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AGE-RAGE Axis in the Aging and Diabetic Heart
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Karen M. O’Shea, Ann Marie Schmidt, Ravichandran Ramasamy
At least two classes of AGEs, which are increased in aging, bind RAGE. First, CML-adduct AGEs bind RAGE in multiple cell types, activate signal transduction and modulate gene expression (Kislinger et al. 1999, Boulanger et al. 2004). As mentioned in the previous section, CML-AGEs accumulate in aging and may be formed by multiple mechanisms, involving the precursor 3-DG or glyoxal intermediates (Niwa 1999, Niwa et al. 1998). Direct phosphorylation of fructose by fructose-3 phosphokinase also results in a potent glycating agent, fructose-3-phosphate. Plasma levels of 3-DG increase, along with increased AR, in erythrocytes, in renal failure (Hasuike et al. 2002). Administration of epalrestat, an inhibitor of aldose reductase, reduced the levels of CML adducts and their precursors in erythrocytes in diabetic patients (Hamada et al. 2000). Second, hydroimidazolones are primarily derived from MH precursors and also bind RAGE (Thornalley 1998).
Diabetic Peripheral Neuropathy
Published in Gary W. Jay, Practical Guide to Chronic Pain Syndromes, 2016
A postmarketing surveillance of more than 5000 patients on epalrestat, another aldose reductase inhibitor, was reported to show improvement of subjective symptoms, including spontaneous pain, in patients with DPN (34). In a three-year study, epalrestat was effective in slowing down the development of neuropathy as measured by changes in median nerve conduction velocity compared with controls. However, there was no significant difference in pain between the treated and untreated group (35).
Marine Algae in Diabetes and Its Complications
Published in Se-Kwon Kim, Marine Biochemistry, 2023
The polyol pathway of glucose metabolism plays a crucial function in the development of neuropathy (Gabbay, 1973). It is an alternative route of glucose metabolism in which the enzyme aldose reductase catalyzes the reduction of glucose to sorbitol, then to fructose by sorbitol dehydrogenase. Aldose reductase (AR) requires NADPH as a co-factor, and sorbitol dehydrogenase (SDH) needs NAD+. During hyperglycemia, sorbitol accumulates in AR-containing tissues, as it is impermeable to the cell membranes and cannot diffuse out and, hence, creates hyperosmotic stress on the cell, thereby inducing neuropathic pain (Niimi et al., 2021; Kinoshita and Nishimura, 1988). Treatment with inhibitors of aldose reductase has been shown to prevent various complications, including nephropathy, neuropathy, and cataractin animal models (Oates and Mylari, 1999). It is reported that the AR inhibitor epalrestat prevents high glucose–induced smooth muscle cell proliferation and hypertrophy (Yasunari et al., 1995), thereby preventing their dysfunction and remodeling (Tawata et al., 1992). Accumulation of intracellular sorbitol and fructose due to polyol activation leads to diminution of other organic electrolytes like taurine and myo-inositol that regulate cellular osmolality (Stevens et al., 1993). Lessening of myo-inositol in the peripheral nerves gets in the way of phosphoinositide production, leading to inadequate diacylglycerol to sustain the content of protein kinase C (PKC) essential for Na+/K+-ATPase activation (Zhu and Eichberg, 1990; Greene et al., 1987). Amendments in PKC activation also interfere with an important myelin protein’s (PO) phosphorylation of peripheral nerves and play an important pathogenetic role in primary segmental demyelination (Row-Rendleman and Eichberg, 1994). Enhanced activity of vascular PKC-β is thought to play a noteworthy role in microvascular complications.
Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Abdelrahman Hamdi, Muhammad Yaseen, Wafaa A. Ewes, Mashooq Ahmad Bhat, Noha I. Ziedan, Hamed W. El-Shafey, Ahmed A. B. Mohamed, Mohamed R. Elnagar, Abdullah Haikal, Dina I. A. Othman, Abdullah A. Elgazar, Ahmed H. A. Abusabaa, Kamal S. Abdelrahman, Osama M. Soltan, Mostafa M. Elbadawi
Orally active ARIs vary structurally and are classified into two major chemical groups: cyclic imides (mainly spirohydantoins) and carboxylic acid derivatives, such as Epalrestat (I)4. The majority of carboxylic acid derivatives were evaluated as ARIs preclinically and clinically, nonetheless, their development is generally restrained by their diminished in vivo potency, several side effects, and pharmacokinetic obstacles12,13. The carboxylic acid ARIs show potent in vitro activity as ARIs; however, their effectiveness decreases in vivo. Carboxylic acid derivatives could be completely ionised at physiological pH, and thus, their in vivo activity is generally lower than that of less ionised compounds. This effect is possibly due to the impaired penetration of physiological membranes of such ionised compounds14–16. Therefore, the development of a new generation of more selective non-carboxylic acid ARIs is prioritised to pursue the desired pharmacokinetic and therapeutic properties with reduced toxicity, fewer side effects and enhanced tissue permeability and drug uptake at the physiological pH. Currently, Epalrestat (I), which is a carboxylic acid derivative bearing 2-thioxo-4-thiazolidinone moiety (Figure 1), is the only approved ARI commercially available in Japan, China, and India. Epalrestat (I) is easily absorbed into the neural tissue and inhibits AR with minimum side effects17–19.
Novel 2-phenoxypyrido[3,2-b]pyrazin-3(4H)-one derivatives as potent and selective aldose reductase inhibitors with antioxidant activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Xin Hao, Gang Qi, Hongxing Ma, Changjin Zhu, Zhongfei Han
All new synthetic compounds 4a–o were tested for their potential inhibitory activity of AKR1B1 isolated from rat lenses. Besides, the inhibitory activity of aldehyde reductase (AKR1A1) isolated from rat kidneys was also investigated to evaluate the selectivity for AKR1B1. The enzyme AKR1A1 is closely related to AKR1B1, and plays an important role in physiological detoxification. The validity of the inhibition results was assessed with respect to epalrestat as a positive ARI. Additionally, the antioxidant activity was assessed by using the model reaction with the stable free radical of 2,2-diphenyl-1-picrylhydrazyl (DPPH) according to the modified method, which was first employed by Blois23.
Diabetic nephropathy: an insight into molecular mechanisms and emerging therapies
Published in Expert Opinion on Therapeutic Targets, 2019
Annabelle M. Warren, Søren T. Knudsen, Mark E. Cooper
Aldose reductase inhibitors (ARI) have demonstrated renoprotection in animal models of diabetic kidney disease for many decades [106]. A number of ARIs have been trialed in humans, with varying success. Clinical trials of the ARI tolrestat showed improvements in urinary albumin excretion and indeed it was approved for clinical use; however, it was later withdrawn due to severe hepatic toxicity [109,110]. An alternative ARI epalrestat has been shown to attenuate increases in urinary albumin excretion in diabetic patients without significant toxicity [111]. Epalrestat remains approved for use in some jurisdictions, but its modest impact has limited its uptake worldwide.