Aldose reductase inhibitors are a class of

drugs A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...

being studied as a way to prevent

eye Eyes are organs of the visual system. They provide living organisms with vision, the ability to receive and process visual detail, as well as enabling several photo response functions that are independent of vision. Eyes detect light and conv ...

and

nerve A nerve is an enclosed, cable-like bundle of nerve fibers (called axons) in the peripheral nervous system. A nerve transmits electrical impulses. It is the basic unit of the peripheral nervous system. A nerve provides a common pathway for the e ...

damage in people with

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

Mechanism

Their target, aldose reductase, is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

that is normally present in many other parts of the body, and catalyzes one of the steps in the

sorbitol 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 g ...

( polyol) pathway that is responsible for

fructose Fructose, or fruit sugar, is a Ketose, ketonic monosaccharide, simple sugar found in many plants, where it is often bonded to glucose to form the disaccharide sucrose. It is one of the three dietary monosaccharides, along with glucose and galacto ...

formation from

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...

. Aldose reductase activity increases as the glucose concentration rises in

in those tissues that are not

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

sensitive, which include the

lenses A lens is a transmissive optical device which focuses or disperses a light beam by means of refraction. A simple lens consists of a single piece of transparent material, while a compound lens consists of several simple lenses (''elements''), ...

, peripheral nerves and

glomerulus ''Glomerulus'' () is a common term used in anatomy to describe globular structures of entwined vessels, fibers, or neurons. ''Glomerulus'' is the diminutive of the Latin ''glomus'', meaning "ball of yarn". ''Glomerulus'' may refer to: * the filter ...

. Sorbitol does not diffuse through cell membranes easily and therefore accumulates, causing osmotic damage which leads to retinopathy and

neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or o ...

Examples

File:Alrestatin.svg,

Alrestatin Alrestatin is an inhibitor of aldose reductase, an enzyme involved in the pathogenesis of complications of diabetes mellitus, including diabetic neuropathy. Alrestat was first synthesized in 1969 and was the first aldose reductase inhibitor (ARI) ...

File:Epalrestat.svg,

Epalrestat 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. ...

File:Fidarestat structure.svg,

Fidarestat Fidarestat (SNK-860) is an aldose reductase inhibitor under investigation for treatment of diabetic neuropathy Diabetic neuropathy is various types of nerve damage associated with diabetes mellitus. Symptoms depend on the site of nerve damage and ...

File:Imirestat.svg, Imirestat File:Lidorestat.svg, Lidorestat File:Minalrestat.svg, Minalrestat File:Ponalrestat.svg, Ponalrestat File:Ranirestat.svg,

Ranirestat Ranirestat (also known as AS-3201) 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. Tri ...

File:Salfredin B11.svg, Salfredin B₁₁ File:Sorbinil.svg,

Sorbinil Sorbinil (INN) is an aldose reductase inhibitor being investigated for treatment of diabetic complications including neuropathy and retinopathy. Aldose reductase is an enzyme present in lens and brain that removes excess glucose by converting it t ...

File:Tolrestat structure.svg,

Tolrestat Tolrestat (INN) (AY-27773) is an aldose reductase inhibitor which was approved for the control of certain diabetic complications. While it was approved for marketed in several countries, it failed a Phase III trial in the U.S. due to toxicity an ...

File:Zenarestat structure.svg,

Zenarestat Zenarestat (FK-366; FR-74366) is an aldose reductase inhibitor. It was investigated as a treatment of diabetic neuropathy and cataract A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often ...

File:Zopolrestat.svg, Zopolrestat Natural sources reported to inhibit aldose reductase include indian gooseberry,

spinach Spinach (''Spinacia oleracea'') is a leafy green flowering plant native to central and western Asia. It is of the order Caryophyllales, family Amaranthaceae, subfamily Chenopodioideae. Its leaves are a common edible vegetable consumed either f ...

cumin Cumin ( or , or Article title
) (''Cuminum cyminum'') is a

fennel Fennel (''Foeniculum vulgare'') is a flowering plant species in the carrot family. It is a hardy, perennial herb with yellow flowers and feathery leaves. It is indigenous to the shores of the Mediterranean but has become widely naturalized ...

seeds, basil leaves, lemon,

black pepper Black pepper (''Piper nigrum'') is a flowering vine in the family Piperaceae, cultivated for its fruit, known as a peppercorn, which is usually dried and used as a spice and seasoning. The fruit is a drupe (stonefruit) which is about in diame ...

, orange,

curry A curry is a dish with a sauce seasoned with spices, mainly associated with South Asian cuisine. In southern India, leaves from the curry tree may be included. There are many varieties of curry. The choice of spices for each dish in tradit ...

leaves,

cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized: ''Cannabis sativa'', '' C. indica'', and '' C. ruderalis''. Alternatively ...

cinnamon Cinnamon is a spice obtained from the inner bark of several tree species from the genus ''Cinnamomum''. Cinnamon is used mainly as an aromatic condiment and flavouring additive in a wide variety of cuisines, sweet and savoury dishes, breakfa ...

and

lichen A lichen ( , ) is a composite organism that arises from algae or cyanobacteria living among filaments of multiple fungi species in a mutualistic relationship.

Luteolin Luteolin is a flavone, a type of flavonoid, with a yellow crystalline appearance. Luteolin is the principal yellow dye compound that is obtained from the plant ''Reseda luteola'', which has been used as a source of the dye since at least the fir ...

, a type of

flavonoid Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans. Chemically, flavonoids ...

found mostly in leaves, and their synthetic derivatives are potential inhibitors of aldose reductase.

Diabetic cataract

Diabetic cataract formation follows an increase in sugars in the lens. The excess sugar within the lens is reduced by aldose reductase to its

alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...

, but the lens capsule is relatively impermeable to sugar alcohols. Because of the excess sugar alcohol (polyol), the lens imbibes water, causing osmotic imbalance. Eventually, increased

sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...

and decreased

potassium Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosphe ...

levels and decreased glutathione levels lead to cataract formation. Topical administration of aldose reductase inhibitors have been shown to prevent the cataract in rats.

Asthma and COPD

This class of drugs is also under investigation as a possible root pathology modulating treatment for

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...

and COPD since it has been shown that they inhibit

goblet cell Goblet cells are simple columnar epithelial cells that secrete gel-forming mucins, like mucin 5AC. The goblet cells mainly use the merocrine method of secretion, secreting vesicles into a duct, but may use apocrine methods, budding off their secre ...

metaplasia in the

respiratory epithelium Respiratory epithelium, or airway epithelium, is a type of ciliated columnar epithelium found lining most of the respiratory tract as respiratory mucosa, where it serves to moisten and protect the airways. It is not present in the vocal cords o ...

, thereby reducing the copious

mucous Mucus ( ) is a slippery aqueous secretion produced by, and covering, mucous membranes. It is typically produced from cells found in mucous glands, although it may also originate from mixed glands, which contain both serous and mucous cells. It is ...

secretion associated with these.

References

{{Enzyme inhibition