Anticonvulsant and sodium channel blocking effects of ralitoline in different screening models.
Ralitoline, a thiazolidinone derivative chemically distinct from known antiepileptic drugs, possesses remarkable anticonvulsant properties as demonstrated in various animal models of epilepsy. The efficacy of this compound seems to be comparable or even better than that of conventional antiepileptics. In the present study, the activity of ralitoline was investigated in four seizure models in rodents in order to characterize the anticonvulsant profile of action further. In the maximal electroshock seizure test (mice), this compound showed marked anticonvulsant effects (ED50 2.8 mg/kg i.p.). The efficacy of clinically established anti-epileptics was significantly increased when ralitoline was given as co-medication. In the strychnine seizure test (mice), ralitoline (5 and 10 mg/kg) prolonged the latency of tonic seizures as well as the survival time. On the other hand, in the subcutaneous pentylenetetrazol seizure threshold test (mice), this drug revealed limited protective actions at higher doses and increased the effectiveness of ethosuximide. In unrestrained rats with chronically implanted electrodes, ralitoline (5 mg/kg) significantly reduced the duration of electrically-evoked hippocampal discharges and raised the focal stimulation threshold (10 mg/kg). In the rotorod ataxia test (mice), a TD50 value of 14.5 mg/kg i.p. was determined for ralitoline (protective index TD50/MES-ED50 5.2). With regard to the possible mode of action, whole-cell voltage-clamp experiments on cultured neonatal rat cardiomyocytes showed that ralitoline may act specifically on voltage-sensitive sodium channels. The compound inhibited the fast sodium inward current in a frequency- and voltage-dependent manner. In conclusion, the findings confirm the potent anticonvulsant effects of ralitoline, especially against generalized tonic-clonic and complex partial seizures. Moreover, in combination with antiepileptics, an additive synergism can be found at lower concentrations. Regarding the mode of action, this drug was capable of depressing the fast sodium inward current in cultured heart ventricular cells, suggesting that the local anesthetic properties may be important for the anticonvulsant activity of ralitoline.
Fischer
W
W
Institut für Pharmacokologie und Toxikologie, Universität Leipzig, Federal Republic of Germany.
Bodewei
R
R
Satzinger
G
G
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004558:Electric Stimulation; D008297:Male; D051379:Mice; D008954:Models, Biological; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors / Q000633:toxicity; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D015222:Sodium Channels / Q000187:drug effects*; D013331:Strychnine / Q000037:antagonists & inhibitors / Q000633:toxicity; D013844:Thiazoles / Q000627:therapeutic use*
D000927:Anticonvulsants; D015222:Sodium Channels; D013844:Thiazoles; D013331:Strychnine; C054894:Ralitoline; D010433:Pentylenetetrazole; D010634:Phenobarbital