Two selective excitatory amino acid antagonists, DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849) and its carboxyethylester (CGP 39551), were studied against audiogenic seizures in genetically epilepsy-prone rats following oral administration. Acute administration of CGP 37849 attenuated the clonic and tonic phases of the audiogenic seizures (109 dB, 12-16 kHz) 120 min after pretreatment (ED(50) 19.7 and 11.2 mu mol kg(-1), respectively). Similarly, CGP 39551 attenuated the clonic and tonic phases of audiogenic seizures 120 min after acute treatment with ED(50) values of 17.2 and 8.8 mu mol kg(-1), respectively. For chronic studies animals were treated orally once daily (at 10 h) for 4 weeks with CGP 37849 (20 or 40 mu mol kg(-1)) or CGP 39551 (15 or 30 mu mol kg(-1)). In order to assess anticonvulsant activity, rats were subjected to auditory stimulation 120 min after drug administration on days 1, 3 and 5 and then every 3 or 4 days. Following 2 and 4 weeks of repeated drug administration with CGP 37849 (20 and 40 mu mol kg(-1)) the ED(50) values against clonic and tonic seizures were not significantly different from those observed following an acute administration. Similarly, 2 and 3 weeks after repeated treatment CGP 39551 (15 and 30 mu mol kg(-1)) the ED(50) values against clonic and tonic seizures were not significantly different from those observed following an acute administration. There was no significant difference between the ED(50) values following either acute or repeated treatment of the two excitatory amino acid antagonists suggesting a lack of development tolerance. The duration of anticonvulsant activity observed between 0.5 and 24 h following administration of CGP 37849 and CGP 39551 was similar in acute and chronic treatment. The effects of CGP 37849 and CGP 39551 on motor behaviour was also evaluated following acute and repeated treatment by a rotarod apparatus 110 min following drug administration. The TD50 values for CGP 37849- and CGP 39551-induced impairment of locomotor performance recorded 2 or 4 weeks of repeated administration were not significantly different from those observed following an acute administration. The TD50 values for CGP 37849- and CGP 39551-induced impairment of locomotor performance were 87.6 and 70.8 mu mol kg(-1) i.p. respectively following 2 weeks treatment and 92.9 and 76.9 mu mol kg(-1) i.p. respectively following 4 weeks treatment. The doses of CGP 37849 and CGP 39551 required to elicit motor impairment were at least an order of magnitude above required for anticonvulsant activity, Since these compounds showed anticonvulsant properties after oral administration and lack of development of tolerance after repeated treatment, a potential use for antiepileptic therapy in man is suggested.
Lack of development of tolerance to anticonvulsant effects of two excitatory amino acid antagonists, CFP 37849 and CGP 39551 in genetically epilepsy-prone rats
De Sarro G;
1996-01-01
Abstract
Two selective excitatory amino acid antagonists, DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849) and its carboxyethylester (CGP 39551), were studied against audiogenic seizures in genetically epilepsy-prone rats following oral administration. Acute administration of CGP 37849 attenuated the clonic and tonic phases of the audiogenic seizures (109 dB, 12-16 kHz) 120 min after pretreatment (ED(50) 19.7 and 11.2 mu mol kg(-1), respectively). Similarly, CGP 39551 attenuated the clonic and tonic phases of audiogenic seizures 120 min after acute treatment with ED(50) values of 17.2 and 8.8 mu mol kg(-1), respectively. For chronic studies animals were treated orally once daily (at 10 h) for 4 weeks with CGP 37849 (20 or 40 mu mol kg(-1)) or CGP 39551 (15 or 30 mu mol kg(-1)). In order to assess anticonvulsant activity, rats were subjected to auditory stimulation 120 min after drug administration on days 1, 3 and 5 and then every 3 or 4 days. Following 2 and 4 weeks of repeated drug administration with CGP 37849 (20 and 40 mu mol kg(-1)) the ED(50) values against clonic and tonic seizures were not significantly different from those observed following an acute administration. Similarly, 2 and 3 weeks after repeated treatment CGP 39551 (15 and 30 mu mol kg(-1)) the ED(50) values against clonic and tonic seizures were not significantly different from those observed following an acute administration. There was no significant difference between the ED(50) values following either acute or repeated treatment of the two excitatory amino acid antagonists suggesting a lack of development tolerance. The duration of anticonvulsant activity observed between 0.5 and 24 h following administration of CGP 37849 and CGP 39551 was similar in acute and chronic treatment. The effects of CGP 37849 and CGP 39551 on motor behaviour was also evaluated following acute and repeated treatment by a rotarod apparatus 110 min following drug administration. The TD50 values for CGP 37849- and CGP 39551-induced impairment of locomotor performance recorded 2 or 4 weeks of repeated administration were not significantly different from those observed following an acute administration. The TD50 values for CGP 37849- and CGP 39551-induced impairment of locomotor performance were 87.6 and 70.8 mu mol kg(-1) i.p. respectively following 2 weeks treatment and 92.9 and 76.9 mu mol kg(-1) i.p. respectively following 4 weeks treatment. The doses of CGP 37849 and CGP 39551 required to elicit motor impairment were at least an order of magnitude above required for anticonvulsant activity, Since these compounds showed anticonvulsant properties after oral administration and lack of development of tolerance after repeated treatment, a potential use for antiepileptic therapy in man is suggested.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
