cgp-37849 and 2-amino-7-phosphonoheptanoic-acid

Epileptic afterdischarges elicited by stimulation of sensorimotor cortex were chosen to test anticonvulsant effects of NMDA receptor antagonists in developing rats (12, 18 and 25 days old) with implanted electrodes. Afterdischarges were elicited four times with 10-min intervals in the experiments with dizocilpine and 20 min with the other two drugs. Dizocilpine (0.5 or 1 mg/kg), CGP 40116 (0.1, 0.5 or 1 mg/kg) or 2-amino-7-phosphonoheptanoic acid (AP7, 30 or 60 mg/kg) was injected intraperitoneally between the first and second stimulation. Intensity of movements accompanying stimulation was diminished regularly only by CGP 40116. Duration of afterdischarges was reduced and intensity of clonic seizures was decreased by CGP 40116 in all age groups; dizocilpine exhibited similar action in 25- and 18-day-old rats, AP7 only in 25-day-old animals. Anticonvulsant action of the three NMDA antagonists exhibited different developmental profiles in our model; this difference might be due to developmental changes of NMDA receptors.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Dizocilpine Maleate; Electric Stimulation; Epilepsy; Excitatory Amino Acid Antagonists; Injections, Intraperitoneal; Motor Cortex; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Time Factors

Seizures were induced in immature 18-day-old rats by i.p. administration of homocysteine (11 mmol/kg) and the effects of selected antagonists of NMDA receptors [MK-801 (0.5 mg/kg), AP7 (0.33 mmol/kg), CGP 40116 (10 mg/kg)] and non-NMDA receptors [GDEE (4 mmol/kg), NBQX (two doses, 30 mg/kg each)] were studied. The effect of MgSO4 (two doses, 2 mmol/kg each) was also tested. The anticonvulsant effect was evaluated not only from the behavioral manifestations of seizures, but also in terms of some indicators of brain energy metabolism. Rat pups were sacrificed during generalized clonic-tonic seizures, corresponding to 16-45 min after homocysteine administration. Comparable time intervals were used for sacrificing the pups which had received the protective drugs. In contrast to neonatal rats, in which only NMDA antagonists could prevent homocysteine-induced seizures, both NMDA and non-NMDA receptor antagonists exerted an anticonvulsant effect in 18-day-old rats. In addition, the pronounced anticonvulsant effect could be achieved by the combined treatment with low subthreshold doses of NMDA (MK-801) and non-NMDA (NBQX) receptor antagonists. The protection was evident not only in suppressing behavioral symptoms of seizures, but also in preventing most of the metabolic changes accompanying seizures, mainly glycogen degradation. More than a sevenfold accumulation of lactate occurring during seizures was markedly reduced by all the tested drugs, but was not completely eliminated. All antagonists, when given alone in the same doses as those used for seizure protection, remained without any effect on lactate levels. Comparison of the present data with previous findings concerning neonatal rats suggests that there may be a developmental change in anticonvulsant efficacy of non-NMDA receptor antagonists against homocysteine-induced seizures in rats.

Topics: 2-Amino-5-phosphonovalerate; Age Factors; Animals; Anticonvulsants; Behavior, Animal; Brain Chemistry; Dizocilpine Maleate; Dose-Response Relationship, Drug; Energy Metabolism; Excitatory Amino Acid Antagonists; Glutamates; Homocysteine; Male; Neuroprotective Agents; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Amygdala; Animals; Anticonvulsants; Electroencephalography; Kindling, Neurologic; Male; Microinjections; Motor Activity; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures; Time Factors

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.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Amygdala; Animals; Calcium; Excitatory Amino Acid Agonists; Kindling, Neurologic; Male; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate