Therapeutic potential of Curcuma longa , the golden spice of India, in drug discovery for ophthalmic diseases Renu Agarwal , Suresh Kumar Gupta † , Sushma Srivastava , Puneet Agarwal & Shyam Sunder Agrawal † Delhi Institute of Pharmaceutical Sciences & Research, Pushp Vihar, Sector 3, MB Road, New Delhi 110017, India
Background : Curcuma longa is among the most commonly used spices in India and other Asian countries. The herb has also been used in Ayurveda and other traditional systems of medicine for the prevention and treatment of a variety of ailments. Curcuminoids are the major chemical constituents of C. longa that are of medicinal importance. Today, a large body of scientific evidence exists to indicate potential therapeutic benefits of C. longa . Several preclinical and clinical studies have investigated the pharmacological properties of C. longa and results indicate strong therapeutic potential for anti-inflammatory, antioxidant, antibacterial, anticancer and many other properties. Objective : This review summarizes the scientific evidences showing possible benefits of C. longa in a variety of ophthalmic diseases. Conclusion : Although the putative mechanism(s), molecular targets and range of therapeutic applications have been researched widely, further investigations are needed to explore the true therapeutic potential and future of curcuminoids as novel drug molecules in ophthalmic diseases.
Spices are the soul of traditional Indian cuisine and are extensively used for seasoning in cooking, as preservative and as remedies to cure various ailments. Among all, turmeric, popularly known as ‘haldi’ in India, is the oldest and most commonly used spice in the subcontinent for its color and flavor. Owing to its golden yellow color, turmeric is also known as the ‘Golden Spice of India’. Since time immemorial, besides being used as a spice and an important component of cosmetics, turmeric has a rich tradition of use in ancient systems of medicine such as Ayurveda and traditional Chinese medicine.
Turmeric is derived from the plant Curcuma longa , which belongs to the family Zingiberaceae (ginger) and is cultivated extensively in India, China and other tropical countries. Curcuma longa is a perennial herb that grows to a height of 3 – 5 feet and has oblong pointed leaves and funnel shaped yellow flowers. Medicinally, the important part of the plant is its rhizome, which is usually made into a yellow powder to be used as a spice, turmeric. The important medicinal uses of C. longa described in literature are particularly as an antiseptic, antibacterial and anti-inflammatory agent both topically and systemically, and for treatment of jaundice, menstrual irregularities, hematuria, hemorrhage, cardiovascular, gastrointestinal disorders and in cancer chemotherapy. In Ayurveda, a poultice of turmeric paste is used to treat common eye infections, and to dress wounds, treat
1. Introduction
2. Biologically active chemicals
from C. longa
3. Pharmacokinetic properties
of curcumin
4. Pharmacodynamics and
therapeutic benefi ts of C. longa
5. Conclusion
6. Expert opinion
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Therapeutic potential of Curcuma longa, the golden spice of India, in drug discovery for ophthalmic diseases
148 Expert Opin. Drug Discov. (2009) 4(2)
bites, burns, acne and various skin diseases. Powdered turmeric is taken with boiled milk to cure cough and related respiratory ailments. Roasted turmeric is used to treat dysentery in children [1] . It is also used for the treatment of dental diseases, digestive disorders and to alleviate hallucinatory effects of psychotropic drugs [2] .
Owing to its multiple pharmacological properties, such as antioxidant, anti-inflammatory, antiangiogenic and anti-apoptotic, therapeutic benefits of C. longa are expected in a wide range of ophthalmic diseases. This review presents the scientific evidence available so far indicating therapeutic potential of C. longa in the treatment of ophthalmic diseases.
2. Biologically active chemicals from C. longa
The phytochemicals isolated so far from Curcuma spp. include turmerin, which is a water-soluble peptide, essential oils such as turmerones, atlantones and zingiberene, and curcuminoids. Curcuminoids are the polyphenolic compounds that give turmeric its golden yellow color. Three major curcuminoids that have been isolated from C. longa include curcumin, demethoxycurcumin and bisdemethoxycurcumin [3] . The dry rhizome of C. longa is the richest source of curcuminoids. Curcuminoids are the polyphenolic compounds and curcumin is the principal and most active curcuminoid. Curcumin was initially described as a chemical compound with a chemical formula, C 21 H 2 OO 6 , by Vogel and Pelletier in 1815 [4] . Lampe et al. in 1910 [5] recognized this compound as diferuloylmethane, which was later synthesized in 1913. Most of the turmeric preparations contain 2 – 8% curcumin [6] . Curcumin is relatively insoluble in water, but dissolves in acetone, dimethylsulfoxide and ethanol. The molecular mass is 368.37 and melting point 183 ° C. Commercial grade curcumin contains the curcuminoids desmethoxy-curcumin (molecular mass 338; usually 10 – 20%) and bisdesmethoxycurcumin (molecular mass 308; usually < 5%). The biological activity of commercial curcumin has been found to be comparable to pure curcumin ( Figure 1 ) [7,8] .
3. Pharmacokinetic properties of curcumin
Early pharmacokinetic studies of curcumin in rats revealed that the absorption of compound after oral administration is very poor. About 75% of the 1 g/kg oral dose was excreted in feces and negligible amount appeared in urine. After intravenous administration or incubation with liver perfusate, it was observed that curcumin undergoes rapid metabolism and active transportation in bile [9] . Another study demon-strated 60% oral absorption of curcumin after 400 mg dose in rats and glucuronide and sulfate conjugates of curcumin were detected in urine [10] . Following intravenous and intra-peritoneal administration, large quantities of curcumin and its metabolites were detected in bile. The results indicated that curcumin undergoes metabolism during absorption in gut and subsequently there is significant enterohepatic circulation.
After intraperitoneal administration at a dose of 0.1 g/kg in mouse, curcumin was first converted to dihydrocurcumin and tetrahydrocurcumin, and these compounds were subsequently converted to monoglucuronide conjugates [11] . Predominant metabolites of curcumin detected in rat plasma in vivo are curcumin glucuronide and curcumin sulfate whereas in in vitro studies using isolated human hepatocytes or liver or gut microsomes, hexahydrocurcumin and hexahydrocurcuminol were the major metabolites. These results indicate that curcumin glucuronide and curcumin sulfate are generated as a result of extrahepatic metabolism in gastrointestinal tract after oral administration and hepatic metabolism reduces curcumin to hexahydrocurcumin and hexahydrocurcuminol, probably through the intermediacy of dihydrocurcumin and tetrahydrocurcumin, two species that were identified in mice [12] . In one of the Phase I clinical trials involving 25 patients with any one of the high-risk conditions: i) recently resected urinary bladder cancer; ii) arsenic Bowen’s disease of the skin; iii) uterine cervical intraepithelial neoplasm; iv) oral leucoplakia; and v) intestinal metaplasia of the stomach, treatment was started with 500 mg/day orally. In the absence of toxicity, the dose was escalated in the order of 1, 2, 4, 8 and 12 g/day. The average peak serum concen-trations after taking 4, 6 and 8 g of curcumin were 0.51 +/- 0.11, 0.63 +/- 0.06 and 1.77 +/- 1.87 µM, respec-tively, at 1 – 2 h after oral intake and gradually declined in 12 h. Urinary excretion of curcumin was undetectable. No toxicity was observed up to 8.0 g/day dose. However, with higher dose the bulky volume of the drug was unacceptable to patients [13] .
The results described above indicate very poor oral bioavailability of curcumin owing to its rapid metabolism in gut wall and liver. The effect of piperine, a known inhibitor of hepatic and intestinal glucuronidation, on bioavailability of curcumin has also been examined. In rats, oral adminis-tration of curcumin (2 g/kg) along with piperine, found in the fruit of the pepper vine, piper nigrum, was found to increase the systemic bioavailability of curcumin by 154%. Similarly, in fasting human volunteers, oral administration of 2 g curcumin resulted in very low plasma levels (< 10 ng/ml) at 1 h post administration but co-administration with piperine increased the bioavailability by 2000% [14] .
Bioavailability of curcumin has been evaluated after encapsulating it in natural biodegradable carriers, namely serum albumin and chitosan, and preparing microspheres. Curcumin could be encapsulated to the extent of 79.49 and 39.66% with albumin and chitosan, respectively. A biphasic drug release pattern was observed in an in vitro release study characterized by a typical burst-effect followed by a slow release that continued for several days. The study indicates that curcumin in the form of biodegradable microspheres could probably be more useful as it can provide prolonged drug delivery as compared to administration of curcumin by oral or subcutaneous route. Synthetic bioconjugates of curcumin di- O -glycinoyl curcumin (I) and 2′-deoxy-2′-curcuminyl
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uridine (2′-cur-U) (IV) were found to improve systemic delivery of curcumin significantly [15] .
4. Pharmacodynamics and therapeutic benefi ts of C. longa
4.1 Diseases of conjunctiva Conjunctivitis or the ‘red eye’ is one of the most common ocular inflammatory conditions. It can be allergic, infectious (bacterial, viral, fungal or parasitic), a part of systemic disease (e.g., erythema multiforme) or as a spread of infection from other areas such as lacrimal sac. Disease often presents with redness, swelling, discharge, foreign body sensation and mild pain. It can present as a hyperacute, acute or chronic disease. Usually, conjunctivitis is a self-limiting disease and
vision is seldom affected. However, in some cases, disease may progress to involve cornea and may lead to blindness if left untreated. Available treatment options suffer from many drawbacks. Treatment of viral conjunctivitis remains a major problem and due to emergence of multi-drug resistance treatment of bacterial conjunctivitis is also an emerging area of concern. At present, treatment of other conjunctival diseases such as dry eyes, pterygium and pinguecula is also often unsatisfactory.
The use of herbal formulations has long been suggested to be beneficial in the treatment of conjunctival diseases, especially conjunctivitis. One teaspoonful powder of C. longa rhizome boiled in a cup of water and filtered when used as eyewash is known to be beneficial in conjunctivitis. A decoction (1 ounce of the bruised root to 20 ounces of water) applied
HO OH
OO
HO
H3CO
OCH3
OH
OCH3
OH
O
Curcumin: bis-keto form
HO OH
OO
OCH3
Demethoxycurcumin
HO OH
OO
Bisdemethoxycurcumin
Curcumin: enolate form
pH > 8pH 3 – 7
H3CO
Figure 1 . Curcuminoids from Curcuma longa.
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Therapeutic potential of Curcuma longa, the golden spice of India, in drug discovery for ophthalmic diseases
150 Expert Opin. Drug Discov. (2009) 4(2)
as a lotion relieves burning in catarrhal and purulent oph-thalmic conjunctivitis and other eye inflammations. A piece of cloth soaked in the decoction, and placed over the afflicted eye also relieves the symptoms [16] . A polyherbal combination (Ophthacare, Himalaya Drug Company, Bangalore, India) containing extracts of Carum copticum , Terminalia belerica , Emblica officinalis, C. longa , Ocimum sanctum , Rosa damascena , Cinnamomum camphora with purified Mel Despumatum (honey) was evaluated for efficacy in 116 patients presenting with symptoms of acute or chronic conjunctivitis. All patients suffering from acute conjunctivitis were advised to instill two drops of Ophthacare eye drops in both eyes, every 2 h for a week, whereas all patients suffering from chronic conjunctivitis were advised to instill two drops in both eyes four times a day for 15 days. At the end of treatment period, there was a significant reduction in mean score for conjunctivitis, congestion, papillae and follicle. There were no clinically significant adverse events either observed or reported, except for mild local allergic manifestations seen in two patients [17] . In another multi-center prospective open uncontrolled clinical study involving 35 patients with acute conjunctivitis, topical treatment with two drops of Ophthacare eye drops four times daily for 15 days resulted in positive therapeutic response in 28 patients. Similar treatment of seven patients with conjunctival xerosis resulted in positive response in four patients. Fifteen out of twenty patients with dacryocystitis showed significant improvement after topical treatment with Ophthacare eye drops, two drops four times a day for 15 days. Ten out of fifteen patients with degenerative conditions such as pterygium and pinguecula showed significant improvement after topical treatment with Ophthacare eye drops, two drops four times a day for 15 days [18] . These clinical studies do not provide conclusive evidence for therapeutic benefits of C. longa as the preparation used was a polyherbal combination.
4.2 Diseases of cornea Diseases of cornea especially those involving neovascularization in the superficial and/or deep corneal stroma are often associated with partial or complete impairment of vision. Common causes include infection, contact lens wear, trauma, chemical burn, immunologic diseases, degeneration or intraocular events such as uveitis, glaucoma and pthisis bulbi. Medical therapy largely involves topical steroid application, which is associated with several side effects.
A large body of evidence indicates the therapeutic potential of C. longa in diseases involving new vessel formation. Steroid like effect of treatment with C. longa extracts on corneal wound healing was observed in one of the experiments involving albino rabbits. Curcuma longa aqueous extract (2.8%) and alcoholic extract (1.125%) were found to delay healing of superficial corneal wounds. Healing of penetrating corneal wounds was also delayed significantly and tensile strength of cornea was found to be markedly reduced [19] . In an in vivo experiment, alkaline burns of the cornea were
produced in Sprague–Dawley rats. Rats were treated topically with curcumin and subsequently slit-lamp biomicroscopy revealed that the corneal neovascularization was significantly inhibited. Expression of VEGF in the corneal tissue as evaluated by reverse transcription polymerase chain reaction and by immunohistochemistry was found to be significantly inhibited by curcumin treatment on days 7 and 14 after alkaline burn [20] . These evidences from animal experiments show potential benefits of curcumin treatment in corneal diseases associated with neovascularization.
4.3 Diseases of uvea Among the wide range of diseases of uvea, uveitis, that is, the inflammation of the middle layer of eye, is one of the commonest clinical conditions. The disease can be acute or chronic and can be secondary to ocular trauma or surgery or as a part of autoimmune diseases. Uveitis often is unilateral and presents with pain, photophobia, blurred vision, circumcorneal redness and small irregular pupil. If left untreated, uveitis can lead to permanent damage to vision or even blindness. At present, the mainstay of treatment is steroids, which are often associated with several side effects such as glaucoma.
In view of the limitations of the now available therapy, it is important to look for alternative therapies that are safe and effective. Treatment with C. longa has been shown to provide positive therapeutic results both in animal and human studies. In one of the studies involving 53 patients with chronic anterior uveitis, curcumin was administered orally at a dose of 375 mg three times a day for 12 weeks. Out of 32 patients who completed 12 weeks treatment, 18 received curcumin only whereas 14 received antitubercular treatment in addition to curcumin. The patients were moni-tored for improvement in vision, circumciliary congestion, aqueous flare, keratic precipitates and vitreous turbidity. All patients from both groups showed improvement by the end of 2nd week of therapy; however, the statistically significant differences between the two groups have not been presented in this study. At the end of treatment period, all patients in curcumin alone group showed improvement whereas the curcumin + antitubercular group showed a response rate of 86%. Recurrence rate was 55% in curcumin alone group and 36% in curcumin + antitubercular group. Twenty-two percent of patients in curcumin alone group and twenty-one percent of patients in curcumin + antitubercular group lost vision due to development of complications. As stated by authors, the efficacy and recurrence rate with curcumin was comparable to steroid therapy with an added advantage of lack of side effects [21] ; however, the facts need to be confirmed in a large, well-designed clinical trial. The anti-inflammatory effect of C. longa extract has recently been demonstrated in our laboratory in rabbits with experimental uveitis. Experi-mental uveitis in rabbits was induced by intravitreal injection of endotoxin from Escherichia coli after pretreatment with C. longa aqueous extract applied topically three times a day
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for 3 days. The aqueous humor from rabbit eye drained 24 h after endotoxin injection showed significantly low levels of proteins, inflammatory cells and TNF- α in C. longa treated group as compared to control group. Clinical and histopathological grading done 72 h after endotoxin injections also showed significantly lower grade of inflammation in C. longa treated group as compared to control group [22] . The results of both the animal and human studies indicate the therapeutic potential of C. longa in cases of uveitis.
4.4 Infl ammatory orbital pseudotumor Pseudotumor is not a neoplastic condition but an inflammatory lesion of orbital tissue. It can be idiopathic or secondary to bacterial, viral, fungal and parasitic infections. This clinical condition is characterized by pain, swelling, diplopia, proptosis, extraocular muscle restriction, reduced vision and ptosis. One of the studies describes the clinical efficacy of curcumin in the treatment of patients suffering from idiopathic inflam-matory orbital pseudotumors. Eight patients were administered curcumin at a dose of 375 mg three times a day orally for a period of 6 – 22 months. They were followed up for a period of 2 years at 3 monthly intervals. Five patients completed the study, out of which four recovered completely and in one patient the swelling regressed completely but some limitation of movement persisted. No side effect was noted in any patient and there was no recurrence. It is suggested that curcumin could be used as a safe and effective drug in the treatment of idiopathic inflammatory orbital pseudotumors [21] .
