AR, the pathway is believed to be relevant in hyperglycaemia.

lungsAR is also known to reduce lipid aldehydes and their glutathione conjugates in response to reactive oxygen species (ROS). The products of the AR-catalysed reduction mediate activation of NFκB and the subsequent generation of inflammatory proteins. This observation led researchers at University of Texas Medical Branch and Louisiana State University Health Sciences Center to hypothesise that AR inhibitors may be useful in inflammatory diseases such as asthma. In a study published in PLoSone, the scientists stimulated primary human small airway epithelial cells (SAEC) with ragweed pollen extract (RWE). In this in vitro experiment, AR inhibition prevented RWE-induced apoptosis and expression of inflammatory mediators. Further, AR inhibition prevented allergic airway inflammation in mice sensitised with endotoxin-free RWE.

The results encourage exploration of AR inhibitors in inflammatory diseases such as asthma.


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