Caffeine-induced epileptiform field potentials in rat hippocampal slices: a pharmacological characterization.
Pharmacological modulation of the epileptiform electric activity induced by caffeine, 10 mM (CAF) on rat hippocampal slices was studied upon field potential recordings in CA3 area of the slices. This concentration of CAF, reportedly releasing Ca2+ ions from the endoplasmic reticulum, led single fimbrial stimuli to evoke repetitive population spikes (PSs) and induced periodic spontaneous field bursts. Carbamazepine, 50 microM reduced (by <40%) the number of repetitive PSs and the rate of spontaneous bursting, with no significant effect on the amplitude of evoked and spontaneous bursts. Valproate, 1 mM reduced only the number (by approximately 25%), but not the amplitudes, of repetitive PSs. Clonazepam, 1 microM consistently reduced the number of repetitive PSs (by approximately 45%), their amplitudes (by 30-60%), and the amplitude of spontaneous bursts (by approximately 70%). The adenosine receptor agonists 2-chloroadenosine, 5 microM and R(-) N6-(2-phenylisopropyl)adenosine, 1 microM had only scanty anti-CAF activity. The depletor of intracellular Ca2+ stores, thapsigargin, 2 microM transiently inhibited the number of evoked PSs and spontaneous bursting. The blocker of ryanodine receptor opening, ruthenium red had an anti-CAF effect, modest at 30 microM, but very strong at 40 microM. Nifedipine, 20 microM opposed CAF-induced spontaneous bursting, but not the evoked PSs. Flunarizine, 50 microM presented only a transient tendency to delay spontaneous bursting. In conclusion, this in vitro slice model appears readily able to reveal antiepileptic properties, though it does not support unequivocal mechanistic interpretation. Nevertheless, anti-CAF activity in this model would suggest the likely involvement of the neuronal ryanodine receptor-related traffic of calcium.
Margineanu
Doru Georg
DG
Preclinical CNS Research, UCB S.A. Pharma Sector, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium. doru.margineanu@ucb-group.com
Klitgaard
Henrik
H
D015762:2-Chloroadenosine / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002110:Caffeine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000139:chemically induced* / Q000503:physiopathology*; D005071:Evoked Potentials / Q000187:drug effects; D005444:Flunarizine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D010477:Perfusion; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D012430:Ruthenium Red / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology
D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D019837:Ryanodine Receptor Calcium Release Channel; D012430:Ruthenium Red; D015762:2-Chloroadenosine; D002110:Caffeine; D019284:Thapsigargin; D005444:Flunarizine; D002118:Calcium