caa a22 4500 469078421 CHVBK 20180323132942.0 cr unu---uuuuu 170328e19921001xx s 000 0 eng 10.1007/BF00171088 doi (NATIONALLICENCE)springer-10.1007/BF00171088 Anticonvulsant and sodium channel blocking effects of ralitoline in different screening models [Elektronische Daten] [W. Fischer, R. Bodewei, G. Satzinger] Summary: 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 antiepileptics 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. Springer-Verlag, 1992 Ralitoline nationallicence Anticonvulsants nationallicence Seizure models nationallicence Whole-cell voltage-clamp (rat cardiomyocytes) nationallicence Sodium channel nationallicence Fischer W. Institut für Pharmakologie und Toxikologie, Universität Leipzig, Härtelstrasse 16-18, O-7010, Leipzig, Federal Republic of Germany aut Bodewei R. Institut für Herz-Kreislauf-Forschung, O-1115, Berlin-Buch, Federal Republic of Germany aut Satzinger G. Gödecke Forschungsinstitut, W-7800, Freiburg, Federal Republic of Germany aut Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 346/4(1992-10-01), 442-452 0028-1298 346:4<442 1992 346 210 https://doi.org/10.1007/BF00171088 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00171088 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Fischer W. Institut für Pharmakologie und Toxikologie, Universität Leipzig, Härtelstrasse 16-18, O-7010, Leipzig, Federal Republic of Germany aut NATIONALLICENCE 700 1- Bodewei R. Institut für Herz-Kreislauf-Forschung, O-1115, Berlin-Buch, Federal Republic of Germany aut NATIONALLICENCE 700 1- Satzinger G. Gödecke Forschungsinstitut, W-7800, Freiburg, Federal Republic of Germany aut NATIONALLICENCE 773 0- Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 346/4(1992-10-01), 442-452 0028-1298 346:4<442 1992 346 210 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer