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Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry


ISSN (Print): 1871-5230
ISSN (Online): 1875-614X

Research Article

Peripheral Anti-nociceptive and Anti-inflammatory Effect of Oleanolic Acid in a Rat Model of Osteoarthritis

Author(s): Israa Salman, Marc Fakhoury, Malak Fouani and Nada Lawand*

Volume 20 , Issue 3 , 2021

Published on: 11 November, 2020

Page: [239 - 249] Pages: 11

DOI: 10.2174/1871523019999201111191754

Price: $65


Background: Oleanolic acid (OA) is a naturally occurring pentacyclic triterpenoid with multifarious actions. The anti-inflammatory effect it exerts when taken orally is the most important; however, the underpinning mechanisms of such effects have not yet been fully explored.

Methods: In the present study, we evaluated the anti-inflammatory and anti-nociceptive effect of OA by injecting it directly into the knee joint using an animal model of osteoarthritis. Behavioral and electrophysiological studies were conducted to determine whether OA exerts a direct modulatory effect on primary sensory afferents that can lead to a decrease in pain-related behaviors and inflammatory responses. Rats were divided into two main groups: a pre- and a post-treatment group. Knee joint inflammation was induced by injecting a mixture of 3% kaolin and carrageenan (K/C). In the pre-treatment group, two different doses of OA [5 mg/ml (n=5) and 30 mg/ml (n=4); 0.1 ml per injection] were administered into the synovial cavity of the knee joint before induction of inflammation. In the post-treatment group, rats received only one dose [5 mg/ml (n=5)] of OA after induction of inflammation.

Results: Results indicate that intra-articular injection of OA improves motor coordination and attenuates nociceptive behavior and inflammatory reactions. More importantly, we observed a direct depolarizing action of OA on articular sensory fibers, a crucial mechanism that activates descending inhibitory pathways and controls incoming nociceptive signals to the spinal cord.

Conclusion: Overall, our findings suggest that OA can be used as a preventive and therapeutic approach for the management of osteoarthritis.

Keywords: Inflammation, Kaolin/carrageenan, motor coordination, nociception, oleanolic acid, osteoarthritis, pain.

Graphical Abstract
Chen, D.; Shen, J.; Zhao, W.; Wang, T.; Han, L.; Hamilton, J.L.; Im, H.J. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res., 2017, 5, 16044.
[] [PMID: 28149655]
Felson, D.T. Clinical practice. Osteoarthritis of the knee. N. Engl. J. Med., 2006, 354(8), 841-848.
[] [PMID: 16495396]
Helmick, C.G.; Felson, D.T.; Lawrence, R.C.; Gabriel, S.; Hirsch, R.; Kwoh, C.K.; Liang, M.H.; Kremers, H.M.; Mayes, M.D.; Merkel, P.A.; Pillemer, S.R.; Reveille, J.D.; Stone, J.H. National arthritis data workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum., 2008, 58(1), 15-25.
[] [PMID: 18163481]
Felson, D.T.; Naimark, A.; Anderson, J.; Kazis, L.; Castelli, W.; Meenan, R.F. The prevalence of knee osteoarthritis in the elderly. The framingham osteoarthritis study. Arthritis Rheum., 1987, 30(8), 914-918.
[] [PMID: 3632732]
Dillon, C.F.; Rasch, E.K.; Gu, Q.; Hirsch, R. Prevalence of knee osteoarthritis in the United States: arthritis data from the Third National Health and Nutrition Examination Survey 1991-94. J. Rheumatol., 2006, 33(11), 2271-2279.
[PMID: 17013996]
Roos, E.M. Joint injury causes knee osteoarthritis in young adults. Curr. Opin. Rheumatol., 2005, 17(2), 195-200.
[] [PMID: 15711235]
Lotz, M.K.; Kraus, V.B. New developments in osteoarthritis. Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options. Arthritis Res. Ther., 2010, 12(3), 211.
[] [PMID: 20602810]
Spector, T.D.; Cicuttini, F.; Baker, J.; Loughlin, J.; Hart, D. Genetic influences on osteoarthritis in women: a twin study. BMJ, 1996, 312(7036), 940-943.
[] [PMID: 8616305]
Raphael, T.J.; Kuttan, G. Effect of naturally occurring triterpenoids glycyrrhizic acid, ursolic acid, oleanolic acid and nomilin on the immune system. Phytomedicine, 2003, 10(6-7), 483-489.
[] [PMID: 13678231]
Yin, M.C.; Lin, M.C.; Mong, M.C.; Lin, C.Y. Bioavailability, distribution, and antioxidative effects of selected triterpenes in mice. J. Agric. Food Chem., 2012, 60(31), 7697-7701.
[] [PMID: 22816768]
Kao, T.C.; Wu, C.H.; Yen, G.C. Bioactivity and potential health benefits of licorice. J. Agric. Food Chem., 2014, 62(3), 542-553.
[] [PMID: 24377378]
Kapil, A.; Sharma, S. Effect of oleanolic acid on complement in adjuvant- and carrageenan-induced inflammation in rats. J. Pharm. Pharmacol., 1995, 47(7), 585-587.
[] [PMID: 8568626]
Kang, X.; Yang, Z.; Sheng, J.; Liu, J.B.; Xie, Q.Y.; Zheng, W.; Chen, K. Oleanolic acid prevents cartilage degeneration in diabetic mice via PPARγ associated mitochondrial stabilization. Biochem. Biophys. Res. Commun., 2017, 490(3), 834-840.
[] [PMID: 28647370]
Liu, J. Pharmacology of oleanolic acid and ursolic acid. J. Ethnopharmacol., 1995, 49(2), 57-68.
[] [PMID: 8847885]
Liu, J. Oleanolic acid and ursolic acid: research perspectives. J. Ethnopharmacol., 2005, 100(1-2), 92-94.
[] [PMID: 15994040]
YM. A review of presence of oleanolic acid in natural products. Natura Proda Medica, 2009, 2, 77-290.
Fukushima, E.O.; Seki, H.; Ohyama, K.; Ono, E.; Umemoto, N.; Mizutani, M.; Saito, K.; Muranaka, T. CYP716A subfamily members are multifunctional oxidases in triterpenoid biosynthesis. Plant Cell Physiol., 2011, 52(12), 2050-2061.
[] [PMID: 22039103]
Park, S.H.; Sim, Y.B.; Kang, Y.J.; Kim, S.S.; Kim, C.H.; Kim, S.J.; Suh, H.W. Mechanisms involved in the antinociceptive effects of orally administered oleanolic acid in the mouse. Arch. Pharm. Res., 2013, 36(7), 905-911.
[] [PMID: 23515934]
Soares, I.C.R.; Santos, S.A.A.R.; Coelho, R.F.; Alves, Y.A.; Vieira-Neto, A.E.; Tavares, K.C.S.; Magalhaes, F.E.A.; Campos, A.R. Oleanolic acid promotes orofacial antinociception in adult zebrafish (Danio rerio) through TRPV1 receptors. Chem. Biol. Interact., 2019, 299, 37-43.
[] [PMID: 30496739]
Maia, J.L.; Lima-Júnior, R.C.; David, J.P.; David, J.M.; Santos, F.A.; Rao, V.S. Oleanolic Acid, a pentacyclic triterpene attenuates the mustard oil-induced colonic nociception in mice. Biol. Pharm. Bull., 2006, 29(1), 82-85.
[] [PMID: 16394515]
Bednarczyk-Cwynar, B.; Wachowiak, N.; Szulc, M.; Kamińska, E.; Bogacz, A.; Bartkowiak-Wieczorek, J.; Zaprutko, L.; Mikolajczak, P.L. Strong and long-lasting antinociceptive and anti-inflammatory conjugate of naturally occurring oleanolic acid and aspirin. Front. Pharmacol., 2016, 7, 202.
[] [PMID: 27462270]
Bednarczyk-Cwynar, B.; Zaprutko, L.; Marciniak, J.; Lewandowski, G.; Szulc, M.; Kaminska, E.; Wachowiak, N.; Mikolajczak, P.L. The analgesic and anti-inflammatory effect of new oleanolic acid acyloxyimino derivative. Eur. J. Pharm. Sci., 2012, 47(3), 549-555.
[] [PMID: 22867936]
Maia, J.L.; Lima-Júnior, R.C.; Melo, C.M.; David, J.P.; David, J.M.; Campos, A.R.; Santos, F.A.; Rao, V.S. Oleanolic acid, a pentacyclic triterpene attenuates capsaicin-induced nociception in mice: Possible mechanisms. Pharmacol. Res., 2006, 54(4), 282-286.
[] [PMID: 16879974]
Meller, S.T. Thermal and mechanical hyperalgesia: A distinct role for different excitatory amino acid receptors and signal transduction pathways? J. Pain, 1994, 3(4), 215-231.
Yoo, S.R.; Jeong, S.J.; Lee, N.R.; Shin, H.K.; Seo, C.S. Quantification analysis and in vitro anti-inflammatory effects of 20-hydroxyecdysone, momordin IC, and oleanolic acid from the fructus of kochia scoparia. Pharmacogn. Mag., 2017, 13(51), 339-344.
[] [PMID: 28839354]
Zhang, Y.; Song, C.; Li, H.; Hou, J.; Li, D. Ursolic acid prevents augmented peripheral inflammation and inflammatory hyperalgesia in high-fat diet-induced obese rats by restoring downregulated spinal PPARα. Mol. Med. Rep., 2016, 13(6), 5309-5316.
[] [PMID: 27108888]
Kang, S.Y.; Yoon, S.Y.; Roh, D.H.; Jeon, M.J.; Seo, H.S.; Uh, D.K.; Kwon, Y.B.; Kim, H.W.; Han, H.J.; Lee, H.J.; Lee, J.H. The anti-arthritic effect of ursolic acid on zymosan-induced acute inflammation and adjuvant-induced chronic arthritis models. J. Pharm. Pharmacol., 2008, 60(10), 1347-1354.
[] [PMID: 18812028]
Bhat, R.A.; Lingaraju, M.C.; Pathak, N.N.; Kalra, J.; Kumar, D.; Kumar, D.; Tandan, S.K. Effect of ursolic acid in attenuating chronic constriction injury-induced neuropathic pain in rats. Fundam. Clin. Pharmacol., 2016, 30(6), 517-528.
[] [PMID: 27414466]
Singh, G.B.; Singh, S.; Bani, S.; Gupta, B.D.; Banerjee, S.K. Anti-inflammatory activity of oleanolic acid in rats and mice. J. Pharm. Pharmacol., 1992, 44(5), 456-458.
[] [PMID: 1359067]
Yang, E.J.; Lee, W.; Ku, S.K.; Song, K.S.; Bae, J.S. Anti-inflammatory activities of oleanolic acid on HMGB1 activated HUVECs. Food Chem. Toxicol., 2012, 50(5), 1288-1294.
[] [PMID: 22386814]
Lee, W.; Yang, E.J.; Ku, S.K.; Song, K.S.; Bae, J.S. Anti-inflammatory effects of oleanolic acid on LPS-induced inflammation in vitro and in vivo. Inflammation, 2013, 36(1), 94-102.
[] [PMID: 22875543]
Liu, B.; Liu, Y.; Yang, G.; Xu, Z.; Chen, J. Ursolic acid induces neural regeneration after sciatic nerve injury. Neural Regen. Res., 2013, 8(27), 2510-2519.
[PMID: 25206561]
Wei, L.; Zhu, Y.M.; Zhang, Y.X.; Liang, F.; Jia, H.; Qu, C.L.; Wang, J.; Tang, J.S.; Lu, S.M.; Huo, F.Q.; Yan, C.X. Activation of α1 adrenoceptors in ventrolateral orbital cortex attenuates allodynia induced by spared nerve injury in rats. Neurochem. Int., 2016, 99, 85-93.
[] [PMID: 27296114]
Pawlak, M.; Schmidt, R.F.; Heppelmann, B.; Hanesch, U. The neurokinin-1 receptor antagonist RP 67580 reduces the sensitization of primary afferents by substance P in the rat. Eur. J. Pain, 2001, 5(1), 69-79.
[] [PMID: 11394924]
Liu, W.; Wong, C. Oleanolic acid is a selective farnesoid X receptor modulator. Phytother. Res., 2010, 24(3), 369-373.
[] [PMID: 19653193]
Jiao, Y.; Lu, Y.; Li, X.Y. Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis. Acta Pharmacol. Sin., 2015, 36(1), 44-50.
[] [PMID: 25500875]
Azuma, K; Casey, SC; Urano, T; Horie-Inoue, K; Ouchi, Y; Blumberg, B Pregnane X receptor knockout mice display aging-dependent wearing of articular cartilage. PLoS One, 2015, 10(3), 0119177.
Choi, J.K.; Kim, S.W.; Kim, D.S.; Lee, J.Y.; Lee, S.; Oh, H.M.; Ha, Y.S.; Yoo, J.; Park, P.H.; Shin, T.Y.; Kwon, T.K.; Rho, M.C.; Kim, S.H. Oleanolic acid acetate inhibits rheumatoid arthritis by modulating T cell immune responses and matrix-degrading enzymes. Toxicol. Appl. Pharmacol., 2016, 290(290), 1-9.
[] [PMID: 26570984]
Stoll, M.L.; Gotte, A.C. Biological therapies for the treatment of juvenile idiopathic arthritis: Lessons from the adult and pediatric experiences. Biologics, 2008, 2(2), 229-252.
[] [PMID: 19707357]
Poddighe, D.; Romano, M.; Gattinara, M.; Gerloni, V. Biologics for the treatment of juvenile idiopathic arthritis. Curr. Med. Chem., 2018, 25(42), 5860-5893.
[] [PMID: 29788871]

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