Modulation of GABA A receptors in the treatment of epilepsy

Background: 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., GABA A Rs) can still be relevant targets of new antiepileptic drugs (AEDs). Methods: Up to now, a variety of modulating agents that directly or indirectly act at GABA A Rs have been proposed for restoring the physiological balance of excitation and inhibition in the epileptogenic brain. While benzodiazepine, barbiturates and allosteric modulators of GABA A Rs 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 GABA A R 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 GABA A R function paving the road to therapeutic approaches based on the modulation of gene expression. Conclusion: Here, we review key physiological, neuropathological and functional studies that altogether strengthen the role of modulation of GABA A Rs function as therapeutic target. The discovery of the novel molecular mechanisms underlying the GABAergic transmission in epilepsy represents another heavy piece in the “epi-leptic puzzle”. Even if GABA A R is an old story in the pharmacology of the epilepsy, the reviewed findings suggest that new players in the scenario need to be considered.