THE COMPETITIVE NMDA RECEPTOR ANTAGONIST CGP-40116 PROTECTS AGAINST STATUS EPILEPTICUS-INDUCED NEURONAL DAMAGE
THE COMPETITIVE NMDA RECEPTOR ANTAGONIST CGP-40116 PROTECTS AGAINST STATUS EPILEPTICUS-INDUCED NEURONAL DAMAGE
复制标题
DOI：
10.1016/0920-1211(94)90051-5
复制
发表时间：
1994-03-01
影响因子：
2.2
通讯作者：
KIM, JS
中科院分区：
文献类型：
--
作者：
FUJIKAWA, DG;DANIELS, AH;KIM, JS
我们研究了竞争性NMDA受体拮抗剂CGP 40116对锂-匹罗卡品诱导的癫痫持续状态（SE）引起的癫痫神经元坏死的保护作用。大鼠在SE之前给予CGP 40116（12 mg/kg i. p.）或15分钟后的SE（4，12和24 mg/kg）;对照组在SE开始后15分钟接受生理盐水。SE 3 h后腹腔注射地西泮和苯巴比妥以停止癫痫发作。24 h后处死大鼠，并对其脑进行光学显微镜检查。神经元损伤发生在24的25个脑区检查盐水注射的动物。在SE发作后，给予12和24 mg/kg CGP 40116的大鼠的保护作用最大：24个受损区域中的19个和21个分别受到保护，但24 mg/kg组的死亡率与注射生理盐水的对照组相当。在两个最高CGP 40116剂量下，在后扣带回和压后神经元中未发现坏死神经元，表明NMDA受体拮抗剂诱导的短暂胞质空泡化不会进展为明显坏死。在大鼠给予CGP 40116癫痫放电没有消除，但其幅度显着降低后2小时SE开始。周期性癫痫样放电（PED）EEG模式，可能是广泛的神经元损伤的迹象，在注射生理盐水的对照组中SE 2-2.5 h后出现，但在给予12和24 mg/kg CGP 40116的大鼠中未出现。CGP 40116提供了广泛的保护作用，以防止脑缺血诱导的神经元坏死，这表明其产生的一个必要步骤是内源性谷氨酸激活NMDA受体。提供的神经保护不仅仅是一种抗癫痫作用，因为尽管NMDA受体阻断，电图癫痫发作仍持续存在。CGP 40116和NMDA受体拮抗剂一般可用作难治性SE患者的持续性神经保护剂。
We studied the efficacy of the competitive NMDA receptor antagonist CGP 40116 in protecting against seizure-induced neuronal necrosis from lithium-pilocarpine-induced status epilepticus (SE). Rats were given CGP 40116 either before SE (12 mg/kg i.p.) or 15 min after the onset of SE (4, 12 and 24 mg/kg); controls received normal saline 15 min after SE began. Diazepam and phenobarbital were given i.p. after 3 h of SE to stop the seizures. Rats were killed 24 h later, and their brains were processed for light microscopic examination. Neuronal damage occurred in 24 of 25 brain regions examined in saline-injected animals. Protection was maximal in rats given 12 and 24 mg/kg CGP 40116 after SE onset: 19 and 21 of the 24 damaged regions were protected respectively, but the 24 mg/kg group had a mortality rate comparable to saline-injected controls. No necrotic neurons were found in posterior cingulate and retrosplenial neurons at the two highest CGP 40116 doses, suggesting that the transient cytoplasmic vacuolization induced by NMDA receptor antagonists does not progress to frank necrosis. In rats given CGP 40116 seizure discharges were not eliminated, but their amplitudes were significantly reduced 2 h after SE began. The periodic epileptiform discharge (PED) EEG pattern, probably a sign of widespread neuronal damage, developed in saline-injected controls after 2-2.5 h of SE but not in rats given 12 and 24 mg/kg of CGP 40116. CGP 40116 provided widespread protection against seizure-induced neuronal necrosis, suggesting that an esssential step in its production is NMDA receptor activation by endogenous glutamate. The neuroprotection provided was not simply an antiepileptic effect, since electrographic seizures persisted despite NMDA receptor blockade. CGP 40116 and NMDA receptor antagonists in general could be useful as adjunctive neuroprotectants in patients with refractory SE.