Combined inhibition of histone deacetylases and BET family proteins as epigenetic therapy for nerve injury-induced neuropathic pain

Abstract

Current treatments for neuropathic pain have often moderate efficacy and present unwanted effects showing the need to develop effective therapies. Accumulating evidence suggests that histone acetylation plays essential roles in chronic pain and the analgesic activity of histone deacetylases (HDACs) inhibitors is documented. Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that interact with acetylated lysine residues on histones, but little is known about their implication in neuropathic pain. Thus, the current study was aimed to investigate the effect of the combination of HDAC and BET inhibitors in the spared nerve injury (SNI) model in mice. Intranasal administration of i-BET762 (BET inhibitor) or SAHA (HDAC inhibitor) attenuated thermal and mechanical hypersensitivity and this antiallodynic activity was improved by co-administration of both drugs. Spinal cord sections of SNI mice showed an increased expression of HDAC1 and Brd4 proteins and combination produced a stronger reduction compared to each epigenetic agent alone. SAHA and i-BET762, administered alone or in combination, counteracted the SNI-induced microglia activation by inhibiting the expression of IBA1, CD11b, inducible nitric oxide synthase (iNOS), the activation of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription-1 (STAT1) with comparable efficacy. Conversely, the epigenetic inhibitors showed a modest effect on spinal proinflammatory cytokines content that was significantly potentiated by their combination. Present results indicate a key role of acetylated histones and their recruitment by BET proteins on microglia-mediated spinal neuroinflammation. Targeting neuropathic pain with the combination of HDAC and BET inhibitors may represent a promising new therapeutic option.