The Effect of Curcumin and Tocotrienol on the Development of Eye Disease

There is growing evidence that inflammation may be one of the causative factors of many chronic diseases especially which is related to eyes such as cataract,age-related macular degeneration and uveitis. Several cytokines such as IL-1,IL-6, RANKL, OPG, and M-CSF were implicated in the pathogenesis of chronic diseases. Anticytokine therapy using cytokine antagonists such as IL-receptor antagonist and TNF-binding protein was able to suppress the activity of the respective cytokines and prevent bone loss. Few animal studies have shown that vitamin E in the forms of palm-derived tocotrienol and α-tocopherol may prevent chronic eye disease in rat models by suppressing IL-1 and IL-6. Free radicals are known to activate transcription factor NFκB which leads to the production of bone resorbing cytokines. Tocotrienol, a potent antioxidant, may be able to neutralize free radicals before they could activate NFκB, therefore suppressing cytokine production and inflammatory reaction. Curcumin is widely reported to have potent anti-oxidative, anti-inflammatory and anticarcinogenic effects. The anti-inflammatory action of curcumin seems to be closely related to inhibition of TNF-α and other inflammatory cytokines production and suppression of NF-κB activation by blocking phosphorylation of inhibitory factor I-kappa B kinase (IκB) Tocotrienol and curcuminhave also been shown to inhibit COX-2, the enzyme involved in inflammatory reactions of the these studied, tocotrienol seemed to be better than tocopherols in terms of its ability to suppress inflammation induced by cytokines.


INTRODUCTION
The free radical (ROS) defined as any atom or molecule possessing unpaired electrons.Molecular oxygen O2ˉ is a biradical with two such unpaired electrons.The biologically relevant free radicals derived from oxygen are the superoxide anion (O2ˉ), the perhydroxyl radical (protonated superoxide, HO2ˉ), the hydroxyl radical (HO2ˉ), and free radical nitric oxide (NO2ˉ).
As antioxidant is a molecule capable of slowing or preventing theoxidation of other molecules.Antioxidants action can terminate these chain reactions byremoving free radicals intermediates (Sies et al., 1997).The use of antioxidants inpharmacology is intensively studied, particularly as treatments forstroke and neurodegenerative diseases.However, it is unknownwhether oxidative stress is the cause or the consequence of disease (Bjelakovic et al., 2007).

Oxidative stress and free radicles
The eye is a highly metabolically active structure, continually bathed in light and the absorption and metabolism will be highly functioning.Thus, oxidative and particularly photooxidative processes are critical factors in ocular pathologic conditions but are often poorly recognized by investigating ocular disease regarding to (Jean et al., 1999;Jennifer et al., 2008).Oxidative stress is a key player in the mechanism of inflammation; thus, we should not be surprised that it is important in eye disease conjunctiva, cornea and uvea (Saraswathy and Rao, 2009).As well as in cataract formation in the lens, retinal degeneration and in optic nerve pathologic conditions, inflammatory in optic neuritis and degenerative in glaucoma due to oxidative stress which occurs throughout the eye and is involved in many different types of tissue damage (Wu et al., 2005;Ferreira et al., 2004;Biswas et al., 2005).This effect of oxidative stress has been increasingly recognized as important factor in pathologic conditions generally in ocular pathologic conditions specifically in the past decade (Mittag, 1984;Bacsi et al., 2005;Kruzel et al., 2006).
In Ophthalmology, the relation between oxidative stress and aging has been given attention for some diseases to aging like age-related macular degeneration, cataract and dystrophy.Regarding to Imamura et al., (2006) the amount and activity of SOD were the highest among the in the human retina, it seemed reasonable to hypothesize that the lack of SOD would accelerate age-related pathological changes in the human retina (Liang & Godley, 2003;Taysi et al., 2007).In many experimental research of uveitis generally involve the posterior segment and retinal mitochondria that exhibit signs of oxidative stress, which seems to result from the up regulation of inducible nitric oxide synthase (iNOS) in photoreceptor mitochondria and retinal cytokine generation by antigen-specific infiltrating T cells (Rajendrum et al., 2007;David et al., 2008).
The relevance to the anterior uveitis seen more commonly, oxidative stress is also seen in models of anterior uveitis, such as that induced by endotoxin (Bhattacherjee et al., 1983;Yan Guex et la., 1996;Satici et al., 2004;Yadav., et al., 2009).The level of malondialdehyde (MDA) in aqueous humor which is consider important key marker of oxidative stress (Rahman and Biswas, 2004).The trophic factor pigment epithelialderived factor (PEDF) is produced by the retinal pigment epithelium and also by the epithelium of the ciliary body, from whence it is secreted into the aqueous humor (Ortego et al., 1996;Neiderkorn et al., 2007).Imamura et al., (2006) have been investigated the agerelated changes of the retinas of mice and found that these mice have many of the key elements of human age-related macular degeneration including thickened Bruch's membrane, and retina neovascularization.Moreover, the retinal pigment epithelium (RPE) cells of these mice showed signs of oxidative stress damage, and their junction integrities have been damaged (Bilgihan et al., 2003).In the other hand some studies revealed that the mechanism of causative role of oxidative stress in the pathogenesis of retinal degeneration and demonstrated a critical role of SOD in protecting the RPE from age-related degeneration (Imamura et al., 2006;Wakamatsu et al., 2008).In vivo studies, it provides a steady supply of free radicals since it is a chain reaction leading to the formation of organic peroxides.The accumulation of peroxides can lead to damage effect on cellular vitality, which might be developing to degeneration and necrosis (Chung et al., 1999;Tezel et al., 2001;Tezel, 2006).
The eye is unique in possessing abundant quantities of antioxidant enzymes and other antioxidant agents.The antioxidant enzymes which include superoxide dismutase (SD), catalase (CAT), glutathione peroxidase (GPX), and glutathione transferase (Delcourt. et al., 2003;Gritzet al., 2006;Jennifer et al., 2008), all ofthese enzymes are distributed in the corneal epithelium and endothelium, lens epithelium, retina and retinal pigment epithelium.The eye also contains other antioxidants, such as ascorbate, vitamin E, ceruloplasmin, and transferrin (Behndig et al., 2001).These agents and the enzymes are contributed to prevent the damaging effects of oxygen and its metabolites (Koh et al., 2000;Balci et al., 2007).As the balance between the production and catabolism of oxidants by cells and tissue is critical for maintenance of the biologic and structural integrity of the tissue, the role of free radical generation in initiation of retinal or other intraocular tissue damage should be studied in clinically relevant models of uveitis in vivo (Barry et al., 2007).

Tocotrienol: Evidences of antioxidant and anti-inflammatory effects
Tocotrienol are capable of scavenging and reducing reactive oxygen species.The antioxidative activity resides mainly with its "chain-breaking" property, which neutralizes peroxyl and alkoxyl radicals generated during lipid peroxidation (Yoshida, et al., 2007).Tocotrienol on the other hand, found in abundance in palm oil used for frying and consider as a potent antioxidant.The main role of the antioxidants represent by mopping up reactive oxygen species (ROS) which is consider one of the potent activator of oxidative stress-induced inflammation (Kamat and Devasagayam, 1995).Tocotrienol is one of the active compounds found in palm oil, together with the more abundant tocopherol (Yoshida, et al., 2007).
Tocopherol has been widely researched and recently was found to control the levels of pro-inflammatory cytokines such as interleukin (IL)-6 by down regulating its expression (Noriko et al., 1999;Sharma and Vinayak, 2011).δ-tocotrienol has been shown to block LPS-induced expression of TNF-α, IL-1β, IL-6 and iNOS in macrophages (Qureshi et al., 2010).The average level of vitamin E (alpha tocopherol) was lower in individuals with macular degeneration than in age and risk matched controls (Satici et al., 2003;Williams, 2006).In placebo-controlled studies, oral vitamin E was able to increase the glutathione levels in the aqueous humor and lenses of humans, rabbits and rats (Bilgihan et al., 2003).Oxidative processes have been implicated in the causation of both cataracts and the age-related disorder of the retina, maculopathy.Cataracts occur when the transparent material in the lens of the eye becomes cloudy and opaque.Oxidation, induced mainly by exposure to ultraviolet light, is believed to be a major cause of damage to the proteins of the lens.Garrett et al., (1999) reported that the average level ofvitamin E (alpha tocopherol) was lower in individualswith macular degeneration than in age and risk matchedcontrols in placebo-controlled studies, oral vitamin Ewas able to increase the glutathione levels in the aqueoushumor and lenses of humans, rabbits and rats.Supplementation of 400IU vitamin E (as natural D-alphatocopherol) is commonly recommended to all individuals to help with the 'normal' oxidative load (Seddon et al., 2005).All three of the major dietary antioxidants (vitamin C, vitamin E and carotenoids) have been associated with decreased cataract risk through the retardation of lens opacity (Leeuwen et al., 2005).Therefore the low plasma levels of vitamin E were associated with the worsening of early cortical lens opacities (Chiu and Taylor, 2007;Sanz et al., 2007) Taylor et al., (2002) investigated the effects of thecombined antioxidant vitamins A, C, and E and zinc onthe development of cataract and (age-related macular degeneration) AMD and showed some partial protective effect of antioxidantsupplements on the progression of moderatelyadvanced AMD (Washington et al., 2001).Age-related eye disease study group(AREDS) ( 2001), used a randomized,placebo-controlled clinical trial, comprising3640 participants, using supplementationwith high-dose antioxidants(average follow-up 6.5 years) showeda significant reduction in rates of atleast moderate visual loss in certaincategories of ARM.Participants wererandomized to daily antioxidants(vitamin C 500 mg, vitamin E 400 IU,b-carotene 15 mg, zinc 80 mg andcopper 2 mg) or placebo.Subjectswith extensive intermediate size drusen,at least one large druse, non-centralgeographic atrophy in one or botheyes, or advanced ARM in one eyehad statistically significant odds reduction for the development ofadvanced (late) ARM.At 5 years, theestimated probability of progression toadvanced ARM (neovascular ARM,geographic atrophy) was 28% forthose assigned to placebo, and 20%for those assigned to antioxidants pluszinc.
Vague effects of the natural antioxidant vitamin E have been described in its relation to sugar cataract development in rodents: a significant prevention of cataractogenesisand an improvement of lens biochemical indices, without affecting the visual cataract score (Ohta et al., 2000).A randomized controlled trial of vitamin E supplementation has not shownany effect on the incidence of early AMD after 4 years of follow-up (Flood et al. 2002).In contrast with the aforementioned studies, our results were based on long-term follow-up of a large, population-based cohort with thorough baseline assessment of dietary intake.Recently, a meta-analysis of 19 clinical trials including AREDS showed that high-dosage (400 IU/d) vitamin E supplementation may increase in all-cause mortality (Miller et al., 2005).Tocotrienols also displayed potent anti-inflammatory activity by inhibiting IL-6 and TNF-α These are the major proinflammatory cytokines released by activated macrophages.IL-6 has been massively studied due to its correlation with poor prognosis and resistance to therapy, interestingly; δ-tocotrienol demonstrated a 51% reduction in IL-6 levels in LPS-stimulated macrophages (Mun et al., 2009;Ndlovu et al., 2009).

Curcumin: Evidences of anti-inflammatory effects
Curcumin, a yellow coloured phenolic pigment extracted from the rhizome of herb Curcuma longa, is widely reported to have potent anti-oxidative, anti-inflammatory and anticarcinogenic effects.The anti-inflammatory action of curcumin seems to be closely related to inhibition of TNF-α and other inflammatory cytokines production and suppression of NF-κB activation by blocking phosphorylation of inhibitory factor I-kappa B kinase (IκB) (Kim et al., 2003).Curcumin is widely used for our preparation of food.Curcumin can be found in turmeric, which is the powdered form of Curcuma longa rhizomes, Curcumin has been shown to have anti-inflammatory activity when applied topically in EIU (Gupta et al., 2008).Curcumin exerts its antiinflammatory effects by up regulating the expression