4.5 Cataract Age-related cataractogenesis is a major public health problem. Cataract is opacity in eye lens. Etiology of cataract is not well understood; however, oxidative damage to the constituents of the eye lens is considered to be a major mechanism in the initiation and progression of various types of cataracts [23] . Several studies have suggested that intake of antioxidant-rich foods may slow the progression of cataract [24-27] . At present, the only available treatment for cataract is surgery. Delay in the progression of cataract, which reduces the need for surgery by 50%, has a significant health impact [28] . Beneficial effects of C. longa on progression and maturation of cataract have been observed in animal studies.
In one of the studies, streptozotocin-induced diabetic rats were subjected to evaluation of anticataract activity of curcumin. Rats in treatment groups received diet supplemented with curcumin 0.002, 0.01 and 0.5% for a period of 8 weeks. During the period of study, progression of cataract was evaluated by examination under slit-lamp and at the end of treatment period rats were sacrificed to examine biochemical pathways involved in the pathogenesis of cataract such as oxidative stress, polyol pathway, alterations in protein content and crystallin profile in the lens. In control diabetic rats receiving diet not supplemented with curcumin, slit-lamp examination at the end of 4 weeks revealed 30% of
the lenses in stage 1, 60% in stage 2 and 10% in stage 3 of cataract formation; none of them was clear after 5 weeks. Animals receiving 0.002% curcumin supplemented diet had 45% of the lenses in stage 1, 25% in stage 2 and 30% in stage 3. Animals receiving 0.01 and 0.5% curcumin supple-mented diet had most of the lenses in stage 1 and only a few were in stages 2 and 3. At the end of 8 weeks treatment, 65% lenses in control diabetic group had mature cataract whereas only 43, 33 and 25% lenses had mature cataract in 0.002, 0.01 and 0.5% curcumin supplemented diet groups, respectively. The results indicate that the progression of hyperglycemia-induced cataract was delayed by curcumin treatment and owing to delayed progression, maturation was also delayed. Evaluation of biochemical parameters showed that the thiobarbituric acid reactive substance (TBARS) levels in control diabetic and diabetic rats receiving diet supplemented with 0.002% curcumin were significantly elevated as compared to non-diabetic controls. TBARS levels in diabetic groups receiving diet supplemented with 0.01 and 0.5% curcumin were significantly low as compared to diabetic rats receiving unsupplemented diet. Protein carbonyl contents of the lens were significantly elevated in untreated diabetic group as compared to non-diabetics, but in diabetic groups receiving diet supplemented with 0.01 and 0.5% curcumin protein carbonyl levels were comparable to non-diabetic group. Estimation of reduced glutathione (GSH) levels also showed significantly low values in untreated and 0.002% curcumin treated diabetic rats, whereas treatment with 0.01 and 0.05% curcumin helped in maintaining the GSH levels close to non-diabetics. The amount of total and soluble proteins was found to be significantly increased in the group treated with curcumin (0.01 and 0.5%) as compared to untreated diabetic group. In untreated diabetic rats, the abundance of β- and γ -crystallin was significantly low and presence of high molecular mass aggregate was prominent. No change in glycemic control was observed [29] . Another study also demonstrated similar biochemical changes in eye lens of alloxan-induced diabetic rats following curcumin treatment. TBARS levels were significantly reduced and NADPH/NADP levels were significantly increased. Activity of GSH peroxidase was significantly increased whereas that of sorbitol dehydro-genase significantly decreased. Curcumin treated rats in this study showed improved glycemic control [30] . Results of both studies described above indicate potent antioxidant effects leading to anticataract effects of curcumin and turmeric treatment.
In another study, development of selenite-induced cataract was inhibited by curcumin treatment. Intraperitoneal injection of sodium selenite to 9-day-old pups induces formation of nuclear cataract on the 16th postnatal day. When sodium selenite was administered after pretreatment with curcumin, development of nuclear cataract was inhibited [31] .
Anticataract activity of curcumin has also been demonstrated in an in vitro rat model. Eye lenses from normal rats when cultured for 72 h in presence of 100 µmol
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Therapeutic potential of Curcuma longa, the golden spice of India, in drug discovery for ophthalmic diseases
152 Expert Opin. Drug Discov. (2009) 4(2)
4-hydroxy-2-nonenal (4-HNE)/l, a highly electrophilic product of lipid peroxidation, become opaque as indicated by transmitted light intensity using digital image analysis. When rats pretreated with 75 mg curcumin/kg in corn oil were subjected to similar in vitro evaluation, eye lenses were found to be much more resistant to 4-HNE-induced opacification [32] . In another in vitro experiment, curcumin treatment signifi-cantly inhibited development of swelling of rat lenses in presence of galactose and also significantly inhibited aldose reductase activity (IC 50 value of 55 µg/ml) and accumulation of polyol in rat lenses in response to exposure to galactose [33] .
Curcumin at very low concentration has shown positive therapeutic response against galactose-induced cataractogenesis. Delay in the onset and progression of cataractous changes was observed with the help of slit-lamp in rats receiving 30% galactose diet supplemented with 0.002% curcumin as compared to rats receiving only 30% galactose diet. However, when 30% galactose diet was supplemented with higher curcumin contents (0.01%), a faster onset and progression of cataract was observed. Feeding of curcumin to normal rats up to a 0.01% level did not result in any changes in lens morphology. Biochemical analysis showed that curcumin at the 0.002% exerted antioxidant and anti-glycating effects, as it inhibited lipid peroxidation, advanced glycated end products and protein aggregation. Although the reasons for faster onset and maturation of cataract in the group receiving higher concentration of curcumin was not clear, the data suggested that under hyperglycemic conditions higher levels of curcumin (0.01%) in the diet may increase oxidative stress, advanced glycation end product (AGE) formation and protein aggregation [34] . In a similar experiment, when curcumin 0.01% was supplemented with vitamin E, the progression and maturation of cataract was significantly delayed and antioxidant defense was significantly elevated as evidenced by inhibition of lipid peroxidation and rise in reduced GSH contents [35] . These results from both the in vivo and in vitro experiments clearly indicate the anticataract activity of C. longa .
4.6 Diseases of retina The therapeutic potential of treatment with C. longa in retinal diseases such as diabetic retinopathy and glaucoma has been investigated in experimental studies.
Diabetic retinopathy is a major cause of acquired blindness in adults and is responsible for 4.8% of the global blindness [36] . In persons with diabetes, the overall prevalence of any retinopathy was found to be 35.0% and the overall prevalence of vision-threatening retinopathy was 9.0% [37] . Major abnormalities in retina in non-proliferative diabetic retinopathy are: formation of microaneurysms, retinal hemorrhages, exudations, dilated capillaries and retinal edema. In natural course, 50% of the non-proliferative diabetic retinopathy patients with severe disease progress to proliferative diabetic retinopathy in 1 year (Early Treatment Diabetic
Retinopathy Study Research Group) [38] . Proliferative diabetic retinopathy is characterized by neovascularization, subsequently leading to vitreous and retinal detachment and blindness. At present, the management largely includes laser photocoagulation and surgery. Pharmacotherapy in diabetic retinopathy mainly consists of steroids, anti-VEGF antibodies, aldose reductase inhibitors, PKC- β isoform-selective inhibitor long acting octreotide and COX-2 inhibitors, and so on. At present, most of these pharmacotherapeutic approaches are still experimental and expensive making it necessary to look for safe, effective and affordable treatment approaches for diabetic retinopathy. Experimental studies have provided evidences showing therapeutic potential of C. longa in the treatment of diabetic retinopathy.
In one of the experiments, streptozotocin-induced diabetic rats were fed with curcumin (0.5 g/kg diet) for a period of 6 weeks after induction of diabetes. Control rats receiving normal diet not supplemented with curcumin and diabetic for 6 weeks showed 30 – 35% reduction in total antioxidant capacity and GSH levels in retina and 70% reduction in oxidatively modified DNA as compared to normal non-diabetic rats. In diabetic rats receiving diet supplemented with curcumin, the total antioxidant capacity and oxidatively modified DNA levels were close to non-diabetic rats. GSH levels in curcumin fed diabetic rats were reduced as compared to non-diabetics but significantly higher than diabetic controls. Nitrotyrosin levels in diabetic controls were 60% higher than non-diabetics but were significantly low in curcumin fed diabetics as compared to diabetic controls. Retina from diabetic controls also showed a 30% elevation in expression of inflammatory cytokine IL-1 β , twofold activation of NF- κ B and VEGF. Supplementation with curcumin prevented diabetes-induced increase in IL-1 β , NF- κ B and VEGF; the values obtained from normal control and diabetes + curcumin rats were not significantly different from each other. Strikingly, the severity of hyperglycemia was not affected by curcumin administration [39] . In another similar study, oral administration of curcumin and turmeric to streptozotocin-induced diabetic rats significantly inhibited expression of VEGF as compared to diabetic control at both protein and transcript levels [40] .
In an in vitro experiment, human retinal endothelial cells (HRECs) from culture were transferred to serum-starved medium (without growth supplement) for 18 to 24 h and then were grown for 72 h in either physiologic (5 mmol/l) or high-glucose (30 mmol/l) medium. When the cells grown in physiological solution were exposed to different concen-trations of curcumin (1, 3, 10 or 30 µM) for 72 h, basal proliferation was significantly inhibited and cell survival was inversely correlated to curcumin concentration. The median IC 50 was calculated as 8.2 – 0.05 µM. HREC grown in medium containing 30 mmol/l D -glucose did not show any alteration in growth and survival. However, with addition of curcumin (10 µM), an inhibition to the extent of 42% was observed. TUNEL assay showed that the number of
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apoptotic bodies was significantly higher in HRECs treated with 10 µM curcumin, when exposed to 30 mmol/l D -glucose, compared with HRECs treated with 30 mmol/l glucose alone. Increased DNA fragmentation characterized by typical smudged ladder pattern of internucleosomal fragmentation was observed in curcumin treated cells whereas no DNA fragmentation was observed in cells without curcumin treat-ment. Curcumin treatment did not affect the LDH activity thus confirming that the curcumin-induced cell death was not due to necrosis. The expression of caspase-3, a marker of apoptosis was upregulated in curcumin treated cells. Curcumin also significantly decreased VEGF mRNA expression at 24 h. Angiogenic process in diabetic retinopathy involves VEGF as well as PKC signal. A 25% increase in the membrane PKC-β II expression was observed after exposure of HREC cells to VEGF 10 ng/ml as compared to basal conditions. Pretreatment of HREC cells with 10 µM curcumin before exposure to VEGF inhibited PKC-β II expression by 31% [41] .
The α -chemokine stromal derived factor (SDF-1 α ) and a G-protein-coupled receptor CXCR4 play a pivotal role in regulating migration of HREC. In one of the in vitro studies, HREC migration was increased dose-dependently (1, 10, 50 and 100 ng/ml) in response to SDF-1 α treatment but treatment with a CXCR4-inhibitor reduced HREC migration dose-dependently (0.1, 0.5, 1.0 and 10 µmol/l). Exposure to curcumin was found to significantly inhibit the SDF-1 α -induced migration of HREC. Curcumin downregulated SDF-1 α -induced expression of CXCR4, phospho AKT, phospho phosphotidylinositol-3-kinase and eNOS. Curcumin also blocked Ca 2+ influx, an important signal for cell migration. The results of this study suggest that inhibitory effect of curcumin on SDF-1 α -induced migration of HREC might involve upstream blockage of Ca 2+ influx and subsequent downstream decreased expression of phospho-AKT, phospho phosphotidylinositol-3-kinase, which are vital proteins responsible for HREC migration [42] .
