Curcumin is a polyphenol derived from the herbal remedy and dietary spice turmeric (Curcuma longa) used by men in the exage as medicinal remedy and spice. In the last decades the curcumin has been an object of multiple studies in vitro and in vivo that have established the scientific bases of their numerous therapeutic activities, emphasizing their powerful anti-inflammatory, anti-cancer and antioxidant properties. In the present work a revision of the anti-inflammatory mechanisms of action is made that include the inhibition of several cell signalling pathways at multiple levels and downregulates cellular enzyme like cyclooxygenase, lipoxygenase and nitric oxide synthase. Also the preclinical and clinical studies that have been carried out in this aspect are mentioned, the support, safety and efficiency of the curcumin used with analgesic and antiinflammatory purposes.
Key words: Curcumin, inflammation, pain, analgesia, anti-inflammatory effect.
The turmeric or curcumin (Curcuma longa) is an herbaceous plant that is grown in tropical regions of Asia, the rhizome or root of this plant contains certain compounds called curcuminoids as demethoxycurcumin1, bisdemethoxycurcumin and the most abundant of them, curcumin (dipherulioilmethane).2 This polyphenol is insoluble in water, unsteady at basic pH (transformed to pheruloilmethane and pheluric acid). Has a low oral biodisposition eliminated by feces 40-60%, the rest can be absorbed in its natural form or as curcumin, dihydrocurcumin and tetrahydrocurcumin resulting from the biotransformation is performed in liver and intestine by reduction, subsequently curcumin and its metabolites are biotransformed to conjugated monoglucuronics are excreted.3
Curcumin is a chemically B enol-diketone with two methoxylated phenols (Figure 1)
Curcumin has been used as a spice in curries such as food dye and as a medicinal remedy. In Indian traditional medicine used in the treatment of biliary disorders, cough, anorexia, liver disorders, pressure ulcers in patients with diabetes, rheumatism and sinusitis; applied through different routes of administration such as oral, topical and inhaled.4 In traditional Chinese medicine the main use is to treat diseases related to abdominal pain and jaundice.1
Figure 1. Chemical structure of curcumin and other Curcuminoids. (Taken from Mesa et al. 2000.)
Currently are being developed numerous studies have highlighted the pharmacological properties of curcumin as an anti-inflammatory4,5, antioxidant, immunomodulatory,6 antineoplasmic, hypolipidemic, antiviral, antiprotozoan, antifungal and antibacterial.5 Because of this broad spectrum of activity using curcumin has been successful in experimental treatment of some diseases such epidermoid carcinoma, colon carcinoma, liver neoplasms, various types of breast neoplasms, T and B cell leukemia, psoriasis, scleroderma, wound healing, muscle regeneration after a trauma, diabetes type II, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, inflammatory bowel disease, cystic fibrosis, HIV-1, salmonellosis, giardiasis, prevention of myocardial infarcts, atherosclerosis, liver injury (hepatoprotectant) among others.7
According to the anti-inflammatory activity, there are preclinical trials in rats and mice demonstrating in acute and chronic inflammation models that oral administration of curcumin is as effective as cortisone or phenylbutazone.8 It’s also effective when applied topically in the skin of rats to counteract irritation and inflammation associated with allergies and other skin inflammatory conditions.7
Clinical studies have been carried out confirm the promising results, Deodhar et al. studied the anti-inflammatory properties in patients with rheumatoid arthritis, using an orally dose of 1200 mg per day for two weeks, observed a decrease in stiffness and articular swelling similar to that generated by the phenylbutazone.9 In another study Satoskar et al. used 1200 mg per day orally for five days in patients with postoperative inflammation (hernia or hydrocele), evaluated the edema and tenderness of the spermatic cord and the site of operation, concluding that curcumin is effective in reducing these parameters.10 Lal et al. tested the efficacy of curcumin at an oral dose of 375 mg three times a day during twelve weeks in the management of chronic anterior uveitis, concluding that the efficacy and recurrence before the treatment are comparable with steroid therapy considered the standard therapy, being the absence of adverse effects of curcumin the main advantage.11 These same authors also evaluated the effect of curcumin in idiopathic inflammatory orbital pseudotumor, for which the above dosage was employed for a period of 6 to 22 months. Of the five patients who completed the study, four recovered completely and in one case the inflammation yielded but persisted some limitation of movement, reported no adverse effects or recurrence.12