of PPARγ (Siddiqui et al., 2006) and by direct action on PPARγ receptor (Rinwa et al., 2011) thus leading to inhibition of the NF-kB pathway (Zhong et al., 2011).Curcumin was also noted to increase neutrophil apoptosis (Siddiqui et al., 2006).Although topical preparation of curcumin has been shown to reduce the level of tumour necrosis factor-α (TNF-α, one of several pro-inflammatory cytokines) (Gupta et al., 2008), the direct effect of curcumin on the expression of pro-inflammatory cytokines has not been demonstrated.Ukil et al ( 2003) investigated the protective effects of curcumin on 2, 4, 6-trinitrobenzenesulphonic acid (TNBS)induced colitis in mice which is a model of Inflammatory bowel disease (IBD).It also had been shown in curcumin-pretreated mice; there was a significant reduction in the degree of both neutrophil infiltration and lipid peroxidation in the inflamed colon as well as decreased serine protease activity (Bereswill et al., 2010;Lin et al., 2011).Curcumin also reduced the levels of NO and O2ˉ associated with the favorable expression of Th1 and Th2 cytokines and inducible NOS.Consistent with these observations, NF-κB activation in colonic mucosa was suppressed in the curcumin treated mice; therefore the studies suggested that curcumin can exert beneficial effects in experimental colitis (Aggarwal et al., 2003;Kunsch et al., 2004;Sikora et al., 2010).The curcumin also have been shown an inhibitory effect on protein kinase C and xanthine oxidase (Kuo et al., 1996;Chao et al., 2007).Pan et al., (2000) demonstrated that the nuclear factor kappa B (NF-κB2) which consider the master factor playing a role in the inflammatory and immune response, was suppressed by curcumin through inhibiting the activity of I-κB kinase (IKK).In principle, curcumin has been widely demonstrated to have potent antioxidant activities.It is well known that reactive oxygen species (ROS) play a key role in enhancing inflammation through the activation of stress kinases and redox sensitive transcription factors such as NF-κB.Oxidative stress activates NF-κB-mediated transcription of pro-inflammatory mediators either through the activation of its activating inhibitor IKK or the enhanced recruitment or activation of transcriptional co-activators (Samuhasaneeto et al., 2009;Naik et al., 2011).
Although numerous different pathways are activated during the inflammatory response, NF-κB is thought to be of the most importance in cancer-related inflammation (Philip and Rowley, 2004).However, curcumin acts as ROS scavenger, increases antioxidant glutathione levels by induction of glutamate cysteine ligase and acts as an anti-inflammatory agent by inhibition of NF-κB signaling (Biswas et al., 2005).Persistent activation of NF-κB has been observed in many different cancers research.Interestingly, Lu et al., (2004) have been identified that the sustained kinase (IKK) activation is achieved to activate NF-κB pathway in many types of human cancer, indicating the activation of NF-κB is likely to result from alterations in its upstream signaling components.In addition, cytotoxic studies in different cell lines have indicated that the toxicity of curcumin was significantly higher in tumor cells if compared to the normal cells (Kunwar et al., 2008).
Basically, curcumin prevents tissue damage by at least two mechanisms: acting as an antioxidant and by inhibiting NF-κB activation to minimized oxidative stress (Shapiro et al., 2006;Reyes-Gordillo et al., 2007).Interestingly, feeding curcumin to the diabetic rats controls oxidative stress by inhibiting the increase in thiobarbituric acid reactive substances (TBARS) and protein carbonyls by reversing altered antioxidant enzyme activities without altering the hyperglycemic state (Suryanarayana et al., 2007).By inhibiting ROS generation, curcumin also protects pancreatic islets against β cell toxins (Kanitkar and Bhonde, 2008).
All evidence shows that curcumin appears to be beneficial in preventing diabetes-induced oxidative stress, and the inhibition of NF-κB-dependent pathway is at least in part involved in the anti-diabetic mechanisms.Curcumin has long been expected to be a therapeutic or preventive agent for several major human diseases because of its anti-oxidative, anti-inflammatory, and anti-cancerous effects.As well as the absorption, bioavailability and metabolism of curcumin have been studied in humans (Chen et al., 2010).In 2001 research have been demonstrated that curcumin is not toxic to humans up to 8,000 mg/day when taken for 3 months (Cheng et al., 2001;Fu et al., 2008).In considering all of these discoveries, therefore, curcumin can be considered as an ideal lead compound for anti-inflammatory and anticancer drug development.In one small study, curcumin was given orally to 32 chronic anterior uveitis patients who were divided into two groups.The first group received curcumin alone, whereas the second group received a combination of curcumin and antitubercular treatment, all the patients treated with curcumin alone improved, compared to a response rate of 86% among those receiving the combination therapy (Lal et al., 1999).
