Aldose reductase inhibitors are a class of drugs being studied as a way to prevent eye and nerve damage in people with diabetes.
Sorbitol, less commonly known as glucitol, is a sugar alcohol with a sweet taste which the human body metabolizes slowly. It can be obtained by reduction of glucose, which changes the converted aldehyde group (−CHO) to a primary alcohol group (−CH2OH). Most sorbitol is made from potato starch, but it is also found in nature, for example in apples, pears, peaches, and prunes. It is converted to fructose by sorbitol-6-phosphate 2-dehydrogenase. Sorbitol is an isomer of mannitol, another sugar alcohol; the two differ only in the orientation of the hydroxyl group on carbon 2. While similar, the two sugar alcohols have very different sources in nature, melting points, and uses.
Anandamide (ANA), also known as N-arachidonoylethanolamine (AEA), an N-acylethanolamine (NAE), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid receptors, the same receptors that the psychoactive compound THC in cannabis acts on. Anandamide is found in nearly all tissues in a wide range of animals. Anandamide has also been found in plants, including small amounts in chocolate. The name 'anandamide' is taken from the Sanskrit word ananda, which means "joy, bliss, delight", plus amide.
Diabetic neuropathy is various types of nerve damage associated with diabetes mellitus. Symptoms depend on the site of nerve damage and can include motor changes such as weakness; sensory symptoms such as numbness, tingling, or pain; or autonomic changes such as urinary symptoms. These changes are thought to result from a microvascular injury involving small blood vessels that supply nerves. Relatively common conditions which may be associated with diabetic neuropathy include distal symmetric polyneuropathy; third, fourth, or sixth cranial nerve palsy; mononeuropathy; mononeuropathy multiplex; diabetic amyotrophy; and autonomic neuropathy.
Galactosemia is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galactose properly. Galactosemia follows an autosomal recessive mode of inheritance that confers a deficiency in an enzyme responsible for adequate galactose degradation.
Diabetic angiopathy is a form of angiopathy associated with diabetic complications. While not exclusive, the two most common forms are diabetic retinopathy and diabetic nephropathy, whose pathophysiologies are largely identical. Other forms of diabetic angiopathy include diabetic neuropathy and diabetic cardiomyopathy.
The polyol pathway is a two-step process that converts glucose to fructose. In this pathway glucose is reduced to sorbitol, which is subsequently oxidized to fructose. It is also called the sorbitol-aldose reductase pathway.
In enzymology, aldose reductase is a cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides. It is primarily known for catalyzing the reduction of glucose to sorbitol, the first step in polyol pathway of glucose metabolism.
Sorbitol dehydrogenase is a cytosolic enzyme. In humans this protein is encoded by the SORD gene.
Ranirestat is an aldose reductase inhibitor being developed for the treatment of diabetic neuropathy by Dainippon Sumitomo Pharma and PharmaKyorin. It has been granted orphan drug status. The drug is to be used orally.
Epalrestat is a carboxylic acid derivative and a noncompetitive and reversible aldose reductase inhibitor used for the treatment of diabetic neuropathy, which is one of the most common long-term complications in patients with diabetes mellitus. It reduces the accumulation of intracellular sorbitol which is believed to be the cause of diabetic neuropathy, retinopathy and nephropathy It is well tolerated, with the most commonly reported adverse effects being gastrointestinal issues such as nausea and vomiting, as well as increases in certain liver enzymes. Chemically, epalrestat is unusual in that it is a drug that contains a rhodanine group. Aldose reductase is the key enzyme in the polyol pathway whose enhanced activity is the basis of diabetic neuropathy. Aldose reductase inhibitors (ARI) target this enzyme. Out of the many ARIs developed, ranirestat and fidarestat are in the trial stage. Others have been discarded due to unacceptable adverse effects or weak efficacy. Epalrestat is the only ARI commercially available. It is easily absorbed into the neural tissue and inhibits the enzyme with minimum side effects.
Aldo-keto reductase family 1, member B1 (AKR1B1), also known as aldose reductase, is an enzyme that is encoded by the AKR1B1 gene in humans. It is a reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-dependent enzyme catalyzing the reduction of various aldehydes and ketones to the corresponding alcohol. The involvement of AKR1B1 in oxidative stress diseases, cell signal transduction, and cell proliferation process endows AKR1B1 with potential as a therapeutic target.
Alcohol dehydrogenase [NADP+] also known as aldehyde reductase or aldo-keto reductase family 1 member A1 is an enzyme that in humans is encoded by the AKR1A1 gene. AKR1A1 belongs to the aldo-keto reductase (AKR) superfamily. It catalyzes the NADPH-dependent reduction of a variety of aromatic and aliphatic aldehydes to their corresponding alcohols and catalyzes the reduction of mevaldate to mevalonic acid and of glyceraldehyde to glycerol. Mutations in the AKR1A1 gene has been found associated with non-Hodgkin's lymphoma.
Aldo-keto reductase family 1 member B10 is an enzyme that in humans is encoded by the AKR1B10 gene.
A galactosemic cataract is cataract which is associated with the consequences of galactosemia.
Tolrestat (INN) (AY-27773) is an aldose reductase inhibitor which was approved for the control of certain diabetic complications.
3-Deoxyglucosone (3DG) is a sugar that is notable because it is a marker for diabetes. 3DG reacts with protein to form advanced glycation end-products (AGEs), which contribute to diseases such as the vascular complications of diabetes, atherosclerosis, hypertension, Alzheimer's disease, inflammation, and aging.
Alrestatin is an inhibitor of aldose reductase, an enzyme involved in the pathogenesis of complications of diabetes mellitus, including diabetic neuropathy.
Zenarestat is an aldose reductase inhibitor. It was investigated as a treatment of diabetic neuropathy and cataract, but its development was terminated.
Fidarestat (SNK-860) is an aldose reductase inhibitor under investigation for treatment of diabetic neuropathy.
