Fenfluramine blocks low-Mg2+-induced epileptiform activity in rat entorhinal cortex.
OBJECTIVE
The entorhinal cortex (EC) represents the main input structure to the hippocampus and seems to be critically involved in temporal lobe epilepsy. Considering that the EC receives a strong serotonergic projection from the raphe nuclei and expresses a high density of serotonin (5-HT) receptors, the effect of the 5-HT-releasing drug fenfluramine (FFA) on epileptiform activity generated in the EC was investigated in an in vitro model of epilepsy.


METHODS
The experiments were performed on 43 horizontal slices containing the EC, the subiculum, and the hippocampal formation obtained from 230-250 g adult Wistar rats. Using extracellular recording techniques, we investigated the effect of bath-applied FFA (200 micromol/L to 1 mmol/L) on epileptiform activity induced by omitting MgSO4 from the artificial cerebrospinal fluid.


RESULTS
We demonstrate that FFA reversibly blocks epileptiform activity in the EC. Surprisingly, in the presence of the 5-HT uptake blocker paroxetine, the FFA-induced effect was diminished. Coapplication of the 5-HT1A receptor antagonist WAY100635 prevented the FFA-induced anticonvulsive effect, suggesting that (a) the FFA-induced suppression of epileptiform activity is mediated by the release of 5-HT from synaptic terminals within the EC rather than by an unspecific effect of FFA and (b) released 5-HT most likely blocks the activity by activation of 5-HT1A receptors.


CONCLUSIONS
FFA, which is primarily used because of its anorectic activity, might get an additional therapeutic value in the treatment of temporal lobe epilepsy with parahippocampal involvement.
Gentsch
K
K
Department of Neurophysiology, Institute of Physiology, University Hospital Charité, Humboldt University Berlin, Germany.
Heinemann
U
U
Schmitz
B
B
Behr
J
J
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D004195:Disease Models, Animal; D018728:Entorhinal Cortex / Q000187:drug effects / Q000503:physiopathology*; D004827:Epilepsy / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000503:physiopathology; D005110:Extracellular Space / Q000378:metabolism; D005277:Fenfluramine / Q000494:pharmacology* / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008274:Magnesium / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000378:metabolism*; D017374:Paroxetine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000378:metabolism / Q000502:physiology; D018490:Serotonin Agents / Q000494:pharmacology* / Q000627:therapeutic use; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D000927:Anticonvulsants; D005277:Fenfluramine; D008274:Magnesium; D017374:Paroxetine; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D012701:Serotonin; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide