A novel gedunin-2-hydroxypropyl-β-cyclodextrin inclusion complex improves anti-nociceptive and anti-inflammatory activities of gedunin in rodents
Click to view file (PDF)

How to Cite

Ologe, M. O. (2022). A novel gedunin-2-hydroxypropyl-β-cyclodextrin inclusion complex improves anti-nociceptive and anti-inflammatory activities of gedunin in rodents. Nigerian Journal of Physiological Sciences, 37(1), 9–19. https://doi.org/10.54548/njps.v37i1.2

Abstract

Gedunin is a bioactive compound, obtained from Entandrophragma angolense (EA), which has limited therapeutic usefulness due to poor aqueous solubility and first-pass effects. Cyclodextrins are cyclic oligosaccharides that form complexes with poorly soluble compounds, thus enhancing their pharmacological activity. In this article, we evaluated the pharmacological activities of gedunin-2-hydroxypropyl-β-cyclodextrin complex (GCD) in rodents. The antinociceptive activity of GCD (50, 100, 200 mg/kg) and Gedunin (50mg/kg) was tested in acetic acid-induced writhing and formalin-induced paw licking in mice. The anti-inflammatory activity was investigated in carrageenan-induced paw oedema and air pouch inflammation models in rats. Leucocytes counts, Tumour Necrosis Factor-alpha (TNF-α) level, nitric oxide, malondialdehyde, reduced glutathione, and myeloperoxidase enzyme activities were assessed in the air pouch exudate. The GCD (200mg/kg) significantly decreased writhing response, reduced licking duration and decreased oedema compared with gedunin and control. Exudate volume and leucocyte count were significantly reduced by GCD (200 mg/kg), it decreased myeloperoxidase activity and inhibited TNF-α release. The carrageenan-induced GSH depletion, increased malondialdehyde and nitrite levels were significantly reversed by GCD (200 mg/kg) relative to gedunin and control.  The GCD complex demonstrated significant antinociceptive and anti-inflammatory activities relative to gedunin alone via mechanisms associated with inhibition of oxidative stress and inflammation in rodents

https://doi.org/10.54548/njps.v37i1.2
Click to view file (PDF)

References

Araujo, D.R., Braga, A.F.A., Fraceto, L.F., de Paula, E. (2005). Drug-delivery systems for racemic bupivacaine (S50-R50) and bupivacaine enantiomeric mixture (S75-R25): cyclodextrins complexation effects on sciatic nerve blockade in mice. Rev Bras Anestesiol. 55:316–27.

Araujo, D.R., Braga, A.F.A., Moraes, C.M., Fraceto, L.F., de Paula, E. (2006). Complexation of 50% enantiomeric excess (S75-R25) bupivacaine with cyclodextrins and spinal block anesthesia in rats. Rev Bras Anestesiol. 56:495–506.

Araujo, D.R., Tsuneda, S.S., Cereda, C.M.S., Carvalho, F.G.F., Preté, P.S.C., Fernandes, S.A., Yokaichiya, F., Franco, M.K., Mazzaro, I., Fraceto, L.F., Braga, A.F.A., de Paula, E. (2008). Development and pharmacological evaluation of ropivacaine-2-hydroxypropyl-beta-cyclodextrin inclusion complex. Eur J Pharm Sci. 33:60–71.

Bandarkar, F.S., Vavia, P.R. (2013). Physico-chemical characterization and in vivo pharmacodynamic evaluation of lyophilized meloxicam: β-cyclodextrin inclusion complexes. Int J Pharm Pharm Sci. 5(3):159-165.

Barrot, M. (2012). Tests and models of nociception and pain in rodents. Neuroscience 211: 39-50. https://doi.org/10.1016/j.neuroscience.2011.12.041

Bickii, J., Njifutie, N., Ayafor JF, Basco LK, Ringwald P. (2000). In vitro antimalarial activity of limonoids from Khaya grandifoliola C.D.C. (Meliaceae). J Ethnopharmacol. 69:27-33.