Mechanisms by which curcumin exerts its anti-inflammatory effects are varied and include the inhibition in the incorporation of arachidonic acid to membrane phospholipids, with a consequent decrease at release.14, 15
It also has been demonstrated inhibition of nuclear factor κ-B (NF-κ B) and hence the decrease of pro-inflammatory cytokines such as interleukin 1B (IL 1-B), interleukin 8 (IL-8) and the tumor necrosis factor (TNF) as well as decreased expression of the cyclooxygenase 2 (COX 2) inducible enzymes and nitric oxide synthase (iNOS).16 However, it also has been found to have an inhibitory effect on the enzyme cyclooxygenase 1 (COX-1) which was recently shown, plays an important role in inflammation and carcinogenesis.17 Other mechanisms involved in the anti-inflammatory activity of curcumin are increased release of steroid hormones,18 the inhibition of lipooxygenase (LOX), and therefore decrease in leukotriene synthesis,19 inhibition in the production in human neutrophils of 5-hydroxy-eicosatetrainoic acid20 (5-HETE) and the reduction in neutrophil infiltration into tissues in inflammatory conditions.21
Indirectly, it was also found that by their strong free radical’s sweeper properties22 (generated by the para hydroxyl group and methoxy) and the ability to stabilize lysosomal membranes also contribute to anti-inflammatory effect.23
The curcumin antinociceptive activity has been shown in tail immersion and hot plate test in neuropathic pain models on diabetic mice.13 It’s believed that the decrease in pain perception is linked to the anti-inflammatory activity, however it has been recently postulated that the curcumin antinociceptive effect also involves activating opioid mechanisms.24
The antinociceptive effect of curcumin was recently evaluated on female Wistar rats, using the test of 1% formalin. The effect of diclofenac was used as a positive control. It was also evaluated the effect that glibenclamide could have, which is a potassium channel blocker ATP sensitive in the antinociceptive effects of curcumin and diclofenac. Finally, in this study, it was evaluated the degree of gastric damage after administration of drugs in different doses. It was demonstrated that curcumin generated a decreased dose dependent nociception, whose highest value (51%) exceeded the antinociception caused by diclofenac (39%). In evaluating the gastric mucosa was confirmed the absence of changes with curcumin, even at the highest dose (400 mg/kg) and was found a statistically significant decrease (p<0.05) in the antinociceptive effect of curcumin, when used in combination with glibenclamide. So it is concluded that the curcumin antinociceptive mechanism involves dependent potassium channels ATP. Moreover, was demonstrated that curcumin is gastric safer than diclofenac.
One of the most interesting features of curcumin is the absence of significant adverse effects at therapeutic doses being reported only gastric irritation.25 Overall curcumin has been classified as "generally recognized as safe" by the Food and Drug Administration.4
It is estimated that in India the average daily per capita consumption ranges from 60-100 mg/kg body weight,4 without the population revealed unwanted effects. Phase I clinical studies indicate that humans can tolerate doses as high as 8 g. per day for three months without adverse side effects.25
The turmeric extract and curcumin have been tested with the Ames test demonstrating that they are not mutagenic,4 however, there is a embryotoxicity and teratogenicity report on embryo zebrafish.26
There is some controversy in the use of curcumin and the generation of gastric ulcers, most of the authors coincide in attributing gastroprotective properties through mechanisms such as inhibiting IL-8 produced by Helicobacter pylori playing a significant role in ulcers and gastritis development,27 increase in mucin secretion,28 decrease in the production of gastric acid by blocking H2 receptors,29 downregulation of the 9 and 2 matrix metalloproteinase expression,30 as well as preventing the activity of peroxidase which decreases free radical production, but other authors report ulcerogenic activity by decrease in mucin secretion and increased gastric acid and/or pepsin secretion.31
Not recommended in patients with cholelithiasis because it can cause gallbladder contraction.32
The medicinal properties of curcumin are known to mankind since ancient times, but now they are getting to know the scientific basis for its numerous therapeutic effects by placing it as a promise in the treatment of a variety of diseases. As for its analgesic and anti-inflammatory activity, curcumin has the potential to be an alternative to nonsteroidal anti-inflammatory drugs (NSAIDs) which are currently worldwide widely-used but also responsible for important adverse effects, some of them fatal. They definitely require more research, but the results achieved so far placed curcumin as a cheap, safe and effective drug in the pain and inflammation treatment.
1 Ammon HP, Walh MA. Pharmacology of Curcuma longa. Planta Med. 1991; 57:1-7.
2 Srinivas L, Shalini VK, Shylaja M. Turmeric: a water soluble antioxidant peptide from turmeric (Curcuma longa). Arch. Biochem. Biophys. 1992;292: 617-623.
3 Pan MH, Huang TM, Lin JK. Biotransformation of curcumin through reduction and glucuronidation in mice Drug Metab. Dispos. 1999;27:486-494.
4 Nita Chainani-Wu. Safety and Anti-Inflammatory Activity of Curcumin: A Component of Tumeric (Curcuma longa). J. Altern. Complement Med. 2003; 1: 161–168.
5 Kohli K, Ali J, Ansari MJ, Raheman Z. Cucumin: A natural antiinflammatory agent. Indian J. Pharmacol. 2005; 37:141-147.
6 Mesa MD, Ramírez-Tortosa MC, Aguilera CM, Ramírez-Boscá A, Gil A. Efectos farmacológicos y nutricionales de los extractos de Curcuma longa y de los cucuminoides. Ars. Pharmaceutica, 2000; 41:3: 307-321.
7 Shishir Shishodia, Gautam Sethi and Bharat B. Aggarwal. Curcumin:Getting back to the roots. Ann. N.Y. Acad. Sci. 2005;1056:206-217.
8 Srimal RC, Dhawan BN. Pharmacology of diferuloyl methane (curcumin), a non-steroidal anti-inflammatory agent. J. Pharm. Pharmac. 1973; 25: 447-452.
9 Deodhar SD, Sethi R, Srimal RC. Preliminary study on antirheumatic activity of curcumin (Diferuloyl methane). Indian J. Med. Res. 1980; 71: 632-643.
10 Satoskar RR, Shah SJ, Shenoy SG. Evalaution of anti-inflammatory property of curcumin in patients with post operative inflammation. Int. J. Clin. Pharmacol. Ther. Toxicol. 1986; 24: 651-654.
11 Lal B, Kapoor AK, Asthana OP, Agrawal PK, Prasad R, Kumar P. Efficacy of curcumin in the management of chronic anterior uveitis. Phytother. Res. 1999; 13: 318-322.
12 Lal B, Kapoor AK, Agrawal PK, Asthana OP, Srimal RC. Role of curcumin in idiophatic inflammatory orbital pseudotumors.Phytother. Res. 2000;14: 443-447.
13 Sharma S, Kulkarni SK, Agrewala JN, Chopra K. Curcumin attenuates thermal hyperalgesia in a diabetic mouse model of neuropathic pain. Eur. J. Pharmacol. 2006; 536: 256-261.
14 Sirvastava KC, Bordia A, Verma SK. Curcumin, a major component of food spice turmeric (Curcuma longa) inhibits aggregation an alters eicosanoid metabolism in human blood platelets. Prostaglandins Leukot. Essent. Fatty Acids. 1995 ; 52: 223-227.
15 Conney AH, Lysz T, Ferraro T, Abidi TF, Manchand PS.Inhibitory effectof curcumin and some related dietary compounds on tumor promotion and arachidonic acid metabolism in mouse skin. Adv. Enzyme Regul. 1991; 31: 385-396.
16 Jobin C, Bradham CA, Russo MP, Juma B, Narula AS, Brenner DA, Sartor RB. Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. J. Immunol. 1999; 163:3474-3483.
