Physio-pharmacological Investigations About the Anti-inflammatory and Antinociceptive Efficacy of (+)-Limonene Epoxide
D-limonene epoxidation generates (+)-limonene epoxide, an understudied compound in the pharmacologically point of view. Herein, we investigated the anti-inflammatory and antinociceptive potentialities of (+)-limonene epoxide and suggested a mechanism of action. The anti-inflammatory potential was analyzed using agents to induce paw edema, permeability, and myeloperoxidase (MPO) activity. Pro-inflammatory cytokines and cell migration of peritoneal cells were also assessed. Antinociceptive effects were evaluated by writhing test induced by acetic acid, formalin, and hot plate assays and contribution of opioid pathways. Pretreated animals with (+)-limonene epoxide showed reduced carrageenan-induced paw edema in all doses (25, 50, and 75 mg/kg) (P < 0.05). At 75 mg/kg, it suppressed edema provoked by compound 48/80, histamine, prostaglandin E2, and serotonin and reduced permeability determined by Evans blue and MPO activity. It also reduced leukocytes, neutrophils, and IL-1β levels in the peritoneal cavity in comparison with carrageenan group (P < 0.05). (+)-Limonene epoxide diminished abdominal contortions induced by acetic acid (78.9%) and paw licking times in both 1 (41.8%) and 2 (51.5%) phases and a pretreatment with naloxone (3 mg/kg) reverted the antinociceptive action in morphine- and (+)-limonene epoxide-treated groups (P < 0.05). Additionally, it enlarged response times to the thermal stimulus after 60 and 90 min. In conclusion, (+)-limonene epoxide inhibited release/activity of inflammatory mediators, vascular permeability, migration of neutrophils and displayed systemic and peripheral analgesic-dependent effects of the opioid system.
KEY WORDSsemisynthetic compound cell migration inhibition cytokine reduction analgesia opioid system involvement
We wish to thank the Federal Brazilian agency “Conselho Nacional de Desenvolvimento Científico e Tecnológico” (CNPq) for financial support in the form of grants (#473167/2012-3) and fellowships.
COMPLIANCE WITH ETHICAL STANDARDS
All procedures were approved by the Committee on Animal Research at the UFPI (Process no. 091/2014) and followed the Brazilian (Colégio Brasileiro de Experimentação Animal—COBEA) and International Standards on the care and use of experimental animals (Directive 2010/63/EU of the European Parliament and of the Council).
Conflict of Interest
The authors declare that there are no conflicts of interest.
- 4.Farias, D.F., T.M. Souza, M.P. Viana, B.M. Soares, A.P. Cunha, I.M. Vasconcelos, N.M. Ricardo, P.M.P. Ferreira, V.M.M. Melo, and A.F.F.U. Carvalho. 2013. Antibacterial, antioxidant, and anticholinesterase activities of plant seed extracts from Brazilian semiarid region. BioMed Research International 2013: 1–9.CrossRefGoogle Scholar
- 5.Pereira, J.B.A., M.M. Rodrigues, I.R. Morais, C.R.S. Vieira, J.P.M. Sampaio, M.G. Moura, M.F.M. Damasceno, J.N. Silva, I.B.F. Calou, F.A. Deus, A.P. Peron, M.C. Abreu, G.C.G. Militão, and P.M.P. Ferreira. 2005. O papel terapêutico do Programa Farmácia Viva e das plantas medicinais no centro-sul piauense. Revista Brasileira de Plantas Medicinais 17: 550–561.CrossRefGoogle Scholar