Bradley, P.P., Christensen, R.D., Rothestein, G. (1982). Cellular and extracellular myeloperoxidase in pyogenic inflammation. Blood. 60: 618–22.

Braga, T.M, Rocha, L., Chung, T.Y. Rita F. Oliveira, R.F., Pinho, C., Oliveira, A. I, Morgado, J. and Cruz, A. (2020). Biological Activities of Gedunin—A Limonoid from the Meliaceae Family. Molecules 25: 493-517. doi:10.3390/molecules 25030493.

Braggio MM, Lima MEL, Veasey EA, Haraguchi, M. (2002). Pharmacological activities of the leaves of the Sesbania virgata (Cav.) Arq. Inst. Biol. 69(4):49-53.

Brandt, G.E.L., Schmidt, M.D., Prisinzano, T.E., Blagg, B.S.J. (2008). Gedunin, a Novel Hsp90 Inhibitor: Semisynthesis of Derivatives and Preliminary Structure–Activity Relationships. J. Med. Chem. 51(20): 6495–6502.

Bray, D.H., Warhust, D.C., Connolly, J.D., O’Neill, M.J., Phillipson, J.D. (1990). Plants as sources of Antimalarial Drugs. Part 7: Activity of some species of Meliaceae plants and their constituent limonoids. Phytother Res. 4(1):29-35.

Brewster, M.E., Loftsson, T. (2007). Cyclodextrins as pharmaceutical solubilizers. Adv. Drug Deliv. Rev.59:645-666.

Brito, R.G., Araujo, A.A.S., Quintans, J.S.S, Sluka, K.A., Quintans-Junior, L.J. (2015). Enhanced analgesic activity by cyclodextrins - a systematic review and meta-analysis. Expert Opin Drug Deliv. 12(10):1677-1688.

Carneiro, S. B., Costa Duarte, F. Í., Heimfarth, L., Siqueira Quintans, J. S., Quintans-Júnior, L. J., Veiga Júnior, V., Neves de Lima, Á. A. (2019). Cyclodextrin-Drug Inclusion Complexes: In Vivo and In Vitro Approaches. International Journal of Molecular Sciences. 20(3): 642-664. https://doi.org/10.3390/ijms2000642

Cusola, O., Tabary, N., Belgacem, M.N., Bras, J. (2013). Cyclodextrin functionalization of several cellulosic substrates for prolonged release of antibacterial agents. J. Appl. Polym. Sci 129(2): 604-613.

Cereda, C.M.S., Tofoli, G.R., Maturana, L.G., Pierucci, A., Nunes, L.A., Franz-Montan, M., de Oliveira, A.L., Arana, S., de Araujo, D.R., de Paula, E. (2012). Local Neurotoxicity and Myotoxicity Evaluation of Cyclodextrin Complexes of Bupivacaine and Ropivacaine. Anesth Analg. 115 (5):1234–41.

Chou, S.C., Chiu, Y.J., Chen, C.J., Lin, Y.C., Wu, C.H., Chao, C.T., Chang, C.W., Peng, W.H. (2012). Analgesic and Anti-Inflammatory Activities of the Ethanolic Extract of Artemisia morrisonensis Hayata in Mice. Evid Based Complement Alternat Med 2012 (1-11) 138954, doi:10.1155/2012/138954.

Conner, E.M. and Grisham, M.B. (1996). Inflammation, Free Radicals and Antioxidants. Nutrition 12:274–277.

Conte, F.P., Ferraris, F.K., Costa, T.E., Pacheco, P., Seito, L.N., Verri Jr, W.A., Fernando, Q., Cunha, F.Q., Penido, C., Henriques, M.G. (2015). Effect of Gedunin on Acute Articular Inflammation and Hypernociception in Mice. Molecules 20:2636-2657.

D'Amour, F.E. and Smith, D.L. (1941). A method for determining loss of pain sensation. J Pharmacol Exp Ther. 72 (1): 74-79.

