Anticonvulsant effect of nifedipine, dizepam and in combination on pentylenetetrazol induced experimental models of epilepsy on albino rats
Keywords:Calcium channel blockers, Diazepam, Epilepsy, Sodium valproate, Pentylenetetrazol
Background: In many patients, the presently available antiepileptic drugs such as phenobarbital, phenytoin, benzodiazepines, sodium valproate, etc., are unable to control seizures efficiently and the problem of adverse effects has also not been circumvented completely and approximately 30% of the patients continue to have seizures with current antiepileptic drugs therapy. Hence, search should continue to develop newer, more effective, and safer neuro-protective agents for treatment of epilepsy. Aim of the study was to investigate the activity of nifedipine, the dihydropyridine calcium channel blocker, diazepam, the benzodiazepine anti- convulsant of established efficacy and their combinations against rat models of pentylenetetrazol (PTZ) induced convulsions. Method: Wister albino rats of either sex, weighing between 150-220gm were used. Rats were divided into 10 groups, in each group n=6 total N=60.
Methods: PTZ was administration 30 min after test drug administration. Intraperitoneal injection of PTZ at the dose of 80mg/Kg body weight were administered to the rats to produce chemically-induced seizure. The effect of nifedipine and diazepam were assessed on such seizure model. The onset and duration of clonic convulsion were recorded.
Results: The onset time of PTZ-induced clonic convulsion was significantly prolonged with the Nifedipine in the doses of 4mg and 8mg per Kg. in comparison to nifedipine in dose of 2mg per Kg. The interesting observation was that while Diazepam in 1mg/Kg. dose significantly (P<0.05) prolonged the onset time, there was significant decrease (P <0.001) in the onset time of PTZ-induced clonic convulsion with diazepam in doses of 2 and 4mg per Kg. in comparison to Diazepam 1mg per Kg. But the combination of diazepam 2.5 mg and Nifedipine 2.6mg and 5.3mg exhibited significant prolongation of the onset time. Diazepam 1 and 2mg per Kg was found to be equally effective in reduction of convulsion time, while 4mg dose showed more reduction of convulsion time. The combination of diazepam and nifedipine showed no better reduction in the convulsion time and also valproic acid in doses of 135mg. Kg.
Conclusions: Nifedipine (3-5mg/Kg) and diazepam (2.5mg/Kg.) combination delayed the onset of convulsion. Diazepam 2mg / Kg. alone was effective in reduction of duration of convulsion. The combination dose having 2.6mg of nifedipine showed comparable protection with valproic acid 135mg per Kg. while the combination having 5.3mg of nifedipine showed significantly better protection.
Bradley WG. Neurological disorders: Neurology in clinical practice. Butter worth - Heinemann Medical, England. 1991;2:1444-6.
Allan H, Roopper, Maurice Victor. Adams and victor’s principles of Neurology. 10th Edition; McGraw Hill Text, New York; 2014:249-294.
Kutt H, Mcdowell F. Clinical Neuropharmacology: Churchill Living Stone, London. 4: 15-18.
James O, Namara Mc. Pharmacotherapy of the Epilepsy: Goodman and Gilman’s Pharmacological basis of Therapeutics. 2005;11:501-698.
Pumani R, Rurlewizl LJ. Fast Extracellular transients: involvement in epileptic processes. Indian J of Pharma. 2000;32:347-52.
Tortella FC, Robles L, Holaday JW. U50 488 a highly selective Kappa opioid anticonvulsant effect in rats. Indian J of Pharma. 1997;29:194-7.
Ezekiel I, Mabrouk MA, Ayo JO, Goji AD, Okpanachi AO, Mohammed A, et al. Study of the effect of hydro-aqueous extract of Commiphoraafricana (stembark) on sleeping time and convulsion in mice. Asian J Med Sci. 2010;2:85-8.
Bhosle V. Anticonvulsant and antioxidant activity of aqueous leaves extract of Desmodiumtriflorum in mice against pentylenetetrazole and maximal electroshock induced convulsion. RevistaBrasileira de Farmacognosia Brazilian Journal of Pharmacognosy. 2013;23(4):692-8.
Cain SM, Snutch TP. Voltage-Gated Calcium Channels in Epilepsy. Jasper's Basic Mechanisms of the Epilepsies. 4th Edition. National Center for Biotechnology Information (US); 2012.
Rosenberg G. The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell Mol Life Sci. 2007;64(16):2090-103.
Michael A. Rogawski, José Enrique Cavazos. Mechanisms of action of antiepileptic drugs. Available at: http://mr.ucdavis.edu/uploads/1/1/7/5/11757140/ch43.pdf
Keshavarz M, Showraki A, Emamghoreishi M. Anticonvulsant Effect of Guaifenesin against Pentylenetetrazol-Induced Seizure in Mice. Iran J Med Sci. 2013;38(2):116-21.
Sangishetty VP, Anthireddy S, Ambareesh K, Nayak BB, Shinde BB, Ambadas B. Protective Role of Oxitard in Drug Induced Ulcers in Rats. Int J Biol Med Res. 2012;3(3):1948-51.
Phulen S, Bhattacharyya A. Models of epilepsy used in antiepileptic drug discovery: A review. Int J Pharm Pharm Sci. 2014;6(11):1-7.
Khanna N, Bhalla S, Verma V, Sharma KK. Modulatory effects of nifedipine and nimodipine in experimental convulsions. Indian J of Pharma. 2000;32:347-52.
Hanada T, Ido K, Kosasa T. Effect of perampanel, a novel AMPA antagonist, on benzodiazepine-resistant status epilepticus in a lithiumpilocarpine rat model. Pharmacology Research and Perspectives. 2014;2(5):63.
Niquet J, Baldwin R, Norman K, Suchomelva L, Lumley, Wasterlain CG. Midazolam ketamine dual therapy stops cholinergic status epilepticus and reduces morris water maze deficits. Epilepsia. 2016;57(9).
Rocha L. Subchronic treatment with antiepileptic drugs modifies pentylenetetrazol-induced seizures in mice: Its correlation with benzodiazepine receptor binding. Neuropsychiatr Dis Treat. 2008;4(3):619-25.
Coyle JT, Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science. 1993;262(5134):689-95.
Sahadevan P, Rema MN. A comparative experimental study of the anticonvulsant effect of three calcium channel blockers in albino mice. Indian J of Pharma. 2002;34:52-5.
Mante PK, Adongo DW, Woode E. Anticonvulsant effects of antiaris toxicaria aqueous extract: investigation using animal models of temporal lobe epilepsy. BMC Research Notes. 2017;10:167.
Czuczwar SJ, Małek U, Kleinrok Z. Influence of calcium channel inhibitors upon the anticonvulsant efficacy of common antiepileptics against pentylenetetrazol-induced convulsions in mice. Neuropharmacology. 1990;29(10):943-8.
Genkova-Papazova MG, Petkova B, Shishkova N, Lazarova-Bakarova. Effect of the calcium channel blockers nifedipine and diltiazem on pentylenetetrazole kindling-provoked amnesia in rats. European Neuro Psychopharmacology. 2001;11(2):91-6.