Antinociceptive and Anti-Inflammatory Effects of Bixin, a Carotenoid Extracted from the Seeds of Bixa orellana

Abstract

Bixin is the main natural apocarotenoid extracted from the seeds of Bixa orellana, widely used as a cosmetic and textile colorant. Despite the description of several pharmacological properties of B. orellana extracts, little has been studied regarding the pharmacological properties of bixin. Then we aimed to investigate the potential anti-inflammatory and antinociceptive effect of bixin in preclinical models of inflammation and acute pain. The anti-inflammatory activity of bixin (15 or 30 mg/kg, orally) was determined using carrageenan-induced paw edema and the myeloperoxidase (MPO) activity in male Wistar rats. The antinociceptive effect of bixin was assessed in the formalin and hot plate tests in rats (at same doses) and in the acetic acid-induced writhing test in Swiss albino male mice (at doses of 27 or 53 mg/kg). General locomotor activity was evaluated in the open field test. Only the higher dose of bixin significantly decreased the carrageenan-induced paw edema and the MPO activity and increased the latency time in the hot plate. Both doses of bixin significantly reduced the number of flinches in both phases of the formalin test and the number of acetic acid-induced writhings without changing the locomotor performance in the open field test. This study validates the use of bixin as an anti-inflammatory trough mechanism related to the reduction of neutrophil migration. Furthermore, this is the first report showing the antinociceptive property of bixin, which does not appear to be related to the sedative effect. Further studies are necessary to characterize the mechanisms involved in these effects.

Key words

Bixa orellana - Bixaceae - inflammation - nociception - myeloperoxidase - carrageenan

