De Sarro G, Ammendola D, Nava F, De Sarro A
Department of Experimental and Clinical Medicine, School of Medicine, University of Reggio Calabria, Cantanzaro, Italy.
Brain Res. 1995 Feb 6;671(1):131-40. doi: 10.1016/0006-8993(94)01328-f.
The behavioural and convulsant effects of imipenem (Imi), a carbapenem derivative, were studied after intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. The anticonvulsant effects of some excitatory amino acid antagonists and muscimol (Msc), a GABAA agonist, against seizures induced by i.p. or i.c.v. administration of Imi were also evaluated. The present study demonstrated that the order of anticonvulsant activity in our epileptic model, after i.p. administration, was (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten-5,10-imine maleate (MK-801) > (+/-)(E)-2-amino-4-methyl-5-phosphono-3-pentenoate ethyl ester (CGP 39551) > 3-((+/-)-2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid (CPPene) > 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CCP) > 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline (NBQX). Ifenprodil, a compound acting on the polyamine site of NMDA receptor complex was unable to protect against seizures induced by Imi, suggesting that the poliamine site did not exert a principal role in the genesis of seizures induced by Imi. In addition, the order of anticonvulsant potency in our epileptic model, after i.c.v. administration, was CPPene > MK-801 > Msc > (-)-2-amino-7-phosphonic acid (AP7) > gamma-D-glutamylaminomethylsulphonate (gamma-D-GAMS) > NBQX > kynurenic acid (KYNA) > 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX). The relationship between the different site of action and the anticonvulsant activity of these derivatives was discussed. Although the main mechanism of Imi induced seizures cannot be easily determined, potential interactions with the receptors of the excitatory amino acid neurotransmitters exists. In fact, antagonists of excitatory amino acids are able to increase the threshold for the seizures or to prevent the seizures induced by Imi. In addition, Imi acts on the central nervous system by inhibition of GABA neurotransmission and Msc, a selective GABAA agonist, was able to protect against seizures induced by Imi.
在对声音诱发的癫痫发作具有遗传易感性的DBA/2小鼠中，研究了碳青霉烯衍生物亚胺培南（Imi）腹腔注射（i.p.）或脑室内注射（i.c.v.）后的行为和惊厥作用。还评估了一些兴奋性氨基酸拮抗剂和GABAA激动剂蝇蕈醇（Msc）对i.p.或i.c.v.注射Imi诱发的癫痫发作的抗惊厥作用。本研究表明，在i.p.给药后，我们癫痫模型中的抗惊厥活性顺序为：马来酸（+）-5-甲基-10,11-二氢-5H-二苯并（a,d）-环庚烯-5,10-亚胺（MK-801）>（+/-）（E）-2-氨基-4-甲基-5-膦酰基-3-戊烯酸乙酯（CGP 39551）> 3-（（+/-）-2-羧基哌嗪-4-基）丙烯基-1-膦酸（CPPene）> 3-（（+/-）-2-羧基哌嗪-4-基）丙基-1-膦酸（CCP）> 2,3-二羟基-6-硝基-7-氨磺酰基苯并（F）喹喔啉（NBQX）。作用于NMDA受体复合物多胺位点的化合物艾芬地尔不能预防Imi诱发的癫痫发作，这表明多胺位点在Imi诱发的癫痫发作的发生中不发挥主要作用。此外，在i.c.v.给药后，我们癫痫模型中的抗惊厥效力顺序为：CPPene > MK-801 > Msc >（-）-2-氨基-7-膦酸（AP7）>γ-D-谷氨酰氨基甲基磺酸盐（γ-D-GAMS）> NBQX >犬尿喹啉酸（KYNA）> 6-氰基-7-硝基喹喔啉-2,3-二酮（CNQX）。讨论了这些衍生物不同作用位点与抗惊厥活性之间的关系。虽然Imi诱发癫痫发作的主要机制不易确定，但与兴奋性氨基酸神经递质受体存在潜在相互作用。事实上，兴奋性氨基酸拮抗剂能够提高癫痫发作阈值或预防Imi诱发的癫痫发作。此外，Imi通过抑制GABA神经传递作用于中枢神经系统，而选择性GABAA激动剂Msc能够预防Imi诱发的癫痫发作。
