Asunto(s)
Amígdala del Cerebelo/fisiología , Excitación Neurológica/fisiología , N-Metilaspartato/farmacología , Convulsiones/fisiopatología , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Aminoácidos/farmacología , Amígdala del Cerebelo/efectos de los fármacos , Animales , Anticonvulsivantes/farmacología , Electroencefalografía/efectos de los fármacos , Excitación Neurológica/efectos de los fármacos , Masculino , Microinyecciones , Actividad Motora/efectos de los fármacos , N-Metilaspartato/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Convulsiones/inducido químicamente , Factores de TiempoRESUMEN
Limbic seizures were kindled by repeated, daily intra-amygdaloid microinjections of N-methyl-D-aspartate (NMDA; 2 nmol). The seizures, and accompanying afterdischarges, closely resembled those seen following electrical kindling of the amygdala. As with electrical kindling, co-administration of the competitive NMDA receptor antagonist DL-2-amino-7-phosphonoheptanoic acid (AP7; 70 nmol) prevented the development of seizure activity. NMDA-induced kindling was durable, lasting at least 1 month, and showed positive transfer to electrical kindling. Fully kindled seizures were inhibited by co-administration of the potent NMDA receptor antagonist DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849) with the agonist. These results strongly support a role for NMDA receptors in kindling epileptogenesis.
Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Excitación Neurológica/efectos de los fármacos , N-Metilaspartato/farmacología , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Aminoácidos/farmacología , Amígdala del Cerebelo/fisiología , Animales , Calcio/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiologíaRESUMEN
A sensitive method of estimation of generalized seizure thresholds (GSTs) was used to estimate the relative anticonvulsant potencies of four competitive NMDA antagonists against fully amygdala-kindled seizures. All of the antagonists tested showed potent, dose-dependent anticonvulsant activity following focal administration at doses causing no, or only minimal, overt behavioural abnormalities. These doses were similar to those which have previously been shown to inhibit the development of the kindling process i.e. which show antiepileptogenic activity. Two novel, competitive NMDA antagonists, CGP 37849 and CGP 39551, both unsaturated analogues of the NMDA antagonist AP5, showed by far the greatest anticonvulsant potencies (211-fold and 33-fold greater activity than the parent molecule, respectively). Recent reports of oral anticonvulsant activity of these two compounds in both rodent and primate models of epilepsy (12, 13) make them leading candidates for clinical testing as novel antiepileptic agents in man. Previous reports of weak or non-existent anticonvulsant activity of competitive NMDA antagonists in the kindling model of epilepsy most likely result from the use of experimental protocols which are inherently insensitive in detecting drug-induced changes in seizure thresholds.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Excitación Neurológica , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Convulsiones/tratamiento farmacológico , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/uso terapéutico , Amígdala del Cerebelo/fisiopatología , Animales , Unión Competitiva , Estimulación Eléctrica , Masculino , Ratas , Ratas Endogámicas , Convulsiones/etiologíaRESUMEN
The anticonvulsant and behavioural actions of CGP 37849 and CGP 39551, two novel competitive NMDA receptor antagonists, were examined in fully amygdala kindled rats following systemic administration. Only weak anticonvulsant effects were observed following either i.p. or i.v. injection of the antagonists. Moreover, behavioural abnormalities (ataxia, hyperactivity, muscular hypotonia) were apparent at all anticonvulsant doses. These results suggest that CGP 37849 and CGP 39551 may be of limited therapeutic usefulness against complex partial seizures in man, the seizure type showing greatest refractoriness to presently available medication.