title: Silibinin, dexamethasone, and doxycycline as potential therapeutic agents for treating vesicant-inflicted ocular injuries.
abstract: There are no effective and approved therapies against devastating ocular injuries caused by vesicating chemical agents sulfur mustard (SM) and nitrogen mustard (NM). Herein, studies were carried out in rabbit corneal cultures to establish relevant ocular injury biomarkers with NM for screening potential efficacious agents in laboratory settings. NM (100nmol) exposure of the corneas for 2h (cultured for 24h), showed increases in epithelial thickness, ulceration, apoptotic cell death, epithelial detachment microbullae formation, and the levels of VEGF, cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9). Employing these biomarkers, efficacy studies were performed with agent treatments 2h and every 4h thereafter, for 24h following NM exposure. Three agents were evaluated, including prescription drugs dexamethasone (0.1%; anti-inflammatory steroid) and doxycycline (100nmol; antibiotic and MMP inhibitor) that have been studied earlier for treating vesicant-induced eye injuries. We also examined silibinin (100μg), a non-toxic natural flavanone found to be effective in treating SM analog-induced skin injuries in our earlier studies. Treatments of doxycycline+dexamethasone, and silibinin were more effective than doxycycline or dexamethasone alone in reversing NM-induced epithelial thickening, microbullae formation, apoptotic cell death, and MMP-9 elevation. However, dexamethasone and silibinin alone were more effective in reversing NM-induced VEGF levels. Doxycycline, dexamethasone and silibinin were all effective in reversing NM-induced COX-2 levels. Apart from therapeutic efficacy of doxycycline and dexamethasone, these results show strong multifunctional efficacy of silibinin in reversing NM-induced ocular injuries, which could help develop effective and safe therapeutics against ocular injuries by vesicants.
authors: Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045, USA. Neera.Tewari-Singh@ucdenver.edu
authors: Neera
authors: N
authors: Tewari-Singh
authors: Anil K
authors: AK
authors: Jain
authors: Swetha
authors: S
authors: Inturi
authors: David A
authors: DA
authors: Ammar
authors: Chapla
authors: C
authors: Agarwal
authors: Puneet
authors: P
authors: Tyagi
authors: Uday B
authors: UB
authors: Kompella
authors: Robert W
authors: RW
authors: Enzenauer
authors: J Mark
authors: JM
authors: Petrash
authors: Rajesh
authors: R
authors: Agarwal
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D003316:Corneal Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004318:Doxycycline / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D019573:Epithelium, Corneal / Q000187:drug effects / Q000473:pathology; D066298:In Vitro Techniques; D007509:Irritants / Q000633:toxicity; D008466:Mechlorethamine / Q000633:toxicity; D009151:Mustard Gas / Q000633:toxicity; D011817:Rabbits; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002619:Chemical Warfare Agents; D007509:Irritants; D012838:Silymarin; D042461:Vascular Endothelial Growth Factor A; D000077385:Silybin; D008466:Mechlorethamine; D003907:Dexamethasone; D051546:Cyclooxygenase 2; D004318:Doxycycline; D009151:Mustard Gas