Nitric Oxide, Epileptic Seizures, and Action of Antiepileptic Drugs
Nitric Oxide, Epileptic Seizures, and Action of Antiepileptic Drugs
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DOI：
10.2174/187152711798072347
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发表时间：
2011-11-01
影响因子：
3
通讯作者：
Borowicz, Kinga K.
中科院分区：
文献类型：
--
作者：
Banach, Monika;Piskorska, Barbara;Borowicz, Kinga K.
一氧化氮（NO）在哺乳动物细胞中发挥着多种生理和病理作用。在中枢神经系统中，NO可作为第二信使、神经调质和神经递质，这可能表明这种气体分子在癫痫和癫痫发生中起重要作用。本综述的目的是调查目前的文献中的实验和临床证据的抗或促惊厥性质的NO及其影响的抗癫痫药物的抗惊厥作用。最新的多种NO合酶（NOS）抑制剂和NO供体被用于过多的癫痫发作模型（如。G.电和药理学诱发的惊厥、杏仁核点燃的癫痫发作）。报告的结果因癫痫发作模型、实验中使用的药理学工具的种类和剂量以及给药途径而异。测试最彻底的NOS抑制剂是7-硝基吲唑（7-NI），它在大多数已知的癫痫发作模型中具有抗惊厥特性。7-NI的明确的促惊厥作用仅在红藻氨酸、尼古丁和梭曼诱导的啮齿动物惊厥中观察到。这种NOS抑制剂增强了除噻加宾、非氨酯和托吡酯以外的几乎所有经典和第二代抗癫痫药物的抗惊厥作用。N（G）-硝基-L-精氨酸甲酯的作用不是那么明确。在戊四唑、象鼻虫毒素和N-甲基-D-天冬氨酸癫痫发作模型中，抑制剂表现出剂量依赖性双向作用。N（G）-硝基-L-精氨酸甲酯增强地西泮和氯硝西泮的疗效，减弱丙戊酸盐和苯巴比妥的疗效，但不影响苯妥英和乙琥胺的抗惊厥作用。另一方面，N（G）-硝基-L-精氨酸在尼古丁、谷氨酸和高压氧诱发的癫痫发作中具有抗惊厥作用，在毛果芸香碱、红藻氨酸、荷包牡丹碱、氨茶碱和4-氨基吡啶诱发的惊厥中具有促惊厥作用。N（G）-硝基-L-精氨酸对经典抗癫痫药物（丙戊酸盐、苯巴比妥、地西泮）和新一代抗癫痫药物（奥卡西平、非氨酯和乙琥胺）的抗惊厥作用均无影响。乙琥胺的作用甚至受损。总之，在目前的知识状态下，唯一合理的结论是NO作为一种神经调质具有双重促惊厥或抗惊厥作用。
Nitric oxide (NO) plays a variety of physiological and pathological roles in mammalian cells. In the central nervous system NO may behave as a second messenger, neuromodulator, and neurotransmitter, which may suggest an essential role of this gaseous molecule in epilepsy and epileptogenesis. The aim of this review is to survey the current literature in terms of experimental and clinical evidence of anti-or proconvulsive properties of NO and its implications in the anticonvulsive action of antiepileptic drugs. Up-to-date multiple NO synthase (NOS) inhibitors and donors of NO were used in a plethora of seizure models (e. g. electrically and pharmacologically-evoked convulsions, amygdala-kindled seizures). Reported results vary depending on the seizure model, kind and doses of pharmacological tools used in experiments, and route of drug administration. The most thoroughly tested NOS inhibitor was 7-nitroindazole (7-NI), which presented anticonvulsive properties in most known models of seizures. The clear-cut proconvulsant action of 7-NI was observed only in kainate-, nicotine-, and soman-induced convulsions in rodents. This NOS inhibitor enhanced the anticonvulsant action of almost all available classic and second-generation antiepileptic drugs except tiagabine, felbamate, and topiramate. The effect of N(G)-nitro-L-arginine methyl ester was not so unambiguous. In pentylenetetrazole, pictotoxin, and N-methyl-D-aspartate seizure models the inhibitor exhibited dose-dependent bidirectional action. N(G)-nitro-L-arginine methyl ester potentiated the efficacy of diazepam and clonazepam, diminished that of valproate and phenobarbital, but did not affect the anticonvulsant action of phenytoin and ethosuximide. On the other hand, N(G)-nitro-L-arginine, was anticonvulsant in nicotine-, glutamate-, and hyperbaric O(2)-evoked seizures, and proconvulsant in pilocarpine-, kainate-, bicuculline-, aminophylline-, and 4-aminopyridine-induced convulsions. N(G)-nitro-L-arginine remained without effect on the anticonvulsant action of both classic (valproate, phenobarbital, diazepam) and new generation (oxcarbazepine, felbamate, and ethosuximide) antiepileptic drugs. The action of ethosuximide was even impaired. Summing up, in the present state of knowledge the only reasonable conclusion is that NO behaves as a neuromodulator with dual - proconvulsive or anticonvulsive - action.