The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on kindling acquisition and expression
The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on kindling acquisition and expression
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DOI：
10.1016/j.eplepsyres.2003.12.010
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发表时间：
2004-03-01
影响因子：
2.2
通讯作者：
White, HS
中科院分区：
文献类型：
--
作者：
Barton, ME;White, HS
CGX-1007是从芋螺（Conus geographus）毒液中分离得到的一种17个氨基酸的多肽，是一种新型的NMDA受体拮抗剂，对NR 2B亚基具有选择性。CI-1041（PD 196860; Co 20046 1）是一种新型的口服NR 2B选择性拮抗剂。这两种化合物在各种成熟的动物癫痫发作模型中均具有抗惊厥活性。本研究旨在评估CGX-1007和CI-1041对点燃癫痫发作的获得和表达的影响。在角膜点燃大鼠中，CGX-1007 [Epilepsia 36（1998）39]和CI-104 1，口服给药，点燃刺激前2小时显示完全表达的角膜点燃癫痫发作的时间和剂量依赖性阻断（CGX-1007和CI-1041的ED 50分别= 300 pmol和2.5 mg/kg）。在杏仁核点燃大鼠中，CGX-1007急性治疗以剂量依赖性方式阻断继发性全身点燃癫痫发作。仅在产生行为损害的剂量（4 nmol）下观察到对继发性全身性癫痫发作的完全保护。Cl-1041急性治疗未提供任何明显的保护作用，防止继发性全身性癫痫发作。两种化合物均未提供针对局灶性点燃癫痫发作的保护。慢性i. c. v.输注CGX-1007或慢性口服CI-1041并不延迟杏仁核点燃的获得。这些研究的结果表明，含有NR 2B亚基的NMDA受体可能有助于完全点燃的继发性全身性癫痫发作的表达;然而，它们对点燃的发展似乎不那么重要。用CGX-1007和CI-1041获得的差异结果表明，可能存在几类机制不同的NR 2B拮抗剂，并且CGX-1007作为NR 2B受体拮抗剂的特异性可能低于最初报道的。(C)2004 Elsevier B. V.保留所有权利。
CGX-1007, a 17-amino acid polypeptide isolated from the venom of Conus geographus, is a novel NMDA receptor antagonist that is selective for the NR2B subunit. CI-1041 (PD 196860; Co 20046 1) is a novel, orally available NR2B selective antagonist. Both compounds possess anticonvulsant activity in a variety of well-established animal seizure models. The present study was designed to assess the effects of CGX-1007 and CI-1041 on the acquisition and expression of kindled seizures.In the corneal kindled rat, CGX-1007 [Epilepsia 36 (1998) 39] and CI-104 1, administered p.o., 2 h prior to the kindling stimulation displayed time- and dose-dependent block of fully expressed corneal kindled seizures (ED50 = 300pmol and 2.5 mg/kg for CGX-1007 and CI-1041, respectively). In amygdala kindled rats, acute treatment with CGX-1007 blocked the secondarily generalized kindled seizure in a dose-dependent manner. Complete protection against the secondarily generalized seizure was only observed at a dose that produced behavioral impairment (4 nmol). Acute treatment with Cl-1041 did not provide any notable protection against secondarily generalized seizures. Neither compound provided protection against the focal kindled seizure. Chronic i.c.v. infusion of CGX-1007 or chronic oral administration of CI-1041 did not delay the acquisition of amygdala kindling.The results from these studies suggest that NMDA receptors containing the NR2B subunit may contribute to the expression of fully kindled secondarily generalized seizures; however, they appear less important for the development of kindling. The differential results obtained with CGX-1007 and CI-1041 suggest that several classes of mechanistically distinct NR2B antagonists may exist and that CGX-1007 may be less specific as a NR2B receptor antagonist than initially reported. (C) 2004 Elsevier B.V. All rights reserved.