title: Catalase therapy corrects oxidative stress-induced pathophysiology in incipient diabetic retinopathy.
abstract: OBJECTIVE
  Preclinical studies have highlighted retinal oxidative stress in the pathogenesis of diabetic retinopathy. We evaluated whether a treatment designed to enhance cellular catalase reduces oxidative stress in retinal cells cultured in high glucose and in diabetic mice corrects an imaging biomarker responsive to antioxidant therapy (manganese-enhanced magnetic resonance imaging [MEMRI]).
  
  
  METHODS
  Human retinal Müller and pigment epithelial cells were chronically exposed to normal or high glucose levels and treated with a cell-penetrating derivative of the peroxisomal enzyme catalase (called CAT-SKL). Hydrogen peroxide (H2O2) levels were measured using a quantitative fluorescence-based assay. For in vivo studies, streptozotocin (STZ)-induced diabetic C57Bl/6 mice were treated subcutaneously once a week for 3 to 4 months with CAT-SKL; untreated age-matched nondiabetic controls and untreated diabetic mice also were studied. MEMRI was used to analytically assess the efficacy of CAT-SKL treatment on diabetes-evoked oxidative stress-related pathophysiology in vivo. Similar analyses were performed with difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase.
  
  
  RESULTS
  After catalase transduction, high glucose-induced peroxide production was significantly lowered in both human retinal cell lines. In diabetic mice in vivo, subnormal intraretinal uptake of manganese was significantly improved by catalase supplementation. In addition, in the peroxisome-rich liver of treated mice catalase enzyme activity increased and oxidative damage (as measured by lipid peroxidation) declined. On the other hand, DFMO was largely without effect in these in vitro or in vivo assays.
  
  
  CONCLUSIONS
  This proof-of-concept study raises the possibility that augmentation of catalase is a therapy for treating the retinal oxidative stress associated with diabetic retinopathy.
authors: Department of Pharmacology, Wayne State University, Detroit, Michigan, United States.
authors: Courtney R
authors: CR
authors: Giordano
authors: Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States.
authors: Robin
authors: R
authors: Roberts
authors: Department of Pharmacology, Wayne State University, Detroit, Michigan, United States.
authors: Kendra A
authors: KA
authors: Krentz
authors: Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States.
authors: David
authors: D
authors: Bissig
authors: Department of Ophthalmology, Wayne State University, Detroit, Michigan, United States.
authors: Deepa
authors: D
authors: Talreja
authors: Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States 3Department of Ophthalmology, Wayne State University, Detroit, Michigan, United States.
authors: Ashok
authors: A
authors: Kumar
authors: Department of Pharmacology, Wayne State University, Detroit, Michigan, United States.
authors: Stanley R
authors: SR
authors: Terlecky
authors: Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States 3Department of Ophthalmology, Wayne State University, Detroit, Michigan, United States.
authors: Bruce A
authors: BA
authors: Berkowitz
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002374:Catalase / Q000494:pharmacology*; D018929:Cell Culture Techniques; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000518:Eflornithine / Q000494:pharmacology; D063928:Ependymoglial Cells / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008345:Manganese / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D065108:Ornithine Decarboxylase Inhibitors / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D065108:Ornithine Decarboxylase Inhibitors; D008345:Manganese; D006861:Hydrogen Peroxide; D002374:Catalase; D005947:Glucose; D000518:Eflornithine