Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy.
The protective and adverse effect potentials of levetiracetam ((S)-alpha-ethyl-2-oxo-pyrrolidine acetamide) in rodent models of seizures and epilepsy were compared with the profile of several currently prescribed and newly developed antiepileptic drugs. Levetiracetam was devoid of anticonvulsant activity in the acute maximal electroshock seizure test and in the maximal pentylenetetrazol seizure test in mice (up to 540 mg/kg, i.p.) but exhibited potent protection against generalised epileptic seizures in electrically and pentylenetetrazol-kindled mice (ED50 values = 7 and 36 mg/kg, respectively, i.p.). This differs markedly from established and most new antiepileptic drugs which induce significant protection in both the acute seizure tests and the kindling models. Furthermore, levetiracetam was devoid of anticonvulsant activity in several maximal chemoconvulsive seizure tests although an interesting exception was the potent protection observed against secondarily generalised activity from focal seizures induced by pilocarpine in mice (ED50 value = 7 mg/kg, i.p.), pilocarpine and kainic acid in rats (minimum active dose = 17 and 54 mg/kg, respectively, i.p.). The protection afforded by levetiracetam on the threshold for methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM)-induced seizures persisted after chronic administration (17-170 mg/kg, i.p., twice daily/14 days) and levetiracetam did not lower the seizure threshold for the proconvulsant action of the inverse benzodiazepine receptor agonist, N-methyl-beta-carboline-3-carboxamide (FG 7142). The main metabolite of levetiracetam (ucb L057; (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid) was found to be inactive in sound-sensitive mice after acute administration of doses up to 548 mg/kg, i.p. Levetiracetam induced only minor behavioural alterations in both normal and amygdala-kindled rats (54-1700 mg/kg, i.p.) resulting in an unusually high safety margin between rotarod impairment and seizure suppression of 148 in corneally kindled mice and 235 in Genetic Absence Epilepsy Rats from Strasbourg. In comparison, existing antiepileptic drugs have ratios between 2 and 17 in the corneally kindled mouse model. These studies reveal a unique profile of levetiracetam in rodent models. Characteristics are a general lack of anticonvulsant activity against maximal, acute seizures and selective protection with a very high safety margin in genetic and kindled animals and against chemoconvulsants producing partial epileptic seizures. This activity differs markedly from that of the established and newly introduced antiepileptic drugs and appears to derive from the parent compound since its major metabolite was inactive in all models studied. Together these results therefore suggest that levetiracetam may offer an effective, broad-spectrum treatment of epileptic seizures in patients, with a minimum of adverse effects.
Klitgaard
H
H
UCB Pharma Sector, Preclinical CNS Research, Chemin du Foriest, Braine-l'Alleud, Belgium.
Matagne
A
A
Gobert
J
J
Wülfert
E
E
D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004565:Electroconvulsive Therapy; D004827:Epilepsy / Q000188:drug therapy*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D007696:Kindling, Neurologic / Q000187:drug effects; D000077287:Levetiracetam; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000494:pharmacology; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
D000927:Anticonvulsants; D002243:Carbolines; D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D058787:GABA-A Receptor Antagonists; D005442:Flumazenil; D000077287:Levetiracetam; C035874:FG 7142; D003975:Diazepam; D010433:Pentylenetetrazole; D010889:Piracetam