- 6.Simoes, E.R.B., E.A. Santos, M.C. Abreu, J.N. Silva, N.M.F. Nunes, M.P. Costa, O.D.L. Pessoa, C. Pessoa, and P.M.P. Ferreira. 2015. Biomedical properties and potentiality of Lippia microphylla Cham. and its essential oils. Journal of Intercultural Ethnopharmacology 4: 256–263.CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Ferreira, P.M.P., D.P. Bezerra, J.N. Silva, M.P. Costa, J.R.O. Ferreira, N.M.N. Alencar, I.S.T. Figueiredo, A.J. Cavalheiro, C.M.L. Machado, R. Chammas, A.P.N.N. Alves, M.O. Moraes, and C. Pessoa. 2016. Preclinical anticancer effectiveness of a fraction from Casearia sylvestris and its component Casearin X: in vivo and ex vivo methods and microscopy examinations. Journal of Ethnopharmacology 186: 270–279.CrossRefPubMedGoogle Scholar
- 10.Silva, J.C., S.R.G.L. Saraiva, R.G. Oliveira-Júnior, and J.R.G.S. Almeida. 2013. Experimental models for evaluation of antinociceptive activity of natural products: a review. Brazilian Journal of Pharmacognosy 94: 18–23.Google Scholar
- 11.Quintans-Júnior, L.J., A.G. Guimarães, M.T. Santana, B.E.S. Araújo, F.V. Moreira, L.R. Bonjardim, A.S.S. Araújo, J.S. Siqueira, A.R. Antoniolli, M.A. Botelho, J.R.G.S. Almeida, and M.R.V. Santos. 2011. Citral reduces nociceptive and inflammatory response in rodents. Brazilian Journal of Pharmacognosy. 21: 497–502.Google Scholar
- 16.Rozza, A.L., T.M. Moraes, H. Kushima, A. Tanimoto, M.O. Marques, T.M. Bauab, C.A. Hiruma-Lima, and C.H. Pellizzon. 2011. Gastroprotective mechanisms of Citrus lemon (Rutaceae) essential oil and its majority compounds limonene and β-pinene: involvement of heat-shock protein-70; vasoactive intestinal peptide; glutathione; sulfhydryl compounds; nitric oxide and prostaglandin E2. Chemico-Biological Interactions 189: 82–89.CrossRefPubMedGoogle Scholar
- 17.Murali, R., and S. Ramalingam. Antidiabetic effect of d-limonene, a monoterpene in streptozotocin-induced diabetic rats. Biomedicine & Preventive Nutrition 2:269–275.Google Scholar
- 20.Thomas, A.F., and Y. Bessiére. 1989. Limonene. Natural Products Reports 291–309.Google Scholar
- 22.Silva, R.O., M.S. Salvadori, F.B.M. Sousa, M.S. Santos, N.S. Carvalho, D.P. Sousa, B.S. Gomes, F.A. Oliveira, A.L.R. Barbosa, R.M. Freitas, R.N. De Almeida, and J.R. Medeiros. 2014. Evaluation of the anti-inflammatory and antinociceptive effects of myrtenol, a plant derived monoterpene alcohol, in mice. Flavour and Fragrance Journal 29: 184–192.CrossRefGoogle Scholar
- 23.Radu, M., and J. Chernoff. 2013. An in vivo assay to test blood vessel permeability. Journal of Visualized Experiments 16, e50062.Google Scholar
- 26.Koster, R., M. Anderson, and E.I. Debeer. 1959. Acetic acid for analgesic screening. Federation Proceedings 18: 412–418.Google Scholar
- 29.McCubrey, J.A., S.L. Abrams, T.L. Fitzgerald, L. Cocco, A.M. Martelli, G. Montalto, M. Cervello, A. Scalisi, S. Candido, M. Libra, and L.S. Steelman. 2015. Roles of signaling pathways in drug resistance, cancer initiating cells and cancer progression and metastasis. Advances in Biological Regulation 57: 75–101.CrossRefPubMedGoogle Scholar
- 36.Silva, R.O., S.R.B. Damasceno, I.S. Silva, V.G. Silva, C.F.C. Brito, A.E.A. Teixera, G.B.L. Nunes, C.A. Camara, J.M.B. Filho, S.J.C. Gutierrez, R.A. Ribeiro, M.H.L.P. Souza, A.L.R. Barbosa, R.M. Freitas, and J.V.R. Medeiros. 2015. Riparin A, a compound from Aniba riparia, attenuates the inflammatory response by modulation of neutrophil migration. Chemico-Biological Interactions 229: 55–63.CrossRefPubMedGoogle Scholar
- 37.Lo, T.N., A.P. Almeida, and M.A. Beaven. 1982. Dextran and carrageenan evoke different inflammatory responses in rat with respect to composition of infiltrates and effect of indomethacin. Journal of Pharmacology and Experimental Therapeutics 222: 261–267.Google Scholar
- 38.Silva, M.G., F.S. Oliveira, L.J. Quintans-Júnior, O.M.L. Thenio, and M.F.M. Diniz. 2005. Investigação de efeito analgésico central e anti-inflamatório de Conocliniopsis prasiifolia (DC) RM King and H Robinson em roedores. Acta Farmaceutica Bonaerense 24: 533–537.Google Scholar
- 39.Damasceno, S.R.B., F.R.A.M. Oliveira, N.S. Carvalho, C.F.C. Brito, I.S. Silva, F.B.M. Sousa, R.O. Silva, D.P. Sousa, A.L.R. Barbosa, R.M. Freitas, and J.R. Medeiros. 2014. Carvacrol acetate, a derivative of carvacrol, reduces nociceptive and inflammatory response in mice. Life Sciences 94: 58–66.CrossRefPubMedGoogle Scholar
- 40.Pereira, L.P., K.E.S. Da Silva, R.O. Da Silva, A.M.S. Assreuy, and M.G. Pereira. 2012. Anti-inflammatory polysaccharides of Azadirachta indica seed tegument. Brazilian Journal of Pharmacognosy 22: 617–622.Google Scholar
- 41.Silva, R.O., F.B.M. Sousa, S.R.B. Damasceno, N.S. Carvalho, V.G. Silva, F.R.M.A. Oliveira, D.P. Sousa, K.S. Aragão, A.L.R. Barbosa, R.M. Freitas, and J.V.R. Medeiros. 2014. Phytol, a diterpene alcohol, inhibits the inflammatory response by reducing cytokine production and oxidative stress. Fundamental & Clinical Pharmacology 28: 455–464.CrossRefGoogle Scholar
- 43.Pereira, J.G., J.X. Mesquita, K.S. Aragão, A.X. Franco, M.H.L.P. Souza, T.V. Brito, J.M. Dias, R.O. Silva, J.R. Medeiros, J.S. Oliveira, C.M.W.S. Abreu, R.C.M. De Paula, A.L.R. Barbosa, and A.L.P. Freitas. 2014. Polysaccharides isolated from Digenea simplex inhibit inflammatory and nociceptive responses. Carbohydrate Polymers 108: 17–25.CrossRefPubMedGoogle Scholar
- 44.Silva-Filho, S.E., F.M.Z. Silva-Comar, L.A.M. Wiirzler, R.J. Pinho, R. Grespan, C.A. Bersani-Amado, and R.K.N. Cuman. 2014. Effect of camphor on the behavior of leukocytes in vitro and in vivo in acute inflammatory response. Tropical Journal of Pharmaceutical Research 13: 2031–2037.CrossRefGoogle Scholar
- 46.Brito, T.V., Prudêncio, A.B. Sales, F.C. Vieira Júnior, S.J.N. Candeira, A.X. Franco, K.S. Aragão, R.A. Ribeiro, M.H.L.P. Souza, L.S. Chaves, A.L.P. Freitas, J.R. Medeiros, and A.L.R. Barbosa. 2013. Anti-inflammatory effect of a sulphated polysaccharide fraction extracted from the red algae Hypnea musciformis via the suppression of neutrophil migration by the nitric oxide signalling pathway. Journal of Pharmacy and Pharmacology 65: 724–733.CrossRefPubMedGoogle Scholar
- 50.Carvalho, V., L. Fernandes, T. Conde, H. Zamith, R. Silva, A. Surrage, V. Frutuoso, H. Castro-Faria-Neto, and F. Amendoeira. 2013. Antinociceptive activity of Stephanolepis hispidus skin aqueous extract depends partly on opioid system activation. Marine Drugs 11: 1221–1255.CrossRefPubMedPubMedCentralGoogle Scholar
- 51.Lima, S.M.A., L.C.C. Araújo, M.M. Sitônio, A.C.C. Freitas, S.L. Moura, M.T. Correia, D.J.N. Malta, and T. Gonçalves-Silva. 2012. Anti-inflammatory and analgesic potential of Caesalpinia ferrea. Brazilian Journal of Pharmacognosy 22: 169–175.Google Scholar
- 52.Sowemimo, A., M. Onakoy, M.S. Fageyinbo, and T. Fadoju. 2012. Studies on the anti-inflammatory and anti-nociceptive properties of Blepharis maderaspatensis leaves. Brazilian Journal of Pharmacognosy 23: 830–835.Google Scholar