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Abstract #27817 Published in IGR 13-1
Ability of dorzolamide hydrochloride and timolol maleate to target mitochondria in glaucoma therapy
Sacca SC; La Maestra S; Micale RT; Larghero P; Travaini G; Baluce B; Izzotti AArchives of Ophthalmology 2011; 129: 48-55
Objective: To test the ability of dorzolamide hydrochloride and timolol maleate to display antioxidant effects. Methods: Antioxidant activity was tested in whole trabecular meshwork (TM) tissue as collected from corneal donors' biopsy specimens, young (third passage) and old (10th passage) human TM cells, and acellular systems composed of pure DNA and subcellular fractions containing or devoid of mitochondria. Oxidative stress was induced by hydrogen peroxide. Monitored end points included DNA fragmentation as evaluated by the halo test, oxidative DNA damage in terms of 8-hydroxy-2'-deoxyguanosine, and mitochondrial function as evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide test. Results: The antioxidant effect of dorzolamide and timolol were observed on TM biopsy specimens and human TM cells exposed to hydrogen peroxide. As evaluated in cell subfractions, timolol displays antioxidant activity regardless of mitochondria presence. Conversely, the antioxidant activity of dorzolamide was maximized in the presence of mitochondria-containing subcellular fractions and in young human TM cells with functional mitochondria. Conclusions: The antioxidant effect of timolol was direct. The antioxidant effect of dorzolamide involves mitochondria and is likely to be exerted mainly during the early glaucoma phases when the mitochondrial damage in the TM tissue still occurs at low levels. Clinical Relevance: Timolol has an antioxidant effect on the entire cell, whereas dorzolamide exerts protective activity toward oxidative stress only in the presence of intact mitochondria (ie, in endothelial cells that are younger when the cellular damage is still limited). The important role of mitochondrial damage in primary openangle glaucoma is supported by the finding that mutant myocilin impairs mitochondrial functions in human TM meshwork cells.
S. C. Sacca. Ophthalmology Unit, Department of Head/Neck Pathologies, San Martino Hospital, Viale Benedetto XV, 16132 Genoa, Italy. sergio.sacca@hsanmartino.it
Classification:
11.5.2 Topical (Part of: 11 Medical treatment > 11.5 Carbonic anhydrase inhibitors)
11.3.4 Betablocker (Part of: 11 Medical treatment > 11.3 Adrenergic drugs)
3.5 Molecular biology incl. SiRNA (Part of: 3 Laboratory methods)
2.5.1 Trabecular meshwork (Part of: 2 Anatomical structures in glaucoma > 2.5 Meshwork)