Therapeutic benefits of C. longa are also expected in glaucoma, the second leading cause of blindness. Glaucoma is a progressive optic neuropathy characterized by visual field loss and characteristic changes in optic disc. The optic disc changes are a result of loss of retinal ganglion cells, mainly by apoptosis. The factors triggering the retinal ganglion cell apoptosis are not well understood; however, several studies have demonstrated that the primary factors such as elevated intraocular pressure and vascular dysregulation lead to retinal ganglion cell apoptosis through NMDA-mediated excitotoxicity, increased TNF- α expression and oxidative stress.
Curcuma longa has been demonstrated to possess anti-apoptotic, antioxidant and TNF- α blocking activity. Moreover, treatment of retinal ganglion cells in culture with C. longa extract was found to protect against excitotoxic cell damage as detected by increased survival and reduced apoptosis. The protection was associated with decrease of NMDA receptor-mediated Ca 2+ rise and reduction in the level of
phosphorylated NR 1 subunit of the NMDA receptor [43] . Further investigations in in vivo models of glaucoma can reveal the true potential of C. longa as an antiglaucoma agent.
4.7 Mechanistics behind therapeutic effi cacy The pharmacodynamic properties responsible for therapeutic efficacy of C. longa as observed in animal and human experiments have been investigated extensively. Some of these properties are summarized here and are also shown in Figure 2 .
4.7.1 The mechanistics of therapeutic benefi ts owing to anti-infl ammatory effects Therapeutic benefits of C. longa in a variety of inflammatory ocular conditions such as conjunctivitis and uveitis have been observed owing to its potent anti-inflammatory effects. The mechanisms involved in anti-inflammatory effects of C. longa are:
Curcuminoids inhibit activation of polymorphonuclear • leukocytes (PMNLs), monocytes and macrophages: Activated PMNLs are the source of proinfl ammatory mediators such as reactive oxygen species (ROS). Curcuminoids act as anti-infl ammatory agent by inhibiting the activation of PMNL. Curcuminoids inhibit production of ROS from activated • PMNL: ROS are one of the most potent stimuli of infl ammation. ROS stimulate monocytes and macrophages to produce cytokines such as IL-8, IL-1 β and TNF- α . Curcuminoids inhibit the production of ROS and thereby abolish infl ammation. Curcuminoids inhibit mediators of infl ammation such as • IL-8 and TNF- α : Cytokines such as ILs and TNF- α are the most potent chemical mediators of infl ammation that further initiate expression of other proteins playing a vital role in infl ammatory process. Curcuminoids by inhibiting ILs and TNF- α suppress infl ammation. Curcuminoids from • C. longa inhibit TNF- α -induced expression of adhesion molecules on endothelial cells: The induction of various cell adhesion proteins such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin on the endothelial cells is directly involved in infl ammation [44] . Adhesion molecules damage the endothelial cells leading to leukocyte adhesion and vascular leakage. Curcuminoids inhibit the expression of cell adhesion molecules, thereby limiting the damage to capillary endothelial cells. Curcuminoids inhibit expression of lipooxygenase (LOX), • COX and inducible nitric oxide synthase enzymes: Mediators of infl ammation derived from arachidonic acid are biosynthesized by pathways dependent on COX and LOX enzymes. The role of LOX and COX isoforms, particularly COX-2, in infl ammation is well known. The specifi c regulation of LOX and COX-2 by curcumin is not fully established; however, existing
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evidence indicates that curcumin regulates LOX and COX-2 predominately at the transcriptional level and, to a certain extent, the post-translational level and this manifests as anti-infl ammatory effects [45,46] . Curcumin causes downregulation of NF- • κ B: NF - κ B is a nuclear transcription factor and is activated in response to proinfl ammatory mediators, hypoxia and oxidative stress [47] . Suppression of COX-2 is likely through the downregulation of NF - κ B, another important property of curcumin contributing to anti-infl ammatory effects. Curcumin suppresses activation of MAPKs p38: MAPKs • p38 modulates the transcription of many genes involved in the infl ammatory process and its suppression contributes signifi cantly to anti-infl ammatory effects of curcumin [45] . Curcumin induces gene expression of peroxisome proliferator-• activated receptor- γ (PPAR- γ ): The PPAR- γ is a member of the nuclear receptor superfamily of ligand-dependent transcription
factors. It inhibits gene expression by antagonizing the activities of the transcription factors such as NF- κ B. PPAR- γ and locally produced prostaglandin D 2 metabolites are involved in the regulation of infl ammatory responses. PPAR- γ agonists such as curcumin suppress monocyte elab-oration of infl ammatory cytokines [48] .
4.7.2 The mechanistics of therapeutic benefi ts in cataract The etiology of cataract is not fully understood; however, evidence suggests that oxidative damage to the constituents of eye is the major mechanism behind initiation and progression of cataract. Increased oxidative stress as observed in diabetes leads to increased oxidation of DNA, proteins and lipids leading to elevated levels of oxidized products that play an important role in the pathogenesis of cataract [23,49] . The therapeutic benefits of treatment with C. longa in cataract
Inhibits activation of PMNL,monocytes, macrophages
Inhibits production ofcytokines
Inhibits production of ROS
Inhibits lenticular lipidoxidation
Inhibits lenticular proteinoxidation
Maintains crystallineprofile
Maintains antioxidantenzyme levels
Normalizes retinalMetabolic abnormalities
Curcumin fromCurcuma longa
Inhibits activation ofpolyol pathway
Inhibits activation ofVEGF
Inhibits expression ofproapoptotic factors
Inhibits expression ofadhesion molecules
Inhibits expression ofLOX, COX
Inhibits, downregulatesNF-κB
Suppresses activation ofMAPKs
Suppresses activation ofPPAR-γ
Prevents leukostasis,retinal ischemia
Inhibits expression ofiNOS
OHHO
O O
H3COOCH3
Figure 2 . Multiple effects of Curcuma longa contributing to its therapeutic potential in ophthalmic diseases. iNOS: Inducible nitric oxide synthase; LOX: Lipooxygenase; PMNL: Polymorphonuclear leukocytes; PPAR: Peroxisome proliferator-activated receptor; ROS: Reactive oxygen species.
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are largely owing to antioxidant effects. The scientific evidences showing potent antioxidant activity of C. longa have been presented by many researchers.
Curcumin prevents lenticular lipid peroxidation: Oxidative • stress leads to oxidation of lenticular lipids leading to accumulation of oxiproducts of fatty acyl content of lenticular lipids. The degree of cataractous opacity is directly related to the amount of lipid oxidation end products in the lens [50] . Curcumin prevents cataractogenesis by protecting against lipid peroxidation and this is evidenced by signifi cantly low TBARS levels in the eye lenses of curcumin or turmeric treated diabetic rats. Curcumin protects against excessive protein oxidation: • Excessive protein oxidation owing to oxidative stress, as induced by hyperglycemia, leads to increased levels of protein carbonyl contents and reduced protein sulfhydryls. Change in protein profi le and increased proportion of insoluble protein is considered the fi nal change leading to lens opacifi cation [51] . Curcumin or turmeric treatment preserves the lens protein profi le close to normal and thereby protects against development of cataract. Curcumin treatment results in normalization of aldose • reducatse and sorbitol dehydrogenase activity: Aldose reductase is a key enzyme in polyol pathway that converts glucose to sorbitol and subsequently sorbitol is converted to fructose by sorbitol dehydrogenase. Excessive quantity of sorbitol and fructose in eye lens causes osmotic trauma to lens epithelium and fi bers fi nally leading to cataractogenesis [52] . Curcumin by inhibiting the key enzymes of polyol pathway, that is, an ethanolic extract of C. Longa , was demonstrated to possess 75% aldose reductase inhibitory activity in vitro using bovine eye lenses [53] . Inhibition of sorbitol dehydrogenase has also been observed in alloxan-induced diabetic rats [30] . Inhibition of aldose reductase and sorbitol dehydrogenase by curcumin contributes signifi cantly to prevention of initiation and progression of cataract. Curcumin maintains the crystalline profi le of the eye lens: • A high glucose concentration in vivo or an increased glucose or glucose 6-phosphate concentration in vitro has been found to lead to the glycosylation of ε -amino groups of lysine residues in bovine and rat lens crystallins. In vitro , this glycosylation imparts an increased susceptibility of the crystallins to sulfhydryl oxidation. Disulfi de crosslinks result in the formation of high molecular mass aggre-gates and opalescence in the crystallin solutions. Curcumin protects against sulfhydryl oxidation, formation of crosslinks and high molecular mass aggregates and thereby cataract development [29] . Curcumin preserves the level of antioxidant enzymes: The • activity of antioxidant enzymes such as superoxide dismutase, catalase and glutathione- S -transferase (GST) is markedly reduced in cataractous lenses. Curcumin treatment results in increased activity of superoxide dismutase and catalase in sodium selenite-induced rat model of cataract. In
an in vitro experiment, curcumin treatment caused a signifi cant induction of the GST isozyme rGST8 – 8 in rat lens epithelium. As rGST8 – 8 utilizes 4-HNE as a preferred substrate, the protective effect of curcumin may possibly be mediated through the induction of this GST isozyme [32] .
4.7.3 The mechanistics of therapeutic benefi ts in diabetic retinopathy and glaucoma Hyperglycemia in diabetes is associated with formation of excessive amount of ROS and oxidative stress leading to retinal metabolic abnormalities. The retinal metabolic abnormalities include elevated polyol pathway activity, increased nonenzymatic glycation and AGEs, and increased PKC activity. These metabolic abnormalities are believed to finally lead to the development of diabetic retinopathy. Several mechanisms involved in therapeutic effects of C. longa in diabetic retinopathy have been investigated and include the following:
Curcumin prevents retinal metabolic abnormalities: The • effi cacy of curcumin in prevention of diabetic retinopathy is owing to potent free radical scavenging property and prevention of lipid peroxidation as evidenced by several parameters mentioned above. Curcumin reduces oxidative stress and inhibits release of • proinfl ammatory cytokines: The vascular changes in diabetic retinopathy are comparable to low grade infl ammatory condition. The levels of cytokines, including IL-1 β , IL-6 and IL-8, are increased in the vitreous of patients with proliferative diabetic retinopathy and in the retina from diabetic rats and mice [54-56] . Some of the early changes in diabetic retinopathy include retinal capillaries ischemia, leukostasis and plugs of platelet–fi brin thrombi. Curcumin, a compound with both anti-infl ammatory and antioxidant properties, prevents diabetes-induced increase in ILs. This suggests that curcumin could inhibit the development of diabetic retinopathy by inhibiting both proinfl ammatory cytokines and oxidative stress [39] . Curcumin suppresses expression of NF- • κ B and proapoptotic factors: the proinfl ammatory changes such as elevated IL-1 β levels stimulate NF- κ B activation, which is a redox sensitive key regulator of antioxidant enzymes and initiates transcription of many genes associated with apoptosis. Apoptosis in retinal capillaries leads to increased capillary permeability. Curcumin inhibits the activation of NF- κ B, accumulation of 8-OhdG and nitrotyrosine in the retina in diabetes [39] . This raises a possibility that curcumin can inhibit apoptosis of retinal capillary cells, a predictor of the development of diabetic retinopathy [57] . Curcumin inhibits activation of VEGF: Oxidative stress • and ischemia associated with proinfl ammatory changes leads to activation of angiogenic factor and VEGF, which is responsible for capillary growth, neovascularization and increased capillary permeability seen in diabetic retinopathy.
