HDAC inhibitors restore C‐fibre sensitivity in experimental neuropathic pain model

Abstract

BACKGROUND AND PURPOSEHypoesthesia is a clinical feature of neuropathic pain. The feature is partly explained by the evidence of epigenetic repression of Nav1.8 sodium channel in the dorsal root ganglion (DRG). EXPERIMENTAL APPROACHWe investigated the possibility of trichostatin A (TSA), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) to reverse the unique C-fibre sensitivity observed following partial ligation of sciatic nerve in mice. KEY RESULTSNerve injury-induced down-regulation of DRG Nav1.8 sodium channel and C-fibre-related hypoesthesia were reversed by TSA, VPA and SAHA treatments, which inhibit histone deacetylase (HDAC), and increase histone acetylation at the regulatory sequence of Nav1.8. CONCLUSIONS AND IMPLICATIONSTaken together, these studies provide the evidence that hypoesthesia and underlying down-regulation of Nav1.8, negative symptoms observed in nerve injury-induced neuropathic pain models are regulated by an epigenetic chromatin remodelling through HDAC-related machineries.

Multiscale Modelling of Relationships between Protein Classes and Drug Behavior Across all Diseases Using the CANDO Platform

“…There are overlapping indications among the best ones for different druggable protein classes suggesting the systems level interplay for these diseases. To verify our predictions of particular druggable classes being involved in the pathways for pathogenesis or treatment of selected indications with high CANDO accuracies, we collected independent evidence from existing literature [28, 52-94], which is summarized in (Supplementary Table S1 ). As an example, the indication congenital limb deformities has high CANDO accuracy with the kinases and ligases protein sets (Fig.…”

Is there any therapeutic value for the use of histone deacetylase inhibitors for chronic pain?

“…In addition, in the PSL model, SAHA (5 mg/kg, i.p., once daily from day 3 to day 9 after nerve injury) restored C-fiber sensitivity at day 1 of SAHA treatment (day 3 of injury) until day 9 of injury. Moreover, SAHA reversed injury-induced repression of Na v 1.8, TRPA1 and TRPM8 expression, but not that of CGRP (Matsushita et al, 2013).…”

“…For example, decreased expression of -opioid receptors (MORs) and Na v 1.8 sodium channels in the DRG is thought to be an underlying cause of neuropathic pain symptoms (Uchida et al, 2010). It has also been reported that reductions in MOR and Na v 1.8 activity are related to enhanced H4 acetylation at the neuron-restrictive silencer factor (NRSF) promoter region, reduction of H3 and H4 acetylation at the MORneuron-restrictive silencer element (NRSE) and at Na v 1.8-NRSE-2, and enhanced H3 acetylation at Na v 1.8-NRSE-1 (Matsushita et al, 2013). Further evidence suggests that histone acetylation in the promoter of the brain derived neurotropic factor (BDNF) gene was significantly enhanced in the DRG and spinal cord in pain models of partial sciatic nerve ligation (PSL) and CCI, as well as during chronic morphine treatment.…”

“…The interactions between HATs and HDACs determine the net balance of histone acetylation (Binder et al, 2013). Mounting evidence suggests that during pain-related synaptic plasticity, the expression and activities of HDACs are dynamic (Geranton and Tochiki, 2015;Cherng et al, 2014;Matsushita et al, 2013;Kiguchi et al, 2013;Denk et al, 2013). Therefore, in the present review, we focus on mechanisms of histone acetylation and the role of HDACs in chronic pain and discuss recent attempts to treat chronic pain with HDAC inhibitors (HDACIs).…”

Epigenetic regulation of persistent pain

“…All of these changes were found positively correlated to the changes in hypersensitivity of C-fibers, instead of Aβ- and Aδ-fibers. Recently they found that downregulated Nav1.8 mRNA in the injured DRGs was reversed by intraplantar injection of HDACi, VPA or TSA, following one pre-surgery dose and daily dose after surgery for 3 days [164]. This finding suggests that class I and IIa HDAC are involved.…”