Dollo, G., Thompson, D., Le Corre, P., Chevanne, F., Le Verge, R. (1998). Inclusion complexation of amide-type local anesthetics with β-cyclodextrin and derivates: III. Biopharmaceutics of bupivacaine-HP β-CD complex following percutaneous sciatic nerve administration in rabbits. Int J Pharm. 164:11–9.

Dollo, G., Le Corre, P., Freville, J.C., Chevanne, F., Le Verge, R. (2000). Biopharmaceutics of local anesthetic cyclodextrin complexes following loco-regional administration. Ann Pharm Fr. 58:425–32.

Eddy, N.B. and Leimbach, D.J. (1953). Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines. J Pharmacol Exp Ther. 107:385-393.

El-Feky, G.S., El-banna, S.T., Khalil, S.K.H. (2013). Preparation, in vitro and in vivo evaluation of oral indomethacin-HP-β-cyclodextrin loaded chitosan nanoparticles. Int J Pharm Pharm Sci. 5(4):638-645.

Esmat, A., Al-Abbasi, F.A., Algandaby, M.M., Moussa, A.Y., Labib, R.M., Ayoub, N.A., Abdel-Naim, A.B. (2012). Anti-Inflammatory Activity of Pistacia khinjuk in Different Experimental Models: Isolation and Characterization of Its Flavonoids and Galloylated Sugars. J Med Food. 15(3): 278–287.

Franco de Lima, R.A., de Jesus, M.B., Saia Cereda, C.M., Tofoli, G.R., Cabeça, L.F., Mazzaro, I., Fraceto, L.F., de Paula, E. (2012). Improvement of tetracaine antinociceptive effect by inclusion in cyclodextrins. J. Drug Target. 20(1):85-96. doi: 10.3109/1061186X.2011.622400.

Franzotti, E.M., Santos, C.V., Rodrigues, H.M., Mourão, R.H., Andrade, M.R., Antoniolli, A.R. (2000). Anti-inflammatory, analgesic activity and acute toxicity of Sida cordifolia L. (Malva-branca). J. Ethnopharmacol, 72(1-2):273-7.

Gidwani, B. and Vyas, A. (2015). A Comprehensive review on cyclodextrin-based carriers for delivery of chemotherapeutic cytotoxic anticancer drugs. Biomed Res. Int. 2015:198268. doi: 10.1155/2015/198268.

Gornall, A.G., Bardawill, C.J., David, M.M. (1949). Determination of serum proteins by means of the biuret reaction. J Biol. Chem. 177:751–766.

Hunskaar, S. and Hole, K. (1987). The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain 30(1):103–114.

Jain, M. and Parmar, H.S. (2011). Evaluation of antioxidative and anti-inflammatory potential of hesperidin and naringin on the rat air pouch model of inflammation. Inflamm. Res. ,60:483– 491.

Khalid, S.A., Duddeck, H., Gonzalez-Sierra, M. (1989). Isolation and characterization of an antimalarial agent of the neem tree Azadirachta indica. J. Nat. Prod. 52(5):922-6.

Kim, J.Y., Kim, D.H., Jeong, H.G. (2006). Inhibitory effect of the coffee diterpene kahweol on carrageenan-induced inflammation in rats. Biofactors. 26: 17 -28.

Kirkova, M., Kassabova, T. and Russanov E. (1992). In vivo effects of indomethacin I. Activity of antioxidant enzymes and lipid peroxidation. Gen Pharmacol. 23:503–507.

Koster, R., Anderson, M., De Beer, E.J. (1959). Acetic acid for analgesic screening. Fed Proc. 18:412.

Kothari, N., Keshari, R.S., Bogra, J., Kohli, M., Abass, H., Malik, A., Dikshit, M., Barthwal, M.K. (2011). Increased myeloperoxidase enzyme activity in plasma is an indicator of inflammation and onset of sepsis. J Crit Care. 26: 435.e1-435.e7.

