Effect of flavonol and its dimethoxy derivatives on paclitaxel-induced peripheral neuropathy in mice

Effect of flavonol and its dimethoxy derivatives on paclitaxel-induced peripheral neuropathy in mice Vijaykumar Sayeli Department of Pharmacology, Mamata Medical College , Khammam, Telangana , India , Phone: 7845362994 Jagan Nadipelly Department of Pharmacology, Faculty of Medicine-Pharmacology, Texila American University , Georgetown , Guyana Parimala Kadhirvelu Department of Pharmacology , Meenakshi Medical College and Research Institute, Meenakshi Academy of Higher Education and Research , Enathur, Kanchipuram, Tamil Nadu , India Binoy Varghese Cheriyan Department of Pharmaceutical Chemistry, VISTAS, Vels School of Pharmaceutical Sciences , Chennai, Tamil Nadu , India Jaikumar Shanmugasundaram Department of Pharmacology , Meenakshi Medical College and Research Institute, Meenakshi Academy of Higher Education and Research , Enathur, Kanchipuram, Tamil Nadu , India Viswanathan Subramanian Department of Pharmacology , Meenakshi Medical College and Research Institute, Meenakshi Academy of Higher Education and Research , Enathur, Kanchipuram, Tamil Nadu , India Abstract Background:

Peripheral neuropathy is the dose limiting side effect of many anticancer drugs. Flavonoids exhibit good antinociceptive effect in animal models. Their efficacy against different types of nociception has been documented. The present study investigated the effect of flavonol (3-hydroxy flavone), 3′,4′-dimethoxy flavonol, 6,3′-dimethoxy flavonol, 7,2′-dimethoxy flavonol and 7,3′-dimethoxy flavonol against paclitaxel-induced peripheral neuropathy in mice.
Methods:

A single dose of paclitaxel (10 mg/kg, i.p.) was administered to induce peripheral neuropathy in mice and the manifestations of peripheral neuropathy such as tactile allodynia, cold allodynia and thermal hyperalgesia were assessed 24 h later by employing Von Frey hair aesthesiometer test, acetone bubble test and hot water tail immersion test, respectively. The test compounds were prepared as a suspension in 0.5% carboxymethyl cellulose and were administered s.c. in various doses (25, 50, 100 and 200 mg/kg). The above behavioral responses were assessed prior to and 30 min after drug treatment. In addition, the effect of test compounds on proinflammatory cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β) and free radicals was investigated by using suitable in vitro assays.
Results:

A dose-dependent attenuation of tactile allodynia, cold allodynia and thermal hyperalgesia was evidenced in mice treated with flavonol derivatives. The test compounds inhibited TNF-α, IL-1β and free radicals in a concentration-dependent manner.
Conclusions:

These results revealed that flavonol and its dimethoxy derivatives ameliorated the manifestations of paclitaxel-induced peripheral neuropathy in mice. The inhibition of proinflammatory cytokines and free radicals could contribute to this beneficial effect.
09 25 2018 04 13 2018 09 01 2018 525 535 10.1515/jbcpp-2016-0127 10.1515/jbcpp-2016-0127 https://www.degruyter.com/document/doi/10.1515/jbcpp-2016-0127/html https://www.degruyter.com/document/doi/10.1515/jbcpp-2016-0127/pdf http://www.degruyter.com/view/j/jbcpp.2018.29.issue-5/jbcpp-2016-0127/jbcpp-2016-0127.xml https://www.degruyter.com/document/doi/10.1515/jbcpp-2016-0127/xml 10.2174/157015906776359568 Scripture CD, Figg WD, Sparreboom A. Peripheral neuropathy induced by Paclitaxel: recent insights and future perspectives. Curr Neuropharmacol 2006;4:165–72.10.2174/15701590677635956818615126 10.1097/01.PHM.0000154905.18445.0F Stacey BR. Management of peripheral neuropathic pain. Am J Phys Med Rehabil 2005;84:4–16. 10.1016/j.pbb.2010.03.010 Vidyalakshmi K, Kamalakannan P, Viswanathan S, Ramaswamy S. Antinociceptive effect of certain dihydroxy flavones in mice. Pharmacol Biochem Behav 2010;96:1–6.2034636910.1016/j.pbb.2010.03.010 10.1016/j.ejphar.2014.01.033 Kamalakannan P, Vidyalakshmi K, Viswanathan S, Ramaswamy S. Antinociceptive effect of certain dimethoxy flavones in mice. Euro J Pharmacol 2014;727:148–57.10.1016/j.ejphar.2014.01.033 10.1124/jpet.105.092825 Meotti FC, Luiz AP, Pizzolathi MG, Kasuya CA, Calixto JB, Santos AR. Analysis of the antinociceptive effects of flavonoid myricitrin; evidence for the role of L-arginine–nitric oxide and protein kinase C pathways. J Pharmacol Exp Ther 2006;316:789–96.16260583 10.1186/1744-8069-9-53 Azevedo MI, Anamaria FP, Ricardo BN, Flavio ER, Gerly AB, Deysi VT, et al. The antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin-induced chronic painful peripheral neuropathy. Mol Pain 2013;9:53.24152430 10.1371/journal.pone.0123122 Xifro X, Vidal-Sancho L, Boedas-Vaello P, Turrado C, Alberch J, Puig T, et al. Novel epigallocatechin-3-gallate (EGCG) derivative as a new therapeutic strategy for reducing neuropathic pain after chronic constriction nerve injury in mice. PLoS One 2015;9:1–15. 10.1016/j.neuroscience.2011.12.023 Xiao WH, Zheng H, Bennett GJ. Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel. Neuroscience 2012;203:194–206.10.1016/j.neuroscience.2011.12.02322200546 10.1016/j.ejpain.2008.03.003 Hidaka T, Shima T, Nagira K, Masahiro L, Takafumi N, Yukiko A, et al. Herbal medicine Shakuyakukanzo – to reduce paclitaxel-induced painful peripheral neuropathy in mice. Eur J Pain 2009;13:22–7.10.1016/j.ejpain.2008.03.003 10.1016/S0304-3959(00)00240-2 Takasaki I, Andoh T, Shiraki K, Kuraishi Y. Allodynia and hyperalgesia induced by herpes simplex virus type-1 infection in mice. Pain 2000;86:95–101.1077966610.1016/S0304-3959(00)00240-2 10.1016/j.pain.2004.01.029 Flatters SJ, Bennett GJ. Ethosuximide reverses paclitaxel and vincristine-induced painful peripheral neuropathy. Pain 2004;109:150–61.1508213710.1016/j.pain.2004.01.029 10.1186/1744-8069-5-9 Ta LE, Low PA, Windebank AJ. Mice with cisplatin and oxaliplatin-induced painful neuropathy develop distinct early responses to thermal stimuli. Mol Pain 2009;5:9.19245717 10.1111/j.2042-7158.1997.tb06761.x Sreejayan N, Rao MN. Nitric oxide scavenging by curcuminoids. J Pharm Pharmacol 1997;49:105–7.10.1111/j.2042-7158.1997.tb06761.x9120760 10.1016/0891-5849(95)02014-4 Cotelle N, Bernier JL, Catteau JP, Pommery J, Wallet JC, Gaydou EM. Anti-oxidant properties of hydroxy flavones. Free Radical Biol Med 1996;20:35–43.10.1016/0891-5849(95)02014-4 10.1056/NEJMoa021420 Rowbotham MC, Twilling L, Davies PS, Reisner L, Taylor K, Mohr D. Oral opioid therapy for chronic peripheral and central neuropathic pain. N Engl J Med 2003;348:1223–32.1266038610.1056/NEJMoa021420 10.1111/j.1440-1681.1993.tb01503.x Thirugnanasambantham P, Viswanathan S, Ramaswamy S, Krishnamoorty V, Mythirayee C, Kameswaran L. Analgesic activity of flavone derivatives, a structure activity study. Clin Exp Pharmacol Physiol 1993;20:59–61.10.1111/j.1440-1681.1993.tb01503.x8432041 10.1016/j.jff.2008.09.003 Li S, Pan M-H, Lo C-Y, Tan D, Wang Y, Shahidi F, et al. Chemistry and health effects of polymethoxy flavones and hydroxylated polymethoxy flavones. J Funct Foods 2009;1:2–12.10.1016/j.jff.2008.09.003 10.1016/S0006-2952(03)00203-X Lin N, Sato T, Takayama Y, Mimakai Y, Sashida Y, Yano M, et al. Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovisl fibroblasts and mouse macrophages. Biochem Pharmacol 2003;65:2065–71.10.1016/S0006-2952(03)00203-X12787887 10.2174/1871523011202030253 Vidyalakshmi K, Kamalakannan P, Viswanathan S, Ramaswamy S. Anti-inflammatory effect of certain dihydroxy flavones and the mechanisms involved. Anti-inflamm Antiallergy Agents Med Chem 2012;11:253–61.10.2174/1871523011202030253 10.1007/s10787-015-0242-3 Kamalakannan P, Vidyalakshmi K, Viswanathan S, Ramaswamy S. Anti-inflammatory effect of certain dimethoxy flavones. Inflammopharmacology 2015;23:307–17.10.1007/s10787-015-0242-326248971 10.1016/j.neulet.2008.03.052 Schafers M, Sorkin L. Effect of cytokines on neuronal excitability. Neurosci Lett 2008;437:188–93.1842034610.1016/j.neulet.2008.03.052 10.1097/00001756-199605310-00010 Tal M. A novel antioxidant alleviates heat hyperalgesia in rats with an experimental painful peripheral neuropathy. Neuro Report 1996;7:1382–4. 10.1097/ALN.0b013e3181ca31bd Kim HK, Zhang YP, Gwak YS, Abdi S. Phenyl N-tert-butylnitrone, a free radical scavenger, reduces mechanical allodynia in chemotherapy-induced neuropathic pain in rats. Anesthesiology 2010;112:432–9.2006845110.1097/ALN.0b013e3181ca31bd 10.1016/0041-0101(81)90022-2 Agarwal OP, Nagarathnam A. Radioprotective property of flavonoids in mice. Toxicon 1981;19:201–4.726879510.1016/0041-0101(81)90022-2 10.1016/0009-3084(92)90019-L Wang PF, Zheng RL. Inhibition of the autooxidation of linoleic acid by flavonoids in micelles. Chem Phys Lipids 1992;63:37–40.10.1016/0009-3084(92)90019-L