17 Handler N, Jaeger W, Puschacher H, Leisser K, Erker T. Synthesis of novel curcumin analogues and their evaluation as selective cyclooxygenase-1 (COX-1) inhibitors. Chem. Pharm. Bull. (Tokyo). 2007; 55: 64-71.
18 Sirvastava R, Srimal RC. Modification of certain inflammation-induced biochemical changes by crcumin. Indian J. Med. Res. 1985; 81: 215-223.
19 Huang MT, Lysz T, Ferraro T, Abidi TF, Laskin JD. Inhibitory effects of curcumin on in vitro lipoxigenase and ciclooxigenase activities in mouse epidermis. Cancer Res. 1991; 51: 813-819.
20 Flynn DL, Rafferty MF, Boctor AM. Inhibition of 5-hydroxy-eicosatetraenoico acid (5-HETE) formation in intact human neutrophils by naturally-occurring diarylheptanoids: Inhibitory activities of curcuminoids and yakuchinones. Prostaglandins Leukot. Med. 1986; 22: 357-360.
21 Lukita-Atmadja W, Ito Y, Baker GL, McCuskey RS. Effects of curcuminoids as anti-inflammatory agents on the hepatic microvascular response to endotoxin. Shock 2002; 17; 399-403.
22 Elizabeth K, Rao MNA. Oxygen radical scavening activity of curcunin. Int. J. Pharm. 1990; 58: 237-240.
23 Joe B, Lokesh BR. Effect of curcumin and capsaicin on arachidonic acid metabolism and lysosomal enzyme secretion by rat peritoneal macrophages. Lipids 1997; 32:1173-1180.
24 Tajik H, Tamaddonfard E, Hamzech-Gooshchi. Interaction between curcumin and opioid system in nthe formalin test. Pak. J. Biol. Sci. 2007; 10: 2538-2586.
25 Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001; 21:2895–2900.
26 Jheng-Yu WU, Chin-Yi Lin,Tien-Wei Lin,Chuian-Fu Ken,And Yu-Der Wen.Curcumin Affects Development of Zebrafish Embryo Biol. Pharm. Bull. 2007;30 :1336-1339.
27 Foryst-Ludwig A, Neumann M, Schneider-Brachert W, Naumann M. Curcumin blocks NF-kappaB and the motogenic response in Helicobacter pylori-infected epithelial cells. Biochem. Biophys. Res. Commun. 2004; 316:1065-1072.
28 Rafatullah S, Tariq M, Al-Yahya MA, Mossa JS, Ageel AM. Evaluation of turmeric (Curcuma longa) for gastric and duodenal antiulcer activity in rats. J. Ethnopharmacol. 1990; 29: 25-34.
29 Kim DC, Kim SH, Choi BH, Baek NI, Kim D, Kim MJ, Kim KT Curcuma longa extract protects against gastric ulcers by blocking H2 histamine receptors. Biol. Pharm. Bull. 2005; 28: 2220-2224.
30 Swarnakar S, Ganguly K, Kundu P, Banerjee A, Maity P, Sharma AV. Curcumin regulates expression and activity of matrix metalloproteinases 9 and 2 during prevention and healing of indomethacin-induced gastric ulcer. J. Biol. Chem. 2005; 280: 9409-9415.
31 Gupta B, Kulsherestha VK, Srivastava RK, Prasad DN. Mechanism of curcumin induced gastric ulcer in rats. Indian J Med. Res. 1980; 71: 806-814.
32 Rasyid A, Lelo A. The effect of curcumin and placebo on human gall-bladder function: An ultrasound study. Aliment. Pharmacol. Ther. 1999; 13: 245–249.
33 De Paz Campos MA. Valoración preclínica de la eficacia antiinflamatoria, antinociceptiva y seguridad gástrica de la curcumina (Cúrcuma longa). México, D.F.: CINVESTAV. IPN. 2009. Tesis para obtener el grado de Maestro en Ciencias.
[a]Pharmacology Department, Research and Advanced Studies Center from Instituto Politécnico Nacional, México, D.F., Mexico