Dual HDAC/BRD4 Inhibitors Relieves Neuropathic Pain by Attenuating Inflammatory Response in Microglia After Spared Nerve Injury

Neurotherapeutics, 2022 · DOI: 10.1007/s13311-022-01243-6 · Published: May 2, 2022

Simple Explanation

This study explores new treatments for neuropathic pain, which is often difficult to manage. Current therapies often have limited effectiveness, leading to the need for combination therapies. The research focuses on epigenetic modifications, specifically histone acetylation, which plays a key role in chronic pain. Altering these modifications can potentially relieve pain. The study investigates dual inhibitors that can simultaneously target histone deacetylases (HDACs) and bromodomain proteins (BETs). These dual inhibitors, SUM52 and SUM35, aim to modulate both BET and HDAC activity to relieve neuropathic pain.

Study Duration

Not specified

Participants

Male CD1 mice (24–26 g, 4 weeks old)

Evidence Level

Not specified

Key Findings

1
SUM52 and SUM35, administered intranasally, reduced thermal and mechