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.

Potential Role of Tocotrienols on Non-Communicable Diseases: A Review of Current Evidence

“…There were several animal studies conducted to investigate the effect of T3 on diabetic cataractogenesis [347,348]. Topical application of T3 mixture in microemulsion formulation or liposomal formulation (0.02% and 0.03%) slightly slowed down the diabetic cataractogenesis in galactose diet-induced diabetic rats by reducing ocular opacity index and normalizing the total lens protein, soluble lens protein, insoluble lens protein, and soluble to insoluble lens protein ratio [347].…”

“…In addition to this, 0.2% microemulsion formulation was reported not beneficial in preventing diabetic cataract progression, possibly due to its pro-oxidant activities [347]. Besides, the anti-cataractogenic effect of microemulsion formulation was found to be associated with normalization of the redox status, lenticular ATP level, sorbitol level, ATPases activities, calpain 2 activity and lens aldose reductase activity, and the suppression of NF-κB activation [347,348].…”

Puerarin prevents cataract development and progression in diabetic rats through Nrf2/HO‑1 signaling

“…Cataract is a common complication of diabetes. In addition to oxidative stress, diabetic cataracts are caused by the accumulation of polyols within the lenses of patients with diabetes (48). In the lens, insulin is not involved in the regulation of the levels of glucose or other sugars (49).…”

Diabetic Cataract in Spontaneously Diabetic Torii Fatty Rats

“…Anesthesia was administered using 2.5% isoflurane; the pupils were dilated by means of topical tropicamide and phenylephrine hydrochloride and subsequently, the eyes were examined using a slit-lamp biomicroscope. Progression of lenticular opacity was unbiasedly graded into five stages by two ophthalmologists (KK and YT), as described in a previous literature: stage 0, normal lenses; stage 1, minimal opacity at the center of the lens; stage 2, patchy appearance of opacity, both in the center and periphery of the lens; stage 3, uniform opalescence all over the lens; stage 4, mature cataract with nuclear opacity [ 16 , 17 ].…”