Anticonvulsant action of the nucleoside transport inhibitor, soluflazine, on synaptic and non-synaptic epileptogenesis in the guinea-pig hippocampus.
The effects of the nucleoside transport inhibitor, soluflazine, were examined on synaptic and non-synaptic epileptogenesis, and on paired-pulse facilitation and inhibition in the CA1 region of the guinea-pig hippocampal slice. In the model of synaptic epileptogenesis, excitation was enhanced by omitting Mg2+ from the artificial cerebrospinal fluid (ACSF). This procedure induced a second epileptogenic population spike (PS) after orthodromic stimulation, which was inhibited by soluflazine (IC50 value 1.2 x 10(-6) M). In the non-synaptic model of epileptogenesis spontaneous depolarizing 'burst' discharges were induced in CA1 by lowering the concentration of Ca2+ and increasing the concentration of K+ and Mg2+. The IC50 value of soluflazine was 6.0 x 10(-7) M for antagonizing 'burst' frequency and 7.5 x 10(-6) M for 'burst' amplitude, indicating a preferential effect on 'burst' initiation. After paired orthodromic stimuli to stratum radiatum, the amount of synaptic facilitation of PS amplitude was significantly increased by soluflazine. This was mainly due to a decrease in the size of the PS induced by the conditioning pulse. The amount of PS inhibition after antidromic/orthodromic stimulation was not significantly altered by soluflazine. With the exception of the failure of soluflazine to attenuate inhibition, the results obtained with soluflazine resemble those reported for adenosine. This strengthens the hypothesis that soluflazine increases the extracellular concentration of adenosine. Further, the results indicate that centrally active nucleoside transport inhibitors may be a new class of antiepileptic drug.
Ashton
D
D
Department of Neuropharmacology, Janssen Pharmaceutica Research Laboratories, Beerse, Belgium.
De Prins
E
E
Willems
R
R
Van Belle
H
H
Wauquier
A
A
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D004558:Electric Stimulation; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D008274:Magnesium / Q000502:physiology; D008297:Male; D009705:Nucleosides / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D000927:Anticonvulsants; D009705:Nucleosides; D010879:Piperazines; C054695:soluflazine; D008274:Magnesium; D002118:Calcium