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Curcumin can abolish IL-18-induced increase in VEGF production, thereby inhibiting key retinal abnormalities of diabetic retinopathy [39,58-60] . Curcumin inhibits SDF-1 • α -induced migration of HRECs: The SDF-1 α and a G-protein-coupled receptor CXCR4 play a pivotal role in regulating migration of HREC. Curcumin causes upstream blockage of Ca 2+ infl ux and subsequent downstream decreased expression of Phopho AKT, Phospho phosphotidylinositol-3-kinase, which are vital proteins responsible for HREC migration [42] . Curcumin blocks release of TNF- • α : Retinal metabolic stress in diabetes leads to accumulation of AGEs that activate retinal microglia cells and enhance expression and secretion of TNF- α through enhanced formation of intracellular ROS, MAPK (ERK1/2, p38, JNK) and NF- κ B mediate the AGEs-induced TNF- α release in retinal microglia [61] . Curcumin inhibits the expression of TNF- α and suppresses expression of MAPK and NF- κ B. Curcumin inhibits production of cell adhesion molecules: • Upregulation of retinal COX-2 and TNF- α in early stages of diabetic retinopathy induces production of various cell adhesion proteins such as intercellular adhesion molecule-1 [62] on the endothelial cells. Cell adhesion molecules favor leukocyte adhesion to retinal vasculature and lead to breakdown of blood–retinal barrier, capillary nonperfusion, endothelial cell injury and death. Curcumin acts by inhibiting the expression of COX-2 and cell adhesion molecules. Curcumin might be neuroprotective in glaucoma: • Oxidative stress [63] , enhanced expression of TNF- α [64,65] , inducible nitric oxide synthase [66,67] and NMDA-mediated cytotoxicity [68] play a crucial role in retinal ganglion cell apoptosis observed in glaucomatous optic neuropathy. As curcumin affects all of these parameters, it seems to have therapeutic potential as an antiglaucoma agent.
5. Conclusion
Benefits of C. longa have long been realized in a wide spectrum of therapeutic areas. To substantiate its benefits described in traditional medicine, enormous amount of scientific evidences are now available from preclinical and clinical researches. Curcuminoids are the major biologically active constituents and their potent anti-inflammatory and antioxidant properties form the basis of its multiple therapeutic uses in ophthalmic conditions. Although the putative mechanism(s), molecular targets and range of therapeutic applications have been researched widely, further investigations are needed to explore the true therapeutic potential and future of curcuminoids as novel drug molecules in ophthalmic diseases.
6. Expert opinion
For thousands of years, natural products have played an important role in treating and preventing human disease. Some of the ophthalmic diseases such as uveitis, diabetic retinopathy, cataract and glaucoma are major public health problems contributing significantly to morbidity, primarily due to non-availability of safe and effective pharmacotherapy. As the historical experiences with plants as therapeutic tools have helped in introducing new chemical entities in modern medicine for treatment of various diseases, systematic investigations are expected to discover effective therapeutic agents for treatment of ophthalmic diseases as well.
Curcuma longa is one such plant known for centuries for its therapeutic benefits. Investigations have revealed that curcuminoids are biologically active phytochemicals and curcumin is the primary physiologically active molecule. Anti-inflammatory and antioxidant properties, which form the basis for most therapeutic benefits, have extensively been researched mainly in experimental studies and also in a few clinical studies. Despite encouraging results from these studies, curcuminoids have still not been recognized as novel drugs for potential therapeutic uses especially for the management of ophthalmic diseases. This may be partly explained by the fact that investigations done so far have been performed primarily in experimental studies. The evidences made available by experimental studies need to be confirmed in well-designed prospective intervention trials. Besides, further studies are required to understand the fate of drug after topical application in healthy and diseased eyes. Studies to reveal ocular pharmaco-kinetic and pharmacodynamic properties of curcumin are of prime importance. Studies are also needed to investigate the extent of ocular availability of curcumin after systemic adminis-tration. The bioavailability of curcumin is very poor as it gets metabolized quickly in gut and liver after oral administration. Therefore, it becomes imperative to evaluate the biological activity of its metabolites using in vitro studies at concentrations observed after usual oral doses. Optimization of doses for various therapeutic uses is also an important issue. Besides, further investigations are required to explain the molecular mechanisms and the entire range of therapeutic uses.
Nonetheless, the existing minefield of scientific data from innumerable studies must be reanalyzed and reinterpreted and then be used to form the basis of future studies, which can clearly define the future of curcumin as a novel drug in the management of ophthalmic diseases.
Declaration of interest
The authors state no conflict of interest and have received no payment in preparation of this manuscript.
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Affi liation Renu Agarwal 1 , Suresh Kumar Gupta † 2 , Sushma Srivastava3 , Puneet Agarwal 4 & Shyam Sunder Agrawal5 † Author for correspondence 1 Faculty of Medicine Department of Pharmacology,Universiti Teknologi Mara, Kuala Lumpur, Malaysia 2 Emeritus Professor Delhi Institute of Pharmaceutical Sciences & Research, Pushp Vihar, Sector 3, MB Road, New Delhi 110017, India Tel: +91 11 20909468 ; Fax: +91 11 29554503 ; E-mail: [email protected][email protected] 3 Research ScientistDelhi Institute of Pharmaceutical Sciences & Research,Pushp Vihar, Sector 3, MB Road,New Delhi 110017, India4International Medical University, Department of Ophthalmology, Bukit Jalil, Kuala Lumpur, Malaysia5DirectorDelhi Institute of Pharmaceutical Sciences & Research,Pushp Vihar, Sector 3, MB Road,New Delhi 110017, India
