Despite the effort on developing new treatments,
therapy for
neuropathic pain is still a clinical challenge and combination
therapy regimes of two or more drugs are often needed to improve efficacy. Accumulating evidence shows an altered expression and activity of
histone acetylation
enzymes in
chronic pain conditions and restoration of these aberrant epigenetic modifications promotes
pain-relieving activity. Recent studies showed a synergistic activity in
neuropathic pain models by combination of
histone deacetylases (HDACs) and bromodomain and extra-terminal domain (BET) inhibitors. On these premises, the present study investigated the pharmacological profile of new dual HDAC/BRD4 inhibitors, named SUM52 and SUM35, in the spared nerve injury (SNI) model in mice as innovative strategy to simultaneously inhibit HDACs and BETs.
Intranasal administration of SUM52 and SUM35 attenuated thermal and mechanical
hypersensitivity in the absence of locomotor side effects. Both dual inhibitors showed a preferential interaction with BRD4-BD2 domain, and SUM52 resulted the most active compound. SUM52 reduced microglia-mediated spinal
neuroinflammation in spinal cord sections of SNI mice as showed by reduction of IBA1 immunostaining,
inducible nitric oxide synthase (iNOS) expression, p65 nuclear factor-κB (NF-κB) and
p38 MAPK over-phosphorylation. A robust decrease of the spinal proinflammatory
cytokines content (IL-6, IL-1ß) was also observed after SUM52 treatment. Present results, showing the
pain-relieving activity of HDAC/BRD4 dual inhibitors, indicate that the simultaneous modulation of BET and HDAC activity by a single molecule acting as multi-target agent might represent a promise for
neuropathic pain relief.