title: Orally active multi-functional antioxidants delay cataract formation in streptozotocin (type 1) diabetic and gamma-irradiated rats.
abstract: BACKGROUND
  Age-related cataract is a worldwide health care problem whose progression has been linked to oxidative stress and the accumulation of redox-active metals. Since there is no specific animal model for human age-related cataract, multiple animal models must be used to evaluate potential therapies that may delay and/or prevent cataract formation.
  
  
  RESULTS
  Proof of concept studies were conducted to evaluate 4-(5-hydroxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 4) and 4-(5-hydroxy-4,6-dimethoxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 8), multi-functional antioxidants that can independently chelate redox metals and quench free radicals, on their ability to delay the progression of diabetic "sugar" cataracts and gamma radiation-induced cataracts. Prior to 15 Gy of whole head irradiation, select groups of Long Evans rats received either diet containing compound 4 or 8, or a single i.p. injection of panthethine, a radioprotective agent. Compared to untreated, irradiated rats, treatment with pantethine, 4 and 8 delayed initial lens changes by 4, 47, and 38 days, respectively, and the average formation of posterior subcapsular opacities by 23, 53 and 58 days, respectively. In the second study, select groups of diabetic Sprague Dawley rats were administered chow containing compounds 4, 8 or the aldose reductase inhibitor AL1576. As anticipated, treatment with AL1576 prevented cataract by inhibiting sorbitol formation in the lens. However, compared to untreated rats, compounds 4 and 8 delayed vacuole formation by 20 days and 12 days, respectively, and cortical cataract formation by 8 and 3 days, respectively, without reducing lenticular sorbitol. Using in vitro lens culture in 30 mM xylose to model diabetic "sugar" cataract formation, western blots confirmed that multi-functional antioxidants reduced endoplasmic reticulum stress.
  
  
  CONCLUSIONS
  Multi-functional antioxidants delayed cataract formation in two diverse rat models. These studies provide a proof of concept that a general cataract treatment focused on reducing oxidative stress instead of a specific mechanism of cataractogenesis can be developed.
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Randazzo
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Makita
authors.forename: Karen
authors.initials: K
authors.lastname: Blessing
authors.forename: Peter F
authors.initials: PF
authors.lastname: Kador
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002386:Cataract / Q000150:complications* / Q000473:pathology / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000473:pathology; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D005449:Fluorenes / Q000494:pharmacology; D005720:Gamma Rays; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology; D006943:Hyperglycemia / Q000150:complications / Q000473:pathology; D007903:Lens Capsule, Crystalline / Q000187:drug effects / Q000473:pathology; D010858:Pigmentation / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D000975:Antioxidants; D000091342:Endoplasmic Reticulum Chaperone BiP; D005449:Fluorenes; D006360:Heat-Shock Proteins; D006827:Hydantoins; C052241:imirestat; D013311:Streptozocin