Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, Rome, Italy.
IRCCS San Raffaele Pisana, Rome, Italy.
Curr Pharm Des. 2017;23(37):5563-5568. doi: 10.2174/1381612823666170809100230.
A variety of evidence suggested that an imbalance in excitatory and inhibitory neurotransmission could be one of the pathophysiological mechanisms underlying the occurrence and progression of seizures. Understanding the causes of this imbalance may provide essential insight into the basic mechanisms of epilepsy and may uncover novel targets for future drug therapies. Accordingly, GABA is the most important inhibitory neurotransmitter in the CNS and its receptors (e.g., GABAARs) can still be relevant targets of new antiepileptic drugs (AEDs).
Up to now, a variety of modulating agents that directly or indirectly act at GABAARs have been proposed for restoring the physiological balance of excitation and inhibition in the epileptogenic brain. While benzodiazepine, barbiturates and allosteric modulators of GABAARs are well-known for their anticonvulsant effect, new compounds as modulators of chloride homeostasis or phytocannabinoids are not completely unraveled and their antiepileptic action is still matter of debate. In addition, several inflammatory mediators as cytokines and chemokines play an important role in the modulation of GABAAR function, even if further research is needed to translate these new findings from the bench to the bedside. Finally yet importantly, a new frontier in epilepsy research is represented by the observation that specific small noncoding RNAs, namely miRNAs, may regulate GABAAR function paving the road to therapeutic approaches based on the modulation of gene expression.
Here, we review key physiological, neuropathological and functional studies that altogether strengthen the role of modulation of GABAARs function as therapeutic target. The discovery of the novel molecular mechanisms underlying the GABAergic transmission in epilepsy represents another heavy piece in the "epileptic puzzle". Even if GABAAR is an old story in the pharmacology of the epilepsy, the reviewed findings suggest that new players in the scenario need to be considered.
多种证据表明，兴奋和抑制性神经递质的失衡可能是癫痫发作发生和发展的病理生理机制之一。了解这种失衡的原因可能为深入了解癫痫的基本机制提供重要线索，并可能为未来的药物治疗发现新的靶点。因此，GABA 是中枢神经系统中最重要的抑制性神经递质，其受体（如 GABAAR）仍然是新型抗癫痫药物（AEDs）的相关靶点。
到目前为止，已经提出了各种调节 GABAA 受体的调制剂，以恢复致痫脑中兴奋和抑制的生理平衡。苯二氮䓬类、巴比妥类和 GABAA 受体的变构调节剂因其抗惊厥作用而广为人知，而氯离子稳态调节剂或植物大麻素等新型化合物的抗癫痫作用仍存在争议，其作用机制仍在研究中。此外，几种炎症介质，如细胞因子和趋化因子，在调节 GABAA 受体功能方面发挥着重要作用，尽管需要进一步的研究将这些新发现从实验室转化到临床。最后但同样重要的是，癫痫研究的一个新领域是观察到特定的小非编码 RNA，即 microRNAs，可能调节 GABAA 受体功能，为基于基因表达调节的治疗方法铺平道路。
本文综述了关键的生理、神经病理学和功能研究，这些研究共同加强了调节 GABAA 受体功能作为治疗靶点的作用。在癫痫的神经传递中发现的新分子机制代表了“癫痫拼图”中的又一重要部分。尽管 GABAA 受体在癫痫药理学中是一个古老的故事，但综述结果表明，需要考虑新的参与者。
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