Unveiling the role of histone deacetylases in neurological diseases: focus on epilepsy

Abstract

Epilepsy remains a prevalent chronic neurological disease that is featured by aberrant, recurrent and hypersynchronous discharge of neurons and poses a great challenge to healthcare systems. Although several therapeutic interventions are successfully utilized for treating epilepsy, they can merely provide symptom relief but cannot exert disease-modifying effect. Therefore, it is of urgent need to explore other potential mechanism to develop a novel approach to delay the epileptic progression. Since approximately 30 years ago, histone deacetylases (HDACs), the versatile epigenetic regulators responsible for gene transcription via binding histones or non-histone substrates, have grabbed considerable attention in drug discovery. There are also substantial evidences supporting that aberrant expressions and/activities of HDAC isoforms are reported in epilepsy and HDAC inhibitors (HDACi) have been successfully utilized for therapeutic purposes in this condition. However, the specific mechanisms underlying the role of HDACs in epileptic progression have not been fully understood. Herein, we reviewed the basic information of HDACs, summarized the recent findings associated with the roles of diverse HDAC subunits in epilepsy and discussed the potential regulatory mechanisms by which HDACs affected the development of epilepsy. Additionally, we also provided a brief discussion on the potential of HDACs as promising therapeutic targets for epilepsy treatment, serving as a valuable reference for basic study and clinical translation in epilepsy field.

Keywords: Epigenetic targets; Epilepsy; Histone deacetylases; Inhibitors; Therapy.

Fig. 1

Mechanistic explanation for epilepsy. There are at least 8 types of mechanistic bases for explaining epilepsy pathogenesis, which includes neuronal hyperexcitation (e.g. elevation of glutamate, decrease of GABA), aberrant ion channel function (e.g. SCN1A, KCNQ2, HCN), Neuroinflammation (e.g. increases of HMGB1 and IL-1β), gliosis (e.g. astrogliosis, microgliosis), oxidative stress (e.g. decreases of GSH, SOD and CAT), Neurogenesis (e.g. increases of BDNF and TrkB) and Blood-brain-barrier damage (e.g. albumin extravasation) and abnormal neural circuits (e.g. hippocampus-motor cortex circuit). These causes may sometimes simultaneously involve in the development of epilepsy. Note: GABA, γ-aminobutyric acid; HMGB1, high mobility group box 1; GSH, glutathione; SOD, superoxide dismutase; CAT, catalase; BDNF, brain-derived neurotrophic factor

Fig. 2

Overview of protein acetylation by histone acetyl-transferases (HATs) and protein deacetylation by histone deacetylases (HDACs). HATs and HDACs are epigenetic enzymes responsible for protein acetylation and protein deacetylation, respectively. Generally, HATs include six categories such as GNAT (KAT2A, 2B), MYST (KAT5, 6 A, 6B, 7, 8), p300/CBP (KAT3A, 3B), cytoplasmic (KAT1, 4), transcription co-activators (KAT4, 12) and steroid receptor co-activators (KAT13A, 13B, 13 C, 13D) while HDACs are composed of four classes of isozymes such as class I (HDACs 1, 2, 3 and 8), class IIa (HDACs 4, 5, 7 and 9), class IIb (HDACs 6 and 10), class III (also called sirtuins (SIRTs), including SIRT1-7) and class IV (HDAC11)

Fig. 3

HDACs mediate pathological mechanism of epilepsy. There are at least four types of HDACs reported to be vital for epilepsy, which include class I (i.e. HDAC2), class IIa (i.e. HDAC4), class IV (i.e. HDAC11) and class III HDACs (i.e. SIRT1, 3, 4, 5). In detail, activation of HDAC2 results in the acetylation of histone 3 and histone 4 and down-regulations of NMDA receptor-related genes including Egr1, c-Fos, Nr2a, Nr2b, Nrn1, CAMKII2α, indicating the protective role in epilepsy. In aspect of HDAC4 belong to class IIa HDAC family, it has versatile roles for the exacerbation of epileptic progression via promotion of neuronal excitotoxicity through decreasing GABAergic signaling, p53-mediated neuronal apoptosis and neuroinflammation through blocking the transcription of SRF. The member of class IV HDAC family HDAC11 possibly has the anti-inflammatory role in epilepsy via decreasing IL-10 expression although the concrete mechanism remains unknown. In terms of class III HDAC family especially SIRT1, 3, 4 and 5 reported in epilepsy research, it has demonstrated that distinct roles of each isotype are observed (SIRT1 for PGC-1α deacetylation-mediated mitochondrial biogenesis and p53 deacetylation-mediated cell survival, SIRT3 for inhibition of ROS via activating MnSOD, SIRT4 for decrease of glutamate via increasing GLT-1 and SIRT5 for alleviation of hippocampal neurodegeneration), however, the overall beneficial effects for epileptic relief. Note: NMDA, N- methyl-d-aspartate; GABA, γ-aminobutyric acid; GABARA1, A type GABA receptor α1; GABARA4, A type GABA receptor α4; GAT-1, GABA transporter 1; GAT-3, GABA transporter 3; SRF, serum response factor; PGC-1α, peroxisome proliferator-activated receptor γ coactivators 1α; ROS, reactive oxygen species; GLT-1, glutamate transporter-1

Fig. 4

Classification of HDACi and representative HDACi. There are four categories of HDACi, namely, SCFAs, hydroxamates, cyclic peptides and benzamides according to their unique chemical structures. The representative HDACi in each sort are displayed. Note: SCFAs, short chain fatty acids