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Published in: Inflammopharmacology 5/2011

01-10-2011 | Research Article

Anti-inflammatory and antihyperalgesic effects of the combination of ibuprofen and hemin in adjuvant-induced arthritis in the Wistar rat

Authors: Shamsherjit Kaur, Krishna Reddy V. Bijjem, Pyare Lal Sharma

Published in: Inflammopharmacology | Issue 5/2011

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Abstract

Aim

Although, pharmacological activation of heme oxygenase (HO)-1 has shown to produce ameliorative effects in various experimental models of inflammation, but such beneficial effects have not been observed in adjuvant-induced arthritis. Further, the upregulated activity of HO-1 has been implicated in the pathogenesis of adjuvant arthritis. The present study was designed to investigate the anti-inflammatory and antihyperalgesic effects of the prophylactic use of hemin alone and/or in combination with ibuprofen using adjuvant-induced arthritis in Wistar rat.

Methods

Arthritis was induced by an intradermal injection of complete Freund’s adjuvant (CFA) into left hind paw. Paw volume, thermal hyperalgesia, mechanical allodynia, joint stiffness and mobility behaviors (score) were measured.

Results

Administration of ibuprofen (8.75, 17.5, 35 mg/kg/day, p.o.) and hemin (1, 5, 10 mg/kg/day, i.p.) were significantly effective in suppressing CFA-induced paw oedema, thermal and mechanical hyperalgesia, joint stiffness and mobility. The combination of low doses of ibuprofen (8.75 mg/kg, p.o.) and hemin (1 mg/kg, i.p.) significantly reduced paw volume, thermal and mechanical hyperalgesia, as compared to the individual dose of the ibuprofen and hemin alone.

Conclusions

Hence, it may be concluded that the prophylactic administration of either hemin produced significantly enhanced anti-inflammatory and analgesic effects. Further, concurrent low dose administration of hemin and ibuprofen produced significantly enhanced anti-inflammatory and analgesic effects, as compared to the either treatment alone, in CFA-induced arthritis in Wistar rats.
Literature
go back to reference Abraham NG, Kappas A (2008) A pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60:79–127PubMedCrossRef Abraham NG, Kappas A (2008) A pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60:79–127PubMedCrossRef
go back to reference Aburada M, Tanaka K, Hocino T et al (2006) Heme oxygenase-1 protects gastric mucosal cells against non-steroidal anti-inflammatory drugs. J Biol Chem 281:33422–33432CrossRef Aburada M, Tanaka K, Hocino T et al (2006) Heme oxygenase-1 protects gastric mucosal cells against non-steroidal anti-inflammatory drugs. J Biol Chem 281:33422–33432CrossRef
go back to reference Alcaraz MJ, Fernandez P, Guillen MI (2003) Anti-inflammatory actions of the heme oxygenase-1 pathway. Curr Pharm Des 9:2541–2551PubMedCrossRef Alcaraz MJ, Fernandez P, Guillen MI (2003) Anti-inflammatory actions of the heme oxygenase-1 pathway. Curr Pharm Des 9:2541–2551PubMedCrossRef
go back to reference Anderson KE, Collins S (2006) Open-label study of hemin for acute porphyria: clinical, practice implications. Am J Med 119(801):e19–e24PubMed Anderson KE, Collins S (2006) Open-label study of hemin for acute porphyria: clinical, practice implications. Am J Med 119(801):e19–e24PubMed
go back to reference Arévalo MI, Escribano E, Calpena A et al (2003) Thermal hyperalgesia and light touch allodynia after intradermal Mycobacterium butyricum administration in rat. Inflammation 27:293–299PubMedCrossRef Arévalo MI, Escribano E, Calpena A et al (2003) Thermal hyperalgesia and light touch allodynia after intradermal Mycobacterium butyricum administration in rat. Inflammation 27:293–299PubMedCrossRef
go back to reference Bae SC, Kim SJ, Sung MK (2003) Inadequate antioxidant nutrient intake and altered plasma antioxidant status of rheumatoid arthritis patients. J Am Coll Nutr 22:311–315PubMed Bae SC, Kim SJ, Sung MK (2003) Inadequate antioxidant nutrient intake and altered plasma antioxidant status of rheumatoid arthritis patients. J Am Coll Nutr 22:311–315PubMed
go back to reference Bandt MD, Grossin M, Driss F et al (2002) Vitamin E uncouples joint destruction and clinical inflammation in a transgenic mouse model of rheumatoid arthritis. Arthritis Rheum 46:522–532PubMedCrossRef Bandt MD, Grossin M, Driss F et al (2002) Vitamin E uncouples joint destruction and clinical inflammation in a transgenic mouse model of rheumatoid arthritis. Arthritis Rheum 46:522–532PubMedCrossRef
go back to reference Benallaoua M, François M, Batteux F et al (2007) Pharmacologic induction of heme oxygenase 1 reduces acute inflammatory arthritis in mice. Arthritis Rheum 56:2585–2594PubMedCrossRef Benallaoua M, François M, Batteux F et al (2007) Pharmacologic induction of heme oxygenase 1 reduces acute inflammatory arthritis in mice. Arthritis Rheum 56:2585–2594PubMedCrossRef
go back to reference Bertorelli R, Corradini L, Rafiq K et al (1999) Nociceptin and the ORL-1 ligand [Phe1ψ (CH2–NH) Gly2]nociceptin(1–13)NH2 exert antiopioid effects in the Freund’s adjuvant-induced arthritic rat model of chronic pain. Br J Pharmacol 128:1252–1258PubMedCrossRef Bertorelli R, Corradini L, Rafiq K et al (1999) Nociceptin and the ORL-1 ligand [Phe1ψ (CH2–NH) Gly2]nociceptin(1–13)NH2 exert antiopioid effects in the Freund’s adjuvant-induced arthritic rat model of chronic pain. Br J Pharmacol 128:1252–1258PubMedCrossRef
go back to reference Bickel A, Dorfs S, Schmelzm M, Forster C, Uhl W, Handwerker HO (1998) Effects of antihyperalgesic drugs on experimentally induced hyperalgesia in man. Pain 76:317–325PubMedCrossRef Bickel A, Dorfs S, Schmelzm M, Forster C, Uhl W, Handwerker HO (1998) Effects of antihyperalgesic drugs on experimentally induced hyperalgesia in man. Pain 76:317–325PubMedCrossRef
go back to reference Butler SH, Godefroy F, Besson JM et al (1992) A limited arthritic model for chronic pain studies in the rat. Pain 48:73–81PubMedCrossRef Butler SH, Godefroy F, Besson JM et al (1992) A limited arthritic model for chronic pain studies in the rat. Pain 48:73–81PubMedCrossRef
go back to reference Chiba T, Sato K, Kudara N et al (2008) Upper gastrointestinal disorders induced by non-steroidal anti-inflammatory drugs. Inflammopharmacol 16:16–20CrossRef Chiba T, Sato K, Kudara N et al (2008) Upper gastrointestinal disorders induced by non-steroidal anti-inflammatory drugs. Inflammopharmacol 16:16–20CrossRef
go back to reference Dayer JM, Choy E (2010) Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology 49:15–24PubMedCrossRef Dayer JM, Choy E (2010) Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology 49:15–24PubMedCrossRef
go back to reference Devesa I, Ferrándiz ML, Guillén I et al (2005a) Potential role of heme oxygenase-1 in the progression of rat adjuvant arthritis. Lab Invest 85:34–44PubMed Devesa I, Ferrándiz ML, Guillén I et al (2005a) Potential role of heme oxygenase-1 in the progression of rat adjuvant arthritis. Lab Invest 85:34–44PubMed
go back to reference Devesa I, Ferrándiz ML, Busserolles J et al (2005b) Effects of heme oxygenase-1 inducers on established rat adjuvant arthritis. Cell Mol Biol (Noisy-le-grand) 51:479–485 Devesa I, Ferrándiz ML, Busserolles J et al (2005b) Effects of heme oxygenase-1 inducers on established rat adjuvant arthritis. Cell Mol Biol (Noisy-le-grand) 51:479–485
go back to reference Fouad AA, Yacoubi MT, El-Bidawy MH (2009) Therapeutic potential of hemin in acetaminophen nephrotoxicity in rats. Environ Toxicol Pharmacol 27:277–282PubMedCrossRef Fouad AA, Yacoubi MT, El-Bidawy MH (2009) Therapeutic potential of hemin in acetaminophen nephrotoxicity in rats. Environ Toxicol Pharmacol 27:277–282PubMedCrossRef
go back to reference Gambaro G, Perazella MA (2003) Adverse renal effects of anti-inflammatory agents: evaluation of selective and nonselective cyclooxygenase inhibitors. J Intern Med 253:643–652PubMedCrossRef Gambaro G, Perazella MA (2003) Adverse renal effects of anti-inflammatory agents: evaluation of selective and nonselective cyclooxygenase inhibitors. J Intern Med 253:643–652PubMedCrossRef
go back to reference Greenwald RA (1991) Animal models for evaluation of arthritis drugs. Methods Find Exp Clin Pharmacol 13:75–83PubMed Greenwald RA (1991) Animal models for evaluation of arthritis drugs. Methods Find Exp Clin Pharmacol 13:75–83PubMed
go back to reference Grosser N, Hemmerle A, Berndt G et al (2004) The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells. Free Radic Biol Med 37:2064–2071PubMedCrossRef Grosser N, Hemmerle A, Berndt G et al (2004) The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells. Free Radic Biol Med 37:2064–2071PubMedCrossRef
go back to reference Hargreaves K, Dubner R, Brown F et al (1998) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–88CrossRef Hargreaves K, Dubner R, Brown F et al (1998) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–88CrossRef
go back to reference Horvath K, Varga C, Berko A et al (2008) The involvement of heme oxygenase-1 activity in the therapeutic actions of 5-aminosalicylic acid in rat colitis. Eur J Pharmacol 581:315–323PubMedCrossRef Horvath K, Varga C, Berko A et al (2008) The involvement of heme oxygenase-1 activity in the therapeutic actions of 5-aminosalicylic acid in rat colitis. Eur J Pharmacol 581:315–323PubMedCrossRef
go back to reference James MW, Hawkey CJ (2003) Assessment of non-steroidal anti-inflammatory drug (NSAID) damage in the human gastrointestinal tract. Br J Clin Pharmacol 56:146–155PubMedCrossRef James MW, Hawkey CJ (2003) Assessment of non-steroidal anti-inflammatory drug (NSAID) damage in the human gastrointestinal tract. Br J Clin Pharmacol 56:146–155PubMedCrossRef
go back to reference Kean WF, Buchanan WW (2005) The use of NSAIDs in rheumatic disorders 2005: a global perspective. Inflammopharmacol 13:343–370CrossRef Kean WF, Buchanan WW (2005) The use of NSAIDs in rheumatic disorders 2005: a global perspective. Inflammopharmacol 13:343–370CrossRef
go back to reference Kean WF, Buchanan WW, Rainsford KD (1999) Therapeutics of ibuprofen in rheumatic and other chronic and painful diseases. In: Rainsford KD (ed) Ibuprofen, a critical bibliographic review. Taylor & Francis, London, pp 279–353 Kean WF, Buchanan WW, Rainsford KD (1999) Therapeutics of ibuprofen in rheumatic and other chronic and painful diseases. In: Rainsford KD (ed) Ibuprofen, a critical bibliographic review. Taylor & Francis, London, pp 279–353
go back to reference Kilo S, Forster C, Geisslinger G et al (1995) Inflammatory models of cutaneous hyperalgesia are sensitive to effects of ibuprofen in man. Pain 62:187–193PubMedCrossRef Kilo S, Forster C, Geisslinger G et al (1995) Inflammatory models of cutaneous hyperalgesia are sensitive to effects of ibuprofen in man. Pain 62:187–193PubMedCrossRef
go back to reference Kumar G, Hota D, Nahar Saikia U (2010) Evaluation of analgesic efficacy, gastrotoxicity and nephrotoxicity of fixed-dose combinations of nonselective, preferential and selective cyclooxygenase inhibitors with paracetamol in rats. Exp Toxicol Pathol 62:653–662PubMedCrossRef Kumar G, Hota D, Nahar Saikia U (2010) Evaluation of analgesic efficacy, gastrotoxicity and nephrotoxicity of fixed-dose combinations of nonselective, preferential and selective cyclooxygenase inhibitors with paracetamol in rats. Exp Toxicol Pathol 62:653–662PubMedCrossRef
go back to reference Lee TS, Chang CC, Zhu Y et al (2004) Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection. Circulation 110:1296–1302PubMedCrossRef Lee TS, Chang CC, Zhu Y et al (2004) Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection. Circulation 110:1296–1302PubMedCrossRef
go back to reference Meregalli C, Canta A, Carozzi VA et al (2010) Bortezomib-induced painful neuropathy in rats: a behavioral, neurophysiological and pathological study in rats. Eur J Pain 14:343–350PubMedCrossRef Meregalli C, Canta A, Carozzi VA et al (2010) Bortezomib-induced painful neuropathy in rats: a behavioral, neurophysiological and pathological study in rats. Eur J Pain 14:343–350PubMedCrossRef
go back to reference Nagakura Y, Okada M, Kohara A et al (2003) Allodynia and hyperalgesia in adjuvant-induced arthritic rats: time course of progression and efficacy of analgesics. J Pharmacol Exp Ther 306:490–497PubMedCrossRef Nagakura Y, Okada M, Kohara A et al (2003) Allodynia and hyperalgesia in adjuvant-induced arthritic rats: time course of progression and efficacy of analgesics. J Pharmacol Exp Ther 306:490–497PubMedCrossRef
go back to reference Nakamichi I, Habtezion A, Zhong B et al (2005) Hemin activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction. J Clin Invest 115:3007–3014PubMedCrossRef Nakamichi I, Habtezion A, Zhong B et al (2005) Hemin activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction. J Clin Invest 115:3007–3014PubMedCrossRef
go back to reference Ozkan Y, Yardy′m-Akaydy′n S, Sepici A et al (2007) Oxidative status in rheumatoid arthritis. Clin Rheumatol l26:64–68CrossRef Ozkan Y, Yardy′m-Akaydy′n S, Sepici A et al (2007) Oxidative status in rheumatoid arthritis. Clin Rheumatol l26:64–68CrossRef
go back to reference Paine A, Eiz-Vesper B, Blasczyk R et al (2010) Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential. Biochem Pharmacol 80:1895–1903PubMedCrossRef Paine A, Eiz-Vesper B, Blasczyk R et al (2010) Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential. Biochem Pharmacol 80:1895–1903PubMedCrossRef
go back to reference Paredes S, Girona J, Hurt-Camejo E et al (2002) Antioxidant vitamins and lipid peroxidation in patients with rheumatoid arthritis: association with inflammatory markers. J Rheumatol 29:2271–2277PubMed Paredes S, Girona J, Hurt-Camejo E et al (2002) Antioxidant vitamins and lipid peroxidation in patients with rheumatoid arthritis: association with inflammatory markers. J Rheumatol 29:2271–2277PubMed
go back to reference Paul G, Bataille F, Obermeier F et al (2005) Analysis of intestinal heme-oxygenase-1 (HO-1) in clinical and experimental colitis. Clin Exp Immunol 140:547–555PubMedCrossRef Paul G, Bataille F, Obermeier F et al (2005) Analysis of intestinal heme-oxygenase-1 (HO-1) in clinical and experimental colitis. Clin Exp Immunol 140:547–555PubMedCrossRef
go back to reference Rahman I, Biswas SK, Kirkham PA et al (2006) Regulation of inflammation and redox signaling by dietary polyphenols. Biochem Pharmacol 72:1439–1452PubMedCrossRef Rahman I, Biswas SK, Kirkham PA et al (2006) Regulation of inflammation and redox signaling by dietary polyphenols. Biochem Pharmacol 72:1439–1452PubMedCrossRef
go back to reference Rainsford KD (2009) Ibuprofen: pharmacology, efficacy and safety. Inflammopharmacol 17:275–342CrossRef Rainsford KD (2009) Ibuprofen: pharmacology, efficacy and safety. Inflammopharmacol 17:275–342CrossRef
go back to reference Sandhu GK, Heyneman CA (2004) Nephrotoxic potential of selective cyclooxygenase-2 inhibitors. Ann Pharmacother 38:700–704PubMedCrossRef Sandhu GK, Heyneman CA (2004) Nephrotoxic potential of selective cyclooxygenase-2 inhibitors. Ann Pharmacother 38:700–704PubMedCrossRef
go back to reference Shinghu M, Takahashi S, Ito M et al (1994) Anti-inflammatory effects of recombinant human manganese superoxide dismutase on adjuvant arthritis in rats. Rheumatol Int 14:77–81CrossRef Shinghu M, Takahashi S, Ito M et al (1994) Anti-inflammatory effects of recombinant human manganese superoxide dismutase on adjuvant arthritis in rats. Rheumatol Int 14:77–81CrossRef
go back to reference Silvana M, Caparroz-Assef A, Ciomar A et al (2007) The metabolic changes caused by dexamethasone in the adjuvant-induced arthritic rat. Mol Cell Biochem 302:87–98CrossRef Silvana M, Caparroz-Assef A, Ciomar A et al (2007) The metabolic changes caused by dexamethasone in the adjuvant-induced arthritic rat. Mol Cell Biochem 302:87–98CrossRef
go back to reference Tatsuo MAKF, Carvalho WM, Silva CV et al (1994) Analgesic and antiinflammatory effects of dipyrone in rat adjuvant arthritis model. Inflammation 18:399–405PubMedCrossRef Tatsuo MAKF, Carvalho WM, Silva CV et al (1994) Analgesic and antiinflammatory effects of dipyrone in rat adjuvant arthritis model. Inflammation 18:399–405PubMedCrossRef
go back to reference Tenhunen R, Marver HS, Schmid R (1968) The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci USA 61:748PubMedCrossRef Tenhunen R, Marver HS, Schmid R (1968) The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci USA 61:748PubMedCrossRef
go back to reference Ueda K, Ueyama T, Yoshida K et al (2008) Adaptive HNE-Nrf2-HO-1 pathway against oxidative stress is associated with acute gastric mucosal lesions. Am J Physiol Gastrointest Liver Physiol 295:G460–G469PubMedCrossRef Ueda K, Ueyama T, Yoshida K et al (2008) Adaptive HNE-Nrf2-HO-1 pathway against oxidative stress is associated with acute gastric mucosal lesions. Am J Physiol Gastrointest Liver Physiol 295:G460–G469PubMedCrossRef
go back to reference Wiesel P, Patel AP, DiFonzo N et al (2000) Endotoxin-induced mortality is related to increased oxidative stress and end-organ dysfunction, not refractory hypotension, in heme oxygenase-1-deficient mice. Circulation 102:3015–3022PubMed Wiesel P, Patel AP, DiFonzo N et al (2000) Endotoxin-induced mortality is related to increased oxidative stress and end-organ dysfunction, not refractory hypotension, in heme oxygenase-1-deficient mice. Circulation 102:3015–3022PubMed
go back to reference Willoughby DA, Moore AR, Colville-Nash PR et al (2000) Resolution of inflammation. Int J Immunopharmacol 22:1131–1135PubMedCrossRef Willoughby DA, Moore AR, Colville-Nash PR et al (2000) Resolution of inflammation. Int J Immunopharmacol 22:1131–1135PubMedCrossRef
go back to reference Wooley PH (2004) The usefulness and the limitations of animal models in identifying targets for therapy in arthritis. Best Pract Res Clin Rheumatol 18:47–58PubMedCrossRef Wooley PH (2004) The usefulness and the limitations of animal models in identifying targets for therapy in arthritis. Best Pract Res Clin Rheumatol 18:47–58PubMedCrossRef
go back to reference Yachie A, Niida Y, Wada T et al (1999) Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Investig 103:129–135PubMedCrossRef Yachie A, Niida Y, Wada T et al (1999) Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Investig 103:129–135PubMedCrossRef
go back to reference Zimmermann M (1988) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110 Zimmermann M (1988) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110
Metadata
Title
Anti-inflammatory and antihyperalgesic effects of the combination of ibuprofen and hemin in adjuvant-induced arthritis in the Wistar rat
Authors
Shamsherjit Kaur
Krishna Reddy V. Bijjem
Pyare Lal Sharma
Publication date
01-10-2011
Publisher
SP Birkhäuser Verlag Basel
Published in
Inflammopharmacology / Issue 5/2011
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI
https://doi.org/10.1007/s10787-011-0090-8

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