Similar research conducted on rats and rabbits found that curcumin effectively inhibited chemically induced cataract formation, even at very low dietary levels (Pandya et al., 2000).Awasthi et al., (1996) found the as a potential cataract therapy, researchers fed two groups of rats diets that included corn oil, or a combination of curcumin and corn oil for 14 days.Afterward, their lenses were removed and examined for the presence of lipid peroxidation.The scientists discovered that "the lenses from curcumin-treated rats were much more resistant to inducedopacification than were lenses from control animals (Chen et al., 2010).Curcuminhave also found exhibited anti-inflammatory effects instandard animal models used for testing antiinflammatory activity as well inhibit leukotriene formation in rat peritonealpolymorphonuclear neutrophils (Lal et al., 1999;Reyes et al., 2007).Possible benefits of oralcurcumin supplementation have been observed in cases ofchronic anterior uveitis as in the case of berberine, curcuminexhibits an ability to suppress TNF-α activity and cytokineproduction in experimental acute liver injury (Chen et al., 2010).Gupta et al., (2008 ) demonstrated a significantantiinflammatory effect including improvementof chronic uveitis by oral supplementation.The reduced severity of inflammatorychanges observed in histopathologic examinationand clinical manifestations in the inflamed eye was the result ofsignificant inhibition of vascular and cellular inflammatory responses.The release of chemical mediators of inflammation isalso suppressed secondary to inhibition of the cellular response.The suppression of vascular and cellular inflammatoryresponses by herbal extracts was evidenced by significantlylow levels of inflammatory cells, proteins, and TNF-αlevel inaqueous humor of treated animals.Significantly reduced protein levels in aqueous humor also indicate a possible inhibitoryrole of extract constituents on leukocyte adherence to thevascular endothelium (Allegri et al., 2010).Kumar et al., (2005) reported that curcumin feeding to rats with chemical-induced hyperglycemia can reduce oxidative stress that is the main cause of progression of cataract (Bengmark, 2006).The beneficial effects of this drug appear now to be related to the effect on up regulation of peroxisome proliferator-activated receptor-γ (PPAR-γ), which is a ligandinducible transcription factor involved mainly in controlling inflammation in peripheral organs.Activation of PPAR-γ has been shown to control the response in microglial cells and limit inflammation (Brigh, 2007;Jacob et al., 2007;Nonn et al., 2007).Curcumin also has been shown significant effect to prevent choroidal and retinal neovascularization in several experimental animal models, notably through the inhibition of VEGF receptor expression (Jacob et al., 2007;Shakibaei et al., 2007;Allegri et al., 2010).

CONCLUSION
Vitamin E, especially the Tocotrienol and regulation of disease has been extensivelystudied in humans, animal models and cell systems.Most ofthese studies focus on the tocopherol isoform of vitamin E.These reports indicate contradictory outcomes for anti-inflammatory functions of the tocopherol isoform of vitaminE.These seemingly disparate clinical resultsare consistent with recently reported unrecognizedproperties of isoforms of vitamin E. The anti-inflammatorypotential of tocotrienols lookspromising and further studiesshould be spear-headed.Understanding of the properties oftocotrienols would lead to greater benefits andprovide good options when planning for thehealth of the public.Tocotrienol treatment has several anti-inflammatory effects that could be mechanistically analogous to the modulation of proteasomal .activity by lactacystin, a well-established proteasome inhibitor that can either increase or decrease proteasomal activity under different conditionsand finally will lead to give good prognosis for chronic disease (Qureshi et al., 2010).In other hand the supplementation ofcurcumin has been shown to be safein humans.The mechanism by which curcumin induces itsanti-inflammatory effects is yet to be fully elucidated, butmany studies have shown its relevance as a potent anti-inflammatory and immuno-modulating agent.PPAR-γ agonists(like curcumin) act on microglia and immune systemcells modulating both innate and adaptive immune responses,and can have a profound effect on the inflammatory cascade.The positive results of the previous study show that Norflo (curcuminphosphatidylcholinecomplex) can play an important rolein the adjunctive therapy of chronic diseasein various origins and gives a contribution to the clinical potential efficacy of thisplant-derived product in medicine (Allegri et al., 2010).