Liao, C.R., Kao, C.P., Peng, W.H., Chang, Y.S., Lai, S.C., Ho, Y.L. (2012). Analgesic and Anti-Inflammatory Activities of Methanol Extract of Ficus pumila L. in Mice. Evid Based Complement Alternat Med 2012:1-9. doi:10.1155/2012/340141.

Miro, A., Quaglia, F., Sorrentino, U., La Rotonda, M.I., Di Villa Bianca, R. D., Sorrentino, R. (2004). Improvement of gliquidone hypoglycaemic effect in rats by cyclodextrin formulations. Eur J Pharm Sci. 23:57–64.

Martin, S.W., Stevens, A.J., Brennan, B.S., Davies, D., Rowland, M., Houston, J.B. (1994). The Six-Day-Old Rat Air Pouch Model of Inflammation: Characterization of the Inflammatory Response to Carrageenan. J Pharmacol Toxicol Methods. 32(3):139 – 147.

Moron, M.S., Depierre, J.W., Mannervick, B. (1979). Levels of glutathione, glutathione reductase and glutathione-s-transferase activities in rat lung and liver. Biochim Biophys Acta. 582(1):67-78.

Manjavachi, M.N., Quintao, N.L.M., Campos, M.M., Deschamps, I.K., Yunes, R.A., Nunes, R.J., Leal, P.C., Calixto, J.B. (2010.) The effects of the selective and non-peptide CXCR2 receptor antagonist SB225002 on acute and long-lasting models of nociception in mice. Eur J Pain. 14(1):23–31. doi: 10.1016/j.ejpain.2009.01.007.

Ohkawa, H., Ohishi N., Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 95:351-358.

Okhale, S.E., Amupitan, J.O., Ndukwe, I.G., Oladosu, P.O., Okogun, J.I. (2012). Synthetic modification of gedunin and comparative antibacterial activity of gedunin and 7-deacetoxy-7α-hydroxygedunin potassium salt. Afr. J Pure Appl. Chem. 6(14):183-189.

Ologe, M.O., Adegoke, A.O., Iwalewa, E.O., Ademowo, O.G. (2016). Spectrophotometric studies of a novel Gedunin-2-Hydroxypropyl-β-cyclodextrin binary complex. Afr J Med Med Sci. 45:159-169.

Ologe, M.O., Tella, A.C., Atolani, O., Adegoke, O.A., Ademowo, O.G. (2021). Inclusion complex of gedunin-2-hydroxypropyl-β-cyclodextrin prepared by kneading and freeze-drying methods: synthesis and structural characterization. Acta Biol Marisiensis 4(1): 83-97.

Otero-Espinar, F.J., Torres-Labandeira, J.J., Alvarez-Lorenzo, C., Blanco-Méndez, J. (2010). Cyclodextrins in drug delivery systems. J Drug Deliv Sci Technol.20 (4):289-301.

Pulli, B., Ali, M., Forghani, R., Schob, S., Hsieh, K.L.C, Wojtkiewicz, G., Linnoila, J.J., Chen, J.W. (2013). Measuring Myeloperoxidase Activity in Biological Samples. PLoS One. 8(7): e67976. doi:10.1371/journal pone.0067976.

Quintans, J de S.S., Menezes, P.P., Santos, M.R.V., Bonjardim, L.R., Almeida, J.R., Gelain, D.P., Araújo, A.A., Quintans-Júnior, L.J. (2013). Improvement of p-cymene antinociceptive and anti-inflammatory effects by inclusion in β-cyclodextrin. Phytomedicine 20(5):436-40. doi: 10.1016/j.phymed.2012.12.009.

