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The Sciatic Nerve Cuffing Model of Neuropathic Pain in Mice
Published on: July 16, 2014
Dual HDAC/BRD4 Inhibitors Relieves Neuropathic Pain by Attenuating Inflammatory Response in Microglia After Spared
Vittoria Borgonetti1, Elisabetta Meacci2, Federica Pierucci2
1Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, 50139, Florence, Italy.
Abstract:
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.
Insights
New dual inhibitors targeting histone deacetylases (HDACs) and bromodomain and extra-terminal domain (BET) proteins show promise for neuropathic pain relief. These compounds effectively reduced pain hypersensitivity and spinal neuroinflammation in mouse models without side effects.
Area of Science:
- Neuroscience
- Pharmacology
- Epigenetics
Background:
- Neuropathic pain remains a significant clinical challenge, often requiring combination therapies.
- Altered histone acetylation is implicated in chronic pain, with epigenetic modifications showing therapeutic potential.
- Synergistic effects have been observed with combined histone deacetylase (HDAC) and bromodomain and extra-terminal domain (BET) inhibitors in pain models.
Purpose of the Study:
- To investigate the pharmacological profile of novel dual HDAC/BRD4 inhibitors (SUM52 and SUM35).
- To evaluate their efficacy in a mouse model of neuropathic pain (spared nerve injury - SNI).
- To explore their potential as a single-molecule strategy for simultaneous epigenetic modulation.
Main Methods:
- Intranasal administration of dual HDAC/BRD4 inhibitors SUM52 and SUM35 in the SNI mouse model.
- Assessment of thermal and mechanical hypersensitivity and locomotor activity.
- Analysis of spinal cord sections for neuroinflammation markers (IBA1, iNOS, NF-κB, p38 MAPK) and cytokine levels (IL-6, IL-1ß).
- Investigation of inhibitor interaction with BRD4 domains.
Main Results:
- Intranasal SUM52 and SUM35 attenuated thermal and mechanical hypersensitivity in SNI mice without causing locomotor impairment.
- Both compounds preferentially interacted with the BRD4-BD2 domain, with SUM52 being the most potent.
- SUM52 significantly reduced spinal microglia activation, iNOS, NF-κB, and p38 MAPK phosphorylation.
- SUM52 treatment led to a marked decrease in spinal proinflammatory cytokines IL-6 and IL-1ß.
Conclusions:
- Dual HDAC/BRD4 inhibitors, particularly SUM52, demonstrate significant pain-relieving effects in a neuropathic pain model.
- Simultaneous inhibition of HDAC and BET proteins by a single molecule offers a promising multi-target therapeutic strategy.
- These findings support the development of dual inhibitors for effective neuropathic pain management.
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