• References

• 1 Vilar DA, Vilar MS, de Lima e Moura TF, Raffin FN, de Oliveira MR, Franco CF, de Athayde-Filho PF, Diniz MF, Barbosa-Filho JM. Traditional uses, chemical constituents, and biological activities of Bixa orellana L.: a review. ScientificWorldJournal 2014; 2014: 857292 doi:10.1155/2014/857292
• 2 Silva CR, Antunes LM, Bianchi ML. Antioxidant action of bixin against cisplatin-induced chromosome aberrations and lipid peroxidation in rats. Pharmacol Res 2001; 43: 561-566
• 3 Jondiko IJO, Pattenden G. Terpenoids and an apocarotenoid from seeds of Bixa orellana . Phytochemistry 1989; 28: 3159-3162
• 4 Tao S, Park SL, Vega D, Zhang DD, Wondrak GT. Free radical biology and medicine systemic administration of the apocarotenoid bixin protects skin against solar UV-induced damage through activation of NRF2. Free Radic Biol Med 2015; 89: 690-700
• 5 Chengaiah B, Rao KM, Kumar KM, Alagusundaram M, Chetty CM. Medicinal importance of natural dyes – a review. Int J PharmTech Res 2010; 2: 144-154
• 6 Ulbricht C, Windsor RC, Brigham A, Bryan JK, Conquer J, Costa D, Giese N, Guilford J, Higdon ERB, Holmes K, Isaac R, Jingst S, Kats J, Peery L, Rusie E, Savinainen A, Schoen T, Stock T, Tanguay-Colucci S, Weissner W. An Evidence-based systematic review of annatto (Bixa orellana L.) by the Natural Standard Research Collaboration. J Diet Suppl 2012; 9: 57-77
• 7 Benoit PS, Fong HH, Svoboda GH, Farmsworth NR. Biological and phytochemical evaluation of plants. XIV. Antiinflammatory evaluation of 163 species of plants. Lloydia 1976; 39: 160-171
• 8 Yoke Keong Y, Arifah AK, Sukardi S, Roslida AH, Somchit MN, Zuraini A. Bixa orellana leaves extract inhibits bradykinin-induced inflammation through suppression of nitric oxide production. Med Princ Pract 2011; 20: 142-146
• 9 Shilpi JA, Taufiq-Ur-Rahman M, Uddin SJ, Alam MS, Sadhu SK, Seidel V. Preliminary pharmacological screening of Bixa orellana L. leaves. J Ethnopharmacol 2006; 108: 264-271
• 10 Hernández-Ortega M, Ortiz-Moreno A, Hernández-Navarro MD, Chamorro-Cevallos G, Dorantes-Alvarez L, Necoechea-Mondragón H. Antioxidant, antinociceptive, and anti-inflammatory effects of carotenoids extracted from dried pepper (Capsicum annuum L.). J Biomed Biotechnol 2012; 2012: 524019
• 11 Boiko YA, Kravchenko IA, Shandra AA, Boiko IA. Extraction, identification and anti-inflammatory activity of carotenoids out of Capsicum Anuum L. J HerbMed Pharmacol 2017; 6: 10-15
• 12 Xu Z, Kong XQ. Bixin ameliorates high fat diet-induced cardiac injury in mice through inflammation and oxidative stress suppression. Biomed Pharmacother 2017; 89: 991-1004
• 13 Tao S, Rojo de la Vega M, Quijada H, Wondrak GT, Wang T, Garcia JG, Zhang DD. Bixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner. Sci Rep 2016; 6: 18760 doi:10.1038/srep18760
• 14 Pinzón-García AD, Cassini-Vieira P, Ribeiro CC, de Matos Jensen CE, Barcelos LS, Cortes ME, Sinisterra RD. Efficient cutaneous wound healing using bixin-loaded PCL nanofibers in diabetic mice. J Biomed Mater Res B Appl Biomater 2017; 105: 1938-1949
• 15 Levy LW, Regalado E, Navarrete S, Watkins RH. Bixin and norbixin in human plasma: determination and study of the absorption of a single dose of annatto food color. Analyst 1997; 122: 977-980
• 16 Food WHO. Safety evaluation of certain food additives and contaminants. Available at: http://www.inchem.org/documents/jecfa/jecmono/v52je03.htm%23abs Accessed August 12, 2019
• 17 Reddy MK, Alexander-Lindo RL, Nair MG. Relative inhibition of lipid peroxidation, cyclooxygenase enzymes, and human tumor cell proliferation by natural food colors. J Agric Food Chem 2005; 53: 9268-9273
• 18 Takahashi N, Goto T, Taimatsu A, Egawa K, Katoh S, Kusudo T, Sakamoto T, Ohyane C, Lee JY, Kim YI, Uemura T, Hirai S, Kawada T. Bixin regulates mRNA expression involved in adipogenesis and enhances insulin sensitivity in 3T3-L1 adipocytes through PPARγ activation. Biochem Biophys Res Commun 2009; 390: 1372-1376
• 19 Di Rosa M, Giroud JP, Willoughby DA. Studies of the mediators of the acute inflammatory response induced in rats in different sites by carrageenan and turpentine. J Pathol 1971; 104: 15-29
• 20 Vinegar R, Schreiber W, Hugo R. Biphasic development of carrageenan edema in rats. J Pharmacol Exp Ther 1968; 166: 96-103
• 21 Somacal S, Figueiredo CG, Quatrin A, Ruviaro AR, Conte L, Augusti PR, Roehrs M, Denardin IT, Kasten J, da Veiga ML, Duarte MMF, Emanuelli T. The antiatherogenic effect of bixin in hypercholesterolemic rabbits is associated to the improvement of lipid profile and to its antioxidant and anti-inflammatory effects. Mol Cell Biochem 2015; 403: 243-253
• 22 Tao S, Park SL, Rojo de la Vega M, Zhang DD, Wondrak GT. Systemic administration of the apocarotenoid bixin protects skin against solar UV-induced damage through activation of NRF2. Free Radic Biol Med 2015; 89: 690-700
