title: Reduction of oxidative-nitrosative stress underlies anticataract effect of topically applied tocotrienol in streptozotocin-induced diabetic rats.
abstract: Cataract, a leading cause of blindness, is of special concern in diabetics as it occurs at earlier onset. Polyol accumulation and increased oxidative-nitrosative stress in cataractogenesis are associated with NFκB activation, iNOS expression, ATP depletion, loss of ATPase functions, calpain activation and proteolysis of soluble to insoluble proteins. Tocotrienol was previously shown to reduce lens oxidative stress and inhibit cataractogenesis in galactose-fed rats. In current study, we investigated anticataract effects of topical tocotrienol and possible mechanisms involved in streptozotocin-induced diabetic rats. Diabetes was induced in Sprague Dawley rats by intraperitoneal injection of streptozotocin. Diabetic rats were treated with vehicle (DV) or tocotrienol (DT). A third group consists of normal, non-diabetic rats were treated with vehicle (NV). All treatments were given topically, bilaterally, twice daily for 8 weeks with weekly slit lamp monitoring. Subsequently, rats were euthanized and lenses were subjected to estimation of polyol accumulation, oxidative-nitrosative stress, NFκB activation, iNOS expression, ATP levels, ATPase activities, calpain activity and total protein levels. Cataract progression was delayed from the fifth week onwards in DT with lower mean of cataract stages compared to DV group (p<0.01) despite persistent hyperglycemia. Reduced cataractogenesis in DT group was accompanied with lower aldose reductase activity and sorbitol level compared to DV group (p<0.01). DT group also showed reduced NFκB activation, lower iNOS expression and reduced oxidative-nitrosative stress compared to DV group. Lenticular ATP and ATPase and calpain 2 activities in DT group were restored to normal. Consequently, soluble to insoluble protein ratio in DT group was higher compared to DV (p<0.05). In conclusion, preventive effect of topical tocotrienol on development of cataract in STZ-induced diabetic rats could be attributed to reduced lens aldose reductase activity, polyol levels and oxidative-nitrosative stress. These effects of tocotrienol invlove reduced NFκB activation, lower iNOS expression, restoration of ATP level, ATPase activities, calpain activity and lens protein levels.
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA Sungai Buloh Campus, Sungai Buloh, Selangor, Malaysia.
authors.forename: Nurul Alimah
authors.initials: NA
authors.lastname: Abdul Nasir
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA Sungai Buloh Campus, Sungai Buloh, Selangor, Malaysia.
authors.forename: Renu
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA Sungai Buloh Campus, Sungai Buloh, Selangor, Malaysia.
authors.forename: Siti Hamimah
authors.initials: SH
authors.lastname: Sheikh Abdul Kadir
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA Sungai Buloh Campus, Sungai Buloh, Selangor, Malaysia.
authors.forename: Sushil
authors.initials: S
authors.lastname: Vasudevan
authors.affiliation: Faculty of Pharmacy, Universiti Teknologi MARA Puncak Alam Campus, Puncak Alam, Selangor, Malaysia.
authors.forename: Minaketan
authors.initials: M
authors.lastname: Tripathy
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA Sungai Buloh Campus, Sungai Buloh, Selangor, Malaysia.|Research Institute of Pharmacology, Volgograd State Medical University, Volgograd, Russia.
authors.forename: Igor
authors.initials: I
authors.lastname: Iezhitsa
authors.affiliation: Department of Community Medicine, Faculty of Medicine and Defence Health, National Defence University of Malaysia, Sungai Besi Camp, Kuala Lumpur, Malaysia.
authors.forename: Aqil
authors.initials: A
authors.lastname: Mohammad Daher
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA Sungai Buloh Campus, Sungai Buloh, Selangor, Malaysia.
authors.forename: Mohd Ikraam
authors.initials: MI
authors.lastname: Ibrahim
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA Sungai Buloh Campus, Sungai Buloh, Selangor, Malaysia.
authors.forename: Nafeeza
authors.initials: N
authors.lastname: Mohd Ismail
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000287:Administration, Topical; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002154:Calpain; D002374:Catalase / Q000378:metabolism; D002386:Cataract / Q000150:complications / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications*; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D007908:Lens, Crystalline / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D015538:Nitrosation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010865:Pilot Projects; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D024508:Tocotrienols / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D016328:NF-kappa B; D024508:Tocotrienols; D000255:Adenosine Triphosphate; D002374:Catalase; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase; D002154:Calpain; C000594975:Capn2 protein, rat; D000251:Adenosine Triphosphatases; D005978:Glutathione