Quintans-Junior, L.J., Barreto, R.S.S., Menezes, P.P., Almeida, J.R.G., Viana, A.S., Rita, C.M., Oliveira, R.C.M., Oliveira, A.P., Daniel, P., Gelain, D.P., de Lucca Junior, W., Araujo, A.A.S. (2013). β-Cyclodextrin-complexed (_)-linalool produces antinociceptive effect superior to that of (_)-linalool in experimental pain protocols. Basic Clin Pharmacol. Toxicol.113: 167–172.

Ravangpai, W., Sommit, D., Teerawatananond, T., Sinpranee, N., Palaga, T., Pengpreecha, S., Muangsin, N., Pudhom, K. (2011). Limonoids from seeds of Thai Xylocarpus moluccensis. Bioorg Med Chem Lett 21(15): 4485-4489.

Ribeiro, R.V., Silva, R.M., Lima, J.C., Martins, D.T. (2010). Antiinflammatory, antinociceptive and antipyretic effects of hydroethanolic extract from Macrosiphonia velame (A. St.-Hil.) M. Arg. in animal models. Braz J Pharm Sci. 46 (3):515 -523.

Rodrigues, P.O., Becker, A.C., Dellagnelo, V.A., Benetti, C.N., Pereira, E.M., Wagner, T.M., Silva, M.A.S. (2014). Pharmacodynamic and Pharmacokinetic Studies of β-Cyclodextrin: Dexamethasone Acetate Complexes in Mice. Braz Arch Biol Technol. 57(6):887-894.

Sensoy, D., Gönüllü, U., Sagirli, O., Yener, G., Altug, T. (2009). Preparation, Characterization and Anti-inflammatory Activity of Celecoxib-β-Cyclodextrin Inclusion Complexes. Asian J. Chem. 21(3):1759-1768.

Sin, Y.M., Pook, S.H., Tan, T.M., Petterssoon, A., Kara, A.U., The, W.F. (1997). Changes in Gluthathione and its Associated Enzymes during Carrageenan-induced Acute Inflammation in Mice. Comp. Biochem. Physiol. 116C:191-195.

Sedgwick, A.D. and Lees, P. (1986). Studies of eicosanoid production in the air pouch model of synovial inflammation. Agents Actions 8:429-438.

Singh, I., Kumar, P., Pahuja, S., Tung, V., Arora, S. (2011). Development and pharmacological evaluation of cyclodextrin complexes of etoricoxib. Acta Pol. Pharm. 68(2):279-284.

Sinha, V.R. and Amita Goel, H. (2010). In vivo bioavailability and therapeutic assessment of host-guest inclusion phenomena for the hydrophobic molecule etodolac: pharmacodynamic and pharmacokinetic evaluation. Sci Pharm.78:103-15.

Tanas, S., Odabasoglu, F., Halici, Z., Cakir, A., Aygun, H., Aslan, A., Suleyman, H. (2010). Evaluation of Anti-Inflammatory and Antioxidant Activities of Peltigera Rufescens Lichen Species In Acute And Chronic Inflammation Models. J Nat Med. 64(1):42–9.

Ueda, K., Higashi, K.K., and Moribe, K. (2021). Amorphous Drug Solubility and Maximum Free Drug Concentrations in Cyclodextrin Solutions: A Quantitative Study Using NMR Diffusometry. Molecular Pharmaceutics 18(7), 2764-2776. DOI: 10.1021/acs.molpharmaceut.1c00311.

Wankar, J., Kotla, N. G., Gera, S., Rasala, S., Pandit, A., Rochev, Y. A. (2020). Recent Advances in Host–Guest Self-Assembled Cyclodextrin Carriers: Implications for Responsive Drug Delivery and Biomedical Engineering. Adv. Funct. Mater. 2020, 30, 1909049. https://doi.org/10.1002/adfm.201909049.

Winter, C.A., Risley, E.A., Nuss, C.W. (1962). Carrageenan–induced oedema in the hind paw of the rat as an assay for anti–inflammatory drugs. Proc. Soc. Exp. Biol. Med. 111:544–547.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Copyright (c) 2022 Nigerian Journal of Physiological Sciences