• 23 Tjølsen A, Berge OG, Hunskaar S, Rosland JH, Hole K. The formalin test: an evaluation of the method. Pain 1992; 51: 5-17
• 24 Dubuisson D, Dennis SG. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 1977; 4: 161-174
• 25 Malmberg AB, Yaksh TL. Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat. J Pharmacol Exp Ther 1992; 263: 136-146
• 26 Berkenkopf JW, Weichman BM. Production of prostacyclin in mice following intraperitoneal injection of acetic acid, phenylbenzoquinone and zymosan: its role in the writhing response. Prostaglandins 1988; 36: 693-709
• 27 Ribeiro RA, Vale ML, Thomazzi SM, Paschoalato ABP, Poole S, Ferreira SH, Cunha FQ. Involvement of resident macrophages and mast cells in the writhing nociceptive response induced by zymosan and acetic acid in mice. Eur J Pharmacol 2000; 3: 111-118
• 28 Deraedt R, Jouquey S, Delevallée F, Flahaut M. Release of prostaglandins E and F in an algogenic reaction and its inhibition. Eur J Pharmacol 1980; 61: 17-24
• 29 Tolone G. Prostaglandin production by human polymorphonuclear leucocytes during phagocytosis in vitro . Experientia 1977; 519: 961-962
• 30 Russell EA, Lynch PB, OʼSullivan K, Kerry JP. Dietary supplementation of alpha-tocopheryl acetate on alpha-tocopherol levels in duck tissues and its influence on meat storage stability. Int J Food Sci Technol 2004; 39: 331-340
• 31 Pinzón-García AD, Cassini-Vieira P, Ribeiro CC, Eduardo C, Jensen DM, Barcelos LS, Cortes ME, Sinisterra RD. Efficient cutaneous wound healing using bixin-loaded PCL nanofibers in diabetic mice. J Biomed Mater Res B Appl Biomater 2016; 105: 1-12
• 32 Ballou LR, Botting RM, Goorha S, Zhang J, Vane JR. Nociception in cyclooxygenase isozyme-deficient mice. Proc Natl Acad Sci 2000; 97: 10272-10276
• 33 Petenate AJ, Rodrigues LM, Alca SC, Meireles MAA. Bixin extraction from defatted annatto seeds. Comptes Rendus Chimie 2014; 17: 268-283
• 34 Golin SD, Garcia CER, Barreira SMW, Bednarczuk VO, Strapasson GC, Zuchetto M, Miguel OG. Teor de bixina em duas variedades de Bixa orellana L. cultivadas no Paraná. Visão acadêmica 2013; 14: 37-48
• 35 Rehbein J, Dietrich B, Grynbaum MD, Hentschel P, Holtin K, Kuehnle M, Schuler P, Bayer M, Albert K. Characterization of bixin by LC-MS and LC-NMR. J Sep Sci 2007; 30: 2382-2390
• 36 Noppe H, Abuín Martinez S, Verheyden K, Van Loco J, Companyó Beltran R, De Brabander HF. Determination of bixin and norbixin in meat using liquid chromatography and photodiode array detection. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2009; 26: 17-24
• 37 Scotter MJ, Thorpe SA, Reynolds SL, Wilson LA, Strutt PR. Characterization of the principal colouring components of annatto using high performance liquid chromatography with photodiode-array detection. Food Addit Contam 1994; 11: 301-315
• 38 Freitas GC, Carregaro AB. Aplicabilidade da extrapolação alométrica em protocolos terapêuticos para animais selvagens. Ciência Rural 2013; 43: 297-304
• 39 Tannenbaum J, Bennett BT. Russell and Burchʼs 3Rs then and now: the need for clarity in definition and purpose. J Am Assoc Lab Anim Sci 2015; 54: 120-132
• 40 Venâncio AM, Onofre AS, Lira AF, Alves PB, Blank AF, Antoniolli AR, Marchioro M, Estevam Cdos S, de Araujo BS. Chemical composition, acute toxicity, and antinociceptive activity of the essential oil of a plant breeding cultivar of basil (Ocimum basilicum L.). Planta Med 2011; 77: 825-829
• 41 Dos Santos GC, Gomes GA, Gonçalves GM, de Sousa LM, Santiago GM, de Carvalho MG, Marinho BG. Essential oil from Myrcia ovata: chemical composition, antinociceptive and anti-inflammatory properties in mice. Planta Med 2014; 80: 1588-1596
• 42 Hirota BCK, Paula CDS, De Oliveira VB, Da Cunha JM, Schreiber AK, Ocampos FMM, Barison A, Miguel OG, Miguel MD. Phytochemical and antinociceptive, anti-inflammatory, and antioxidant studies of smilax larvata (Smilacaceae). Evid Based Complement Alternat Med 2016; 2016: 9894610
• 43 De Young LM, Kheifets JB, Ballaron SJ, Young JM. Edema and cell infiltration in the phorbol ester-treated mouse ear are temporally separate and can be differentially modulated by pharmacologic agents. Agents Actions 1989; 26: 335-341
• 44 Mothana RAA, Al-Said MS, Al-Rehaily AJ, Thabet TM, Awad NA, Lalk M, Lindequist U. Anti-inflammatory, antinociceptive, antipyretic and antioxidant activities and phenolic constituents from Loranthus regularis Steud. ex Sprague. Food Chem 2012; 130: 344-349
• 45 Meotti FC, Luiz AP, Pizzolatti MG, Kassuya CA, Calixto JB, Santos AR. Analysis of the antinociceptive effect of the flavonoid myricitrin: evidence for a Role of the arginine-nitric oxide and protein kinase C pathways. J Pharmacol Exp Ther 2006; 316: 789-796