DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20203980

Potentiation of anticonvulsant effect of phenytoin by celecoxib against maximum electroshock induced convulsions in albino rats

Mohammed Naseeruddin Nadeem, Maliha Maqdoom

Abstract


Background: Epilepsy, a chronic neurological disorder affects more than 1% of world population. Despite the availability of a number of antiepileptics, refractoriness to them exists in approximately one third of cases worldwide. Induction of cycloxygenase and increased levels of proinflammatory meditators are seen in epilepsy. P-glycoprotein upregulation due to phenytoin was found to contribute to its pumping out of cell, leading to refractoriness to phenytoin therapy. Also, cycloxygenase-2 inhibitors were found to prevent P-glycoprotein upregulation. Since cycloxygenase-2 inhibition decreases levels of proinflammatory cytokines responsible for neuroinflammation, this study aims to evaluate anticonvulsant effect of celecoxib and also to investigate whether it potentiates the anticonvulsant effect of phenytoin.

Methods: Maximum electroshock seizures (MES) were induced in Albino rats using electroconvulsiometer to evaluate tonic convulsions, identified by tonic hind limb extension (THLE) in rats. A delay in onset of THLE and a reduction in duration of THLE were taken as deciding parameters to ascertain anticonvulsive activity. Rats randomly divided into groups, received pretreatment with celecoxib at 3 doses (10, 20, 40 mg/kg), phenytoin (6.25 mg/kg), phenytoin (12.5 mg/kg) and combination of phenytoin (6.25 mg/kg) with celecoxib (ED50, i.e. 20 mg/kg), before inducing MES seizures and findings compared to control group.

Results: Celecoxib (20 and 40 mg/kg) showed significant anticonvulsant effect by MES test. Also, its combination with phenytoin caused significant decrease in the duration of THLE when compared to phenytoin alone at the same dose.

Conclusions: The results of this study indicate that celecoxib potentiates the anticonvulsant effect of phenytoin.


Keywords


Celecoxib, Phenytoin, Maximum electroshock test, Prostaglandin E2, P-glycoprotein

Full Text:

PDF

References


Epilepsy. World Health Organization. 2019. Available at: https://www.who.int/news-room/fact-sheets/detail/epilepsy. Accessed on 20 June 2019.

Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J. Epileptic seizures and epilepsy: definitions proposed by the international league against epilepsy (ILAE and the International Bureau for Epilepsy (IBE). Epilepsia. 2005;46:470-2.

Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51:1069-77.

Schiller Y, Najjar Y. Quantifying the response to antiepileptic drugs: effect of past treatment history. Neurology. 2008;70:54-65.

Luciano AL, Shorvon SD. Results of treatment changes in patients with apparently drug-resistant chronic epilepsy. Ann Neurol. 2007;62:375-81.

Loscher, W. Current status and future directions in the pharmacotherapy of epilepsy. Trends Pharmacol Sci. 2002;23(3):113-8.

Wallenstein MC, Mauss EA. Effect of prostaglandin synthetase inhibitors on experimentally induced convulsions in rats. Pharmacology. 1984;29:85.

Wolfe LS. Possible role of prostaglandins in the nervous system. Adv Neurochem. 1975;1:1.

Loscher W, Potschka H. Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol. 2005;76:22-76.

Wen T, Liu YC, Yang HW, Liu HY, Liu XD, Wang GJ, Xie L. Effect of 21-day exposure of phenobarbital, carbamazepine and phenytoin on P-glycoprotein expression and activity in the rat brain. J Neurol Sci. 2008;270:99-106.

Moerman L, Wyffels L, Slaets D, Raedt R, Boon P, De Vos F. Antiepileptic drugs modulate Pglycoproteins in the brain: a mice study with (11)C-desmethylloperamide. Epilepsy Res. 2011;94:18-25.

Bauer B, Hartz AM, Pekcec A, Toellner K, Miller DS, Potschka H. Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling. Mol Pharmacol. 2008;73:1444-53.

Zibell G, Unkruer B, Pekcec A, Hartz AM, Bauer B, Miller DS, Potschka H. Prevention of seizure induced up-regulation of endothelial P-glycoprotein by COX-2 inhibition. Neuropharmacology.2009;56:849-55.

van Vliet EA, Zibell G, Pekcec A, Schlichtiger J, Edelbroek PM, Holtman L, Aronica E, Gorter JA, Potschka H. COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats. Neuropharmacology. 2010;58:404-12.

Löscher W. The pharmacokinetics of antiepileptic drugs in rats: consequences for maintaining effective drug levels during prolonged drug administration in rat models of epilepsy. Epilepsia. 2007;48(7):1245-58.

Shafiq N, Malhotra S, Pandhi P. Anticonvulsant action of celecoxib (alone and in combination with sub-threshold dose of phenytoin) in electroshock induced convulsion. Method Find Ex. Clin Pharmacol. 2003;25(2):87-90.

Castel-Branco MM, Alves GL, Figueiredo IV, Falcão AC, Caramona MM. The maximal electroshock seizure (MES) model in the preclinical assessment of potential new antiepileptic drugs. Methods Find Exp Clin Pharmacol. 2009;31(2):101-6.

Jung KH, Chu K, Lee ST, Kim J, Sinn DI, Kim JM, Park DK, Lee JJ, Kim SU, Kim M, Lee SK, Roh JK. Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neurobiol Dis. 2006;23:237-46.

Citraro R, Leo A, Marra R, De Sarro G, Russo E. Antiepileptogenic effects of the selective COX-2 inhibitor etoricoxib, on the development of spontaneous absence seizures in WAG/Rij rats. Brain Res Bull. 2015;113:1-7.

Dhir A, Naidu PS, Kulkarni SK. Effect of cyclooxygenase-2 (COX-2) inhibitors in various animal models (bicuculline, picrotoxin, maximal electroshock induced convulsions) of epilepsy with possible mechanism of action. Indian J Exp Biol. 2006;44:286-91.

Srivastava AK, Gupta YK. Aspirin modulates the anticonvulsant effect of diazepam and sodium valproate in pentylenetetrazole and maximal electroshock induced seizures in mice. Indian J Physiol Pharmacol. 2001;45:475-80.

Dhir A, Kulkarni SK. Rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor potentiates the anticonvulsant activity of tiagabine against pentylenetetrazol-induced convulsions in mice. Inflammopharmacology. 2006;14(5-6):222-5.

Dhir A, Akula KK, Kulkarni SK. Rofecoxib potentiates the anticonvulsant effect of topiramate. Inflammopharmacology. 2008;16(2):83-6.

Kaminski R, Kozicka M, Parada-turska J, Dziki M, Kleinrok Z, Turski WA, et al. Effect of non-steroidal anti-inflammatory drugs on the anticonvulsive activity of valproate and diphenyl hydantoin against maximal electroshock induced seizures in mice. Pharmacol Res. 1998;37:375-81.

Dey A, Kang X, Qiu J, Du Y, Jiang J. Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside. Trends Pharmacol Sci. 2016;37(6):463-84.

Molina-Holgado E, Ortiz S, Molina-Holgado F, Guaza C. Induction of COX-2 and PGE(2) biosynthesis by IL-1beta is mediated by PKC and mitogen-activated protein kinases in murine astrocytes. Br J Pharmacol. 2000;131:152-9.

Mark KS, Trickler WJ, Miller DW. Tumor necrosis factor-alpha induces cyclooxygenase-2 expression and prostaglandin release in brain microvessel endothelial cells. J Pharmacol Exp Ther. 2001;297:1051-8.

Kawaguchi K, Hickey RW, Rose ME, Zhu L, Chen J, Graham SH. Cyclooxygenase-2 expression is induced in rat brain after kainate-induced seizures and promotes neuronal death in CA3 hippocampus. Brain Res. 2005;1050:130-7.

Takemiya T, Maehara M, Matsumura K, Yasuda S, Sugiura H, Yamagata K. Prostaglandin E2 produced by late induced COX-2 stimulates hippocampal neuron loss after seizure in the CA3 region. Neurosci Res. 2006;56:103-10.

Nishihara I, Minami T, Watanabe Y, Ito S, Hayaishi O. Prostaglandin E2 stimulates glutamate release from synaptosomes of rat spinal cord. Neurosci Lett. 1995;196:57-60.

Sang N, Zhang J, Marcheselli V, Bazan NG, Chen C. Postsynaptically synthesized prostaglandin E2 (PGE2) modulates hippocampal synaptic transmission via a presynaptic PGE2 EP2 receptor. J Neurosci. 2005;25:9858-70.

Jiang J, Quan Y, Ganesh T, Pouliot WA, Dudek FE, Dingledine R. Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation. Proc Natl Acad Sci USA. 2013;110:3591-6.

Lin TY, Lu CW, Wang CC, Huang SK, Wang SJ. Cyclooxygenase 2 inhibitor celecoxib inhibits glutamate release by attenuating the PGE2/EP2 pathway in rat cerebral cortex endings. J Pharmacol Exp Ther. 2014;351:134-45.

Vieira MJ, Perosa SR, Argaaaraz GA, Silva JA Jr, Cavalheiro EA, Graca Naffah- Mazzacoratti M. Indomethacin can downregulate the levels of inflammatory mediators in the hippocampus of rats submitted to pilocarpine-induced status epilepticus. Clinics. 2014;69:621-6.

Kunz T, Oliw EH. The selective cyclooxygenase-2 inhibitor rofecoxib reduces kainate-induced cell death in the rat hippocampus. Eur J Neurosci. 2001b;13:569-75.

Oliveira MS, Furian AF, Royes LF, Fighera MR, Fiorenza NG, Castelli M, Machado P, Bohrer D, Veiga M, Ferreira J, Cavalheiro EA, Mello CF. Cyclooxygenase-2/PGE2 pathway facilitates pentylenetetrazol-induced seizures. Epilepsy Res. 2008;79:14-21.

Polascheck N, Bankstahl M, Löscher W. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp Neurol. 2010;224:219-33.

Loscher W, Potschka H. Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol. 2005;76:22-76.

Brandt C, Bethmann K, Gastens AM, Loscher W. The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol Dis. 2006;24:202-11.

van Vliet EA, van Schaik R, Edelbroek PM, Redeker S, Aronica E, Wadman WJ, Marchi N, Vezzani A, Gorter JA. Inhibition of the multidrug transporter P-glycoprotein improves seizure control in phenytoin-treated chronic epileptic rats. Epilepsia. 2006;47:672-80.