cgp-39653 and Epilepsy

In order to specify the nature of interactions between the analgesic compound nefopam and the glutamatergic system, we examined the effects of nefopam on binding of specific ligands on the three main subtypes ionotropic glutamate receptors: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), or quisqualic acid (QA) and kainic acid (KA) in rat brain membrane preparations. Functionally, we investigated the effects of nefopam against the seizures induced by agonists of these excitatory glutamate receptors in mice. Since the synaptic release of glutamate mainly depends upon the activation of membrane voltage-sensitive sodium channels (VSSCs), the nature of interactions between nefopam and these ionic channels was studied by evaluating the effects of nefopam on binding of 3H-batrachotoxinin, a specific ligand of the VSSCs in rat brain membrane preparations. The functional counterpart of the binding of nefopam on VSSCs was evaluated by its effects on the 22Na uptake-stimulated by veratridine on human neuroblastoma cells and in the maximal electroshock test in mice. Nefopam showed no affinity for the subtypes of ionotropic glutamate receptors up to 100 microM. On the other hand, nefopam was effective against NMDA, QA and KA induced clonic seizures in mice. Nefopam displaced 3H-batrachotoxinin and inhibited the uptake of 22Na in the micromolar range and it protected mice against electroshock induced seizures. Nefopam may block the VSSCs activity: consequently, at the presynaptic level, this effect led to a reduction of glutamate release and at the postsynaptic level, it led to a decrease of the neuronal excitability following activation of the glutamate receptors.

Topics: 2-Amino-5-phosphonovalerate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Analgesics, Non-Narcotic; Animals; Binding, Competitive; Electroshock; Epilepsy; Excitatory Amino Acid Agonists; Glutamic Acid; Ion Channel Gating; Kainic Acid; Male; Mice; Mice, Inbred Strains; N-Methylaspartate; Nefopam; Quisqualic Acid; Rats; Rats, Sprague-Dawley; Sodium Channels; Synaptic Transmission; Tritium

The objective of this study was to determine if a change in brain tissue excitatory amino acid receptor binding occurs during pregnancy using in vitro quantitative autoradiography and to examine seizure potential during pregnancy via central injection of N-methyl-D-aspartate (NMDA). For the receptor autoradiography studies, eight pregnant rats (day 21) and eight non-pregnant rats were euthanized with carbon dioxide, perfused, their brains dissected and frozen. Cryostat sections were taken and labeled in vitro by one of the following ligands: [3H]-CGP 39653, [3H]-glycine, [3H]-MK-801, [3H]-2-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) or [3H]-kainate. Optical density measurements of binding in 11 brain regions were performed using image analysis. To test seizure susceptibility, 74 rats were surgically implanted with an electrode into the hippocampus and a cannula into the lateral ventricle. Rats were mated; others served as non-pregnant controls. On gestational day 20, rats were randomized to receive no drug or an injection of NMDA (34, 68 or 136 nmol) through their indwelling cannulae. Seizures were assessed for 20 min. During pregnancy, the density of the NMDA competitive antagonist site measured by [3H]-CGP 39653 was decreased in the hippocampus, thalamus and hypothalamus (P<0.01), while the glycine modulation site was decreased in the cortex, hippocampus, thalamus, caudate and cerebellum (P<0.01). Kainate binding was significantly decreased in the hippocampus (P<0. 05). Total seizure duration and total number of seizures were significantly reduced in pregnant vs. non-pregnant rats (P<0.05). Pregnancy is associated with a significant alteration of NMDA and non-NMDA receptor binding in rats. These findings suggest that pregnancy affords some protection against seizures induced by an activation of NMDA receptors in the brain.

Topics: 2-Amino-5-phosphonovalerate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Convulsants; Dizocilpine Maleate; Epilepsy; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Glycine; Hippocampus; Male; N-Methylaspartate; Pregnancy; Pregnancy, Animal; Radioligand Assay; Rats; Rats, Long-Evans; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Tritium