RESEARCH PAPER
Isobolographic characterization of interaction of levetiracetam with clobazam in the mouse 6 Hz psychomotor seizure model
 
More details
Hide details
1
Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland; Department of Pathophysiology, Medical University, Lublin, Poland
 
2
Department of Pathophysiology, Medical University, Lublin, Poland
 
3
Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland
 
4
Department of Public Health, Institute of Rural Health, Lublin, Poland
 
 
Corresponding author
Jarogniew J. Łuszczki   

Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, 20-090 Lublin, Poland.
 
 
J Pre Clin Clin Res. 2012;6(1):25-30
 
KEYWORDS
ABSTRACT
Introduction and objective:
The aim of this study was to characterize the anticonvulsant effects of levetiracetam (LEV) in combination with clobazam (CLB – a second-generation antiepileptic drug), in the mouse 6 Hz psychomotor seizure model.

Material and Methods:
Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes. Isobolographic analysis for parallel dose-response relationship curves (DRRCs) was used to characterize the consequent anticonvulsant interactions between the drug combinations. Potential concurrent adverse-effect profiles of interactions between LEV and CLB were evaluated in the chimney (motor performance), passive-avoidance (long-term memory), and grip-strength (muscular strength) tests.

Results:
LEV administered singly was associated with a DRRC that was parallel to that for CLB. With isobolography for parallel DRRCs, the combination of LEV with CLB at three fixed-ratios of 1:3, 1:1 and 3:1 exerted additive interaction. None of the combinations were associated with any concurrent adverse effects with regards to motor coordination, long-term memory or muscular strength.

Conclusions:
LEV combined with CLB exerted additive interaction in the mouse 6 Hz psychomotor seizure model.

 
REFERENCES (53)
1.
Gower AJ, Hirsch E, Boehrer A, Noyer M, Marescaux C. Effects of levetiracetam, a novel antiepileptic drug, on convulsant activity in two genetic rat models of epilepsy. Epilepsy Res. 1995; 22: 207-213.
 
2.
Gower AJ, Noyer M, Verloes R, Gobert J, Wulfert E. Ucb L059, a novel anti-convulsant drug: pharmacological profile in animals. Eur J Pharmacol. 1992; 222: 193-203. Erratum published in: Eur J Pharmacol. 1993; 230: 389.
 
3.
Klitgaard H, Matagne A, Gobert J, Wulfert E. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Eur J Pharmacol. 1998; 353: 191-206.
 
4.
Loscher W, Fassbender CP, Nolting B. The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models. Epilepsy Res. 1991; 8: 79-94.
 
5.
Loscher W, Honack D, Fassbender CP, Nolting B. The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III. Pentylenetetrazole seizure models. Epilepsy Res. 1991; 8: 171-189.
 
6.
Łuszczki JJ, Czuczwar SJ. How significant is the difference between drug doses influencing the threshold for electroconvulsions? Pharmacol Rep. 2005; 57: 782-786.
 
7.
Toman JE. Neuropharmacologic considerations in psychic seizures. Neurology 1951; 1: 444-460.
 
8.
Toman JE, Everett GM, Richards RK. The search for new drugs against epilepsy. Tex Rep Biol Med. 1952; 10: 96-104.
 
9.
Loscher W, Honack D. Profile of ucb L059, a novel anticonvulsant drug, in models of partial and generalized epilepsy in mice and rats. Eur J Pharmacol 1993; 232: 147-158.
 
10.
Brown WC, Schiffman DO, Swinyard EA, Goodman LS. Comparative assay of an antiepileptic drugs by psychomotor seizure test and minimal electroshock threshold test. J Pharmacol Exp Ther. 1953; 107: 273-283.
 
11.
Barton ME, Klein BD, Wolf HH, White HS. Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy. Epilepsy Res. 2001; 47: 217-227.
 
12.
Wojda E, Wlaź A, Patsalos PN, Łuszczki JJ. Isobolographic characterization of interactions of levetiracetam with the various antiepileptic drugs in the mouse 6 Hz psychomotor seizure model. Epilepsy Res. 2009; 86: 163-174.
 
13.
Marrosu F, Bortolato M, Frau R, Orru M, Puligheddu M, Fa M, Muroni A, Tuveri A, Mereu G. Levetiracetam attenuates spontaneous spikeand- wave discharges in DBA/2J mice. Epilepsy Res. 2007; 75: 224-227.
 
14.
Vinogradova LV, van Rijn CM. Anticonvulsive and antiepileptogenic effects of levetiracetam in the audiogenic kindling model. Epilepsia 2008; 49, 1160-1168.
 
15.
Sills GJ, Butler E, Thompson GG, Brodie MJ. Pharmacodynamic interaction studies with topiramate in the pentylenetetrazol and maximal electroshock seizure models. Seizure 2004; 13: 287-295.
 
16.
Donato Di Paola E, Gareri P, Davoli A, Gratteri S, Scicchitano F, Naccari C, De Sarro G. Influence of levetiracetam on the anticonvulsant efficacy of conventional antiepileptic drugs against audiogenic seizures in DBA/2 mice. Epilepsy Res. 2007; 75: 112-121.
 
17.
Kaminski RM, Matagne A, Patsalos PN, Klitgaard H. Benefits of combination therapy in epilepsy: a review of preclinical evidence with levetiracetam. Epilepsia 2009; 50: 387-397.
 
18.
Łuszczki JJ, Andres MM, Czuczwar P, Cioczek-Czuczwar A, Ratnaraj N, Patsalos PN, Czuczwar SJ. Pharmacodynamic and pharmacokinetic characterization of interactions between levetiracetam and numerous antiepileptic drugs in the mouse maximal electroshock seizure model: an isobolographic analysis. Epilepsia 2006; 47: 10-20.
 
19.
Mazarati AM, Baldwin R, Klitgaard H, Matagne A, Wasterlain CG. Anticonvulsant effects of levetiracetam and levetiracetam-diazepam combinations in experimental status epilepticus. Epilepsy Res. 2004; 58: 167-174.
 
20.
Łuszczki JJ, Andres-Mach MM, Ratnaraj N, Patsalos PN, Czuczwar SJ. Levetiracetam and felbamate interact both pharmacodynamically and pharmacokinetically: an isobolographic analysis in the mouse maximal electroshock model. Epilepsia 2007; 48: 806-815.
 
21.
Dudra-Jastrzebska M, Andres-Mach MM, Ratnaraj N, Patsalos PN, Czuczwar SJ, Łuszczki JJ. Isobolographic characterization of the anticonvulsant interaction profiles of levetiracetam in combination with clonazepam, ethosuximide, phenobarbital and valproate in the mouse pentylenetetrazole-induced seizure model. Seizure 2009; 18: 607-614.
 
22.
Dudra-Jastrzebska M, Andres-Mach MM, Sielski M, Ratnaraj N, Patsalos PN, Czuczwar SJ, Łuszczki JJ. Pharmacodynamic and pharmacokinetic interaction profiles of levetiracetam in combination with gabapentin, tiagabine and vigabatrin in the mouse pentylenetetrazole-induced seizure model: An isobolographic analysis. Eur J Pharmacol. 2009; 605: 87-94.
 
23.
Łuszczki JJ, Andres MM, Czuczwar P, Cioczek-Czuczwar A, Wojcik- Cwikla J, Ratnaraj N, Patsalos PN, Czuczwar SJ. Levetiracetam. selectively potentiates the acute neurotoxic effects of topiramate and carbamazepine in the rotarod test in mice. Eur Neuropsychopharmacol. 2005; 15: 609 616.
 
24.
Litchfield JT, Wilcoxon F. A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther. 1949; 96: 99-113.
 
25.
Łuszczki JJ, Czuczwar SJ. Isobolographic profile of interactions between tiagabine and gabapentin: a preclinical study. Naunyn-Schmiedebergs Arch Pharmacol. 2004; 369: 434-446.
 
26.
Łuszczki JJ, Ratnaraj N, Patsalos PN, Czuczwar SJ. Isobolographic and behavioral characterizations of interactions between vigabatrin and gabapentin in two experimental models of epilepsy. Eur J Pharmacol. 2008; 595: 13-21.
 
27.
Tallarida RJ. Drug synergism and dose-effect data analysis. Chapman & Hall/CRC, Boca Raton, USA. 2000.
 
28.
Łuszczki JJ, Ratnaraj N, Patsalos PN, Czuczwar SJ. Isobolographic analysis of interactions between loreclezole and conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model. Naunyn-Schmiedebergs Arch Pharmacol. 2006; 373: 169-181.
 
29.
Loewe S. The problem of synergism and antagonism of combined drugs. Arzneimittelforschung 1953; 3: 285-290.
 
30.
Łuszczki JJ, Antkiewicz-Michaluk L, Czuczwar SJ. Isobolographic analysis of interactions between 1-methyl-1,2,3,4-tetrahydroisoquinoline and four conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model. Eur J Pharmacol. 2009; 602: 298- 305.
 
31.
Meyer OA, Tilson HA, Byrd WC, Riley MT. A method for the routine assessment of fore- and hindlimb grip strength of rats and mice. Neurobehav Toxicol. 1979; 1: 233-236.
 
32.
Boissier JR, Tardy J, Diverres JC. Une nouvelle methode simple pour explorer l’action tranquilisante: le test de la cheminee. Med Exp. (Basel) 1960; 3: 81-84.
 
33.
Venault P, Chapouthier G, de Carvalho LP, Simiand J, Morre M, Dodd RH, Rossier J. Benzodiazepine impairs and beta-carboline enhances performance in learning and memory tasks. Nature 1986; 321: 864-866.
 
34.
Patsalos PN. Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet. 2004; 43: 707-724.
 
35.
Ng YT, Collins SD. Clobazam. Neurotherapeutics 2007; 4: 138-144.
 
36.
Doi T, Ueda Y, Tokumaru J, Willmore LJ. Molecular regulation of glutamate and GABA transporter proteins by clobazam during epileptogenesis in Fe(+++)-induced epileptic rats. Brain Res Mol Brain Res. 2005; 142: 91-96.
 
37.
Madeja M, Margineanu DG, Gorji A, Siep E, Boerrigter P, Klitgaard H, Speckmann EJ. Reduction of voltage-operated potassium currents by levetiracetam: a novel antiepileptic mechanism of action? Neuropharmacology 2003; 45: 661-671.
 
38.
Lukyanetz EA, Shkryl VM, Kostyuk PG. Selective blockade of N-type calcium channels by levetiracetam. Epilepsia 2002; 43: 9-18.
 
39.
Niespodziany I, Klitgaard H, Margineanu DG. Levetiracetam inhibits the high-voltage-activated Ca(2+) current in pyramidal neurones of rat hippocampal slices. Neurosci Lett. 2001; 306: 5-8.
 
40.
Zona C, Niespodziany I, Marchetti C, Klitgaard H, Bernardi G, Margineanu DG. Levetiracetam does not modulate neuronal voltagegated Na+ and T-type Ca2+ currents. Seizure 2001; 10: 279-286.
 
41.
Rigo JM, Hans G, Nguyen L, Rocher V, Belachew S, Malgrange B, Leprince P, Moonen G, Selak I, Matagne A, Klitgaard H. The antiepileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents. Br J Pharmacol. 2002; 136: 659-672.
 
42.
Palma E, Roseti C, Maiolino F, Fucile S, Martinello K, Mazzuferi M, Aronica E, Manfredi M, Esposito V, Cantore G, Miledi R, Simonato M, Eusebi F. GABA(A)-current rundown of temporal lobe epilepsy is associated with repetitive activation of GABA(A) “phasic” receptors Proc Natl Acad Sci USA 2007; 104: 20944-20948.
 
43.
Nagarkatti N, Deshpande LS, DeLorenzo RJ. Levetiracetam inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture. Neurosci Lett. 2008; 436: 289-293.
 
44.
Lee CH, Lee CY, Tsai TS, Liou HH. PKA-mediated phosphorylation is a novel mechanism for levetiracetam, an antiepileptic drug, activating ROMK1 channels. Biochem Pharmacol. 2008; 76: 225-235.
 
45.
Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, Fuks B. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA 2004; 101: 9861-9866.
 
46.
Łuszczki JJ, Swiader M, Czuczwar M, Kis J, Czuczwar SJ. Interactions of tiagabine with some antiepileptics in the maximal electroshock in mice. Pharmacol Biochem Behav. 2003; 75: 319-327.
 
47.
Łuszczki JJ, Andres-Mach M, Barcicka-Klosowska B, Florek-Łuszczki M, Haratym-Maj A, Czuczwar SJ. Effects of WIN 55,212-2 mesylate (a synthetic cannabinoid) on the protective action of clonazepam, ethosuximide, phenobarbital and valproate against pentylenetetrazoleinduced clonic seizures in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35: 1870-1876.
 
48.
Łuszczki JJ, Misiuta-Krzesinska M, Florek M, Tutka P, Czuczwar SJ. Synthetic cannabinoid WIN 55,212-2 mesylate enhances the protective action of four classical antiepileptic drugs against maximal electroshockinduced seizures in mice. Pharmacol Biochem Behav. 2011; 98: 261-267.
 
49.
Łuszczki JJ, Swiader M, Parada-Turska J, Czuczwar SJ. Tiagabine synergistically interacts with gabapentin in the electroconvulsive threshold test in mice. Neuropsychopharmacology 2003; 28: 1817-1830.
 
50.
Łuszczki JJ, Wojcik-Cwikla J, Andres MM, Czuczwar SJ. Pharmacological and behavioral characteristics of interactions between vigabatrin and conventional antiepileptic drugs in pentylenetetrazole-induced seizures in mice: an isobolographic analysis. Neuropsychopharmacology 2005; 30: 958-973.
 
51.
Perucca E. Pharmacological principles as a basis for polytherapy. Acta Neurol Scand Suppl. 1995; 162: 31-34.
 
52.
Deckers CLP, Genton P, Sills GJ, Schmidt D. Current limitations of antiepileptic drug therapy: a conference review. Epilepsy Res. 2003; 53: 1-17.
 
53.
Łuszczki JJ, Czuczwar SJ. Preclinical profile of combinations of some second-generation antiepileptic drugs: an isobolographic analysis. Epilepsia 2004; 45: 895-907.
 
eISSN:1898-7516
ISSN:1898-2395
Journals System - logo
Scroll to top