Czuczwar S J, Patsalos P N
Department of Pathophysiology, Medical University, Lublin, and Isotope Laboratory, Institute of Agricultural Medicine, Lublin, Poland.
CNS Drugs. 2001;15(5):339-50. doi: 10.2165/00023210-200115050-00001.
gamma-Aminobutyric acid (GABA) is considered to be the major inhibitory neurotransmitter in the brain and loss of GABA inhibition has been clearly implicated in epileptogenesis. GABA interacts with 3 types of receptor: GABAA, GABAB and GABAC. The GABAA receptor has provided an excellent target for the development of drugs with an anticonvulsant action. Some clinically useful anticonvulsants, such as the benzodiazepines and barbiturates and possibly valproic acid (sodium valproate), act at this receptor. In recent years 4 new anticonvulsants, namely vigabatrin, tiagabine, gabapentin and topiramate, with a mechanism of action considered to be primarily via an effect on GABA, have been licensed. Vigabatrin elevates brain GABA levels by inhibiting the enzyme GABA transaminase which is responsible for intracellular GABA catabolism. In contrast, tiagabine elevates synaptic GABA levels by inhibiting the GABA uptake transporter, GAT1, and preventing the uptake of GABA into neurons and glia. Gabapentin, a cyclic analogue of GABA, acts by enhancing GABA synthesis and also by decreasing neuronal calcium influx via a specific subunit of voltage-dependent calcium channels. Topiramate acts, in part, via an action on a novel site of the GABAA receptor. Although these drugs are useful in some patients, overall, they have proven to be disappointing as they have had little impact on the prognosis of patients with intractable epilepsy. Despite this, additional GABA enhancing anticonvulsants are presently under development. Ganaxolone, retigabine and pregabalin may prove to have a more advantageous therapeutic profile than the presently licensed GABA enhancing drugs. This anticipation is based on 2 characteristics. First, they act by hitherto unique mechanisms of action in enhancing GABA-induced neuronal inhibition. Secondly, they act on additional antiepileptogenic mechanisms. Finally, CGP 36742, a GABAB receptor antagonist, may prove to be particularly useful in the management of primary generalised absence seizures. The exact impact of these new GABA-enhancing drugs in the treatment of epilepsy will have to await their licensing and a period of postmarketing surveillance. As to clarification of their role in the management of epilepsy, this will have to await further clinical trials, particularly direct comparative trials with other anticonvulsants.
γ-氨基丁酸（GABA）被认为是大脑中的主要抑制性神经递质，GABA抑制作用的丧失与癫痫发生密切相关。GABA与3种类型的受体相互作用：GABAA、GABAB和GABAC。GABAA受体为开发具有抗惊厥作用的药物提供了一个很好的靶点。一些临床上有用的抗惊厥药，如苯二氮䓬类、巴比妥类以及可能的丙戊酸（丙戊酸钠），作用于该受体。近年来，4种新型抗惊厥药，即氨己烯酸、噻加宾、加巴喷丁和托吡酯，已获许可，其作用机制被认为主要是通过对GABA的影响。氨己烯酸通过抑制负责细胞内GABA分解代谢的GABA转氨酶来提高脑内GABA水平。相反，噻加宾通过抑制GABA摄取转运体GAT1并阻止GABA摄取到神经元和神经胶质细胞中来提高突触GABA水平。加巴喷丁是GABA的环状类似物，其作用方式是增强GABA合成，还通过电压依赖性钙通道的一个特定亚基减少神经元钙内流。托吡酯部分通过作用于GABAA受体的一个新位点发挥作用。尽管这些药物对一些患者有用，但总体而言，它们已被证明令人失望，因为它们对难治性癫痫患者的预后几乎没有影响。尽管如此，目前仍在开发其他增强GABA的抗惊厥药。加奈索酮、瑞替加滨和普瑞巴林可能被证明比目前已获许可的增强GABA的药物具有更有利的治疗特征。这种预期基于两个特点。首先，它们通过迄今独特的作用机制来增强GABA诱导的神经元抑制。其次，它们作用于其他抗癫痫发生机制。最后，GABAB受体拮抗剂CGP 36742可能被证明在原发性全身性失神发作的治疗中特别有用。这些新型增强GABA的药物在癫痫治疗中的确切影响将有待其获得许可并经过一段时间的上市后监测。至于阐明它们在癫痫管理中的作用，这将有待进一步的临床试验，特别是与其他抗惊厥药的直接对比试验。
