Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders

Abstract

Oxidative stress-induced inflammation is a major contributor to several disease conditions including sepsis, carcinogenesis and metastasis, diabetic complications, allergic asthma, uveitis and after cataract surgery posterior capsular opacification. Since reactive oxygen species (ROS)-mediated activation of redox-sensitive transcription factors and subsequent expression of inflammatory cytokines, chemokines and growth factors are characteristics of inflammatory disorders, we envisioned that by blocking the molecular signals of ROS that activate redox-sensitive transcription factors, various inflammatory diseases could be ameliorated. We have indeed demonstrated that ROS –induced lipid peroxidation-derived lipid aldehydes such as 4-hydroxy-trans-2-nonenal (HNE) and their glutathione-conjugates (e.g. GS-HNE) are efficiently reduced by aldose reductase to corresponding alcohols which mediate the inflammatory signals. Our results showed that inhibition of aldose reductase (AKR1B1) significantly prevented the inflammatory signals induced by cytokines, growth factors, endotoxins, high glucose, allergens and auto-immune reactions in cellular as well as animal models. We have demonstrated that AKR1B1 inhibitor, fidarestat, significantly prevents tumor necrosis factor-alpha (TNF-α)-, growth factors-, lipopolysachharide (LPS)-, and environmental allergens-induced inflammatory signals that cause various inflammatory diseases. In animal models of inflammatory diseases such as diabetes, cardiovascular, uveitis, asthma, and cancer (colon, breast, prostate and lung) and metastasis, inhibition of AKR1B1 significantly ameliorated the disease. Our results from various cellular and animal models representing a number of inflammatory conditions suggest that ROS-induced inflammatory response could be reduced by inhibition of AKR1B1, thereby decreasing the progression of the disease and if the therapy is initiated early, the disease could be eliminated. Since fidarestat has already undergone phase III clinical trial for diabetic neuropathy and found to be safe, though clinically not very effective, our results indicate that it can be developed for the therapy of a number of inflammation- related diseases. Our results thus offer a novel therapeutic approach to treat a wide array of inflammatory diseases.

Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA1 and Clinically Used Prostaglandins

“…Although they play a protective role under physiologic situations, their increased activity is considered a pathogenic factor (Alexiou et al, 2009). AKR1B1 is an important mediator of inflammation and diabetic complications (Alexiou et al, 2009;Srivastava et al, 2011;Laffin and Petrash, 2012). AKR1B1 metabolizes reactive aldehydes, like 4-hydroxy-trans-2-nonenal (Ramana et al, 2006), yielding products that perpetuate inflammation .…”

Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications

“…In this model, AR inhibition was without effect on microalbuminuria, which follows glomerular and tubular dysfunction [123]. Fidarestat seems clinically not very effective, although it has already undergone late phase clinical trial for diabetic neuropathy and found to be safe [117]. As a result, very few ARIs could be passed through late stage of clinical trials, and only epalrestat is on the markets.…”

“…Also, it significantly ameliorated the diseases in animal models of inflammatory diseases such as diabetes, cardiovascular, uveitis, asthma, and cancer (colon, breast, prostate and lung) and metastasis. Thereby ROSinduced inflammatory response could be reduced with ARIs [117,118].…”

Effects of Postmeal Walking on Postprandial Glucose Control and Oxidative Stress

“…This process results in decreased NAD + /NADH and decreased levels of glutathione (GSH), which compromises cellular antioxidant capacity (Bravi et al, 1997). Conversely, aldose reductase inhibitors have been shown to block the metabolism of the polyol pathway and attenuate levels of oxidative stress, as well as diabetic complications Srivastava et al, 2011;Vegantham et al, 2012).…”