Aldose reductase inhibitor

Aldose reductase inhibitors are a class of drugs being studied as a way to prevent eye and nerve damage in people with diabetes.

Mechanism

Their target, aldose reductase, is an enzyme that is normally present in many other parts of the body, and catalyzes one of the steps in the sorbitol (polyol) pathway that is responsible for fructose formation from glucose. Aldose reductase activity increases as the glucose concentration rises in diabetes in those tissues that are not insulin sensitive, which include the lenses, peripheral nerves, and glomerulus. Sorbitol does not diffuse through cell membranes easily and therefore accumulates, causing osmotic damage which leads to retinopathy and neuropathy.

Examples

• 
  Alrestatin
• 
  Epalrestat
• 
  Fidarestat
• 
  Imirestat
• 
  Lidorestat
• 
  Minalrestat
• 
  Ponalrestat
• 
  Ranirestat^[1]
• 
  Salfredin B₁₁
• 
  Sorbinil
• 
  Tolrestat
• 
  Zenarestat
• 
  Zopolrestat

Natural sources reported to inhibit aldose reductase include indian gooseberry, spinach, cumin seeds, fennel seeds, basil leaves, lemon, black pepper, orange, curry leaves, cannabis,^[2] cinnamon^[3] and lichen.^[4][5] Luteolin, a type of flavonoid found mostly in leaves, and their synthetic derivatives are potential inhibitors of aldose reductase.^[6]

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, 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 and decreased potassium levels and decreased glutathione levels lead to cataract formation. Topical administration of aldose reductase inhibitors have been shown to prevent the cataract in rats.^[7]

Asthma and COPD

This class of drugs is also under investigation as a possible root pathology modulating treatment for asthma and COPD since it has been shown that they inhibit goblet cell metaplasia in the respiratory epithelium, thereby reducing the copious mucous secretion associated with these.^[8]

References

1. Várkonyi T, Kempler P (February 2008). "Diabetic neuropathy: new strategies for treatment". Diabetes, Obesity & Metabolism. 10 (2): 99–108. doi:10.1111/j.1463-1326.2007.00741.x. PMID 17593238. S2CID 13025417.
2. Smeriglio A, Giofrè SV, Galati EM, Monforte MT, Cicero N, D'Angelo V, Grassi G, Circosta C (June 2018). "Inhibition of aldose reductase activity by Cannabis sativa chemotypes extracts with high content of cannabidiol or cannabigerol". Fitoterapia. 127: 101–108. doi:10.1016/j.fitote.2018.02.002. PMID 29427593.
3. Saraswat M, Muthenna P, Suryanarayana P, Petrash JM, Reddy GB (2008). "Dietary sources of aldose reductase inhibitors: prospects for alleviating diabetic complications". Asia Pac J Clin Nutr. 17 (4): 558–65. PMID 19114390.
4. Raj PS, Prathapan A, Sebastian J, Antony AK, Riya MP, Rani MR, Biju H, Priya S, Raghu KG (2014). "Parmotrema tinctorum exhibits antioxidant, antiglycation and inhibitory activities against aldose reductase and carbohydrate digestive enzymes: an in vitro study". Nat. Prod. Res. 28 (18): 1480–4. doi:10.1080/14786419.2014.909420. PMID 24735436. S2CID 19749777.
5. Sebastian, Jomon; A, Prathapan; Sulochana, Priya; KG, Raghu (2014-08-01). "Kinetic and docking studies reveal aldose reductase inhibition potential of edible lichen Parmotrema tinctorum". The Pharma Innovation Journal. 3 (6).
6. Sebastian J (2016). "Structure-Activity Relationship Study Reveals Benzazepine Derivatives of Luteolin as New Aldose Reductase Inhibitors for Diabetic Cataract". Curr Drug Discov Technol. 13 (3): 152–163. doi:10.2174/1570163813666160701023100. PMID 27396410.
7. Newell FW (1982). Ophthalmology: Principles and Concepts (Fifth ed.). London: The CV Mosby Company. p. 332.
8. Yadav UC, Aguilera-Aguirre L, Ramana KV, Boldogh I, Srivastava SK (2010). "Aldose reductase inhibition prevents metaplasia of airway epithelial cells". PLOS ONE. 5 (12): e14440. Bibcode:2010PLoSO...514440Y. doi:10.1371/journal.pone.0014440. PMC 3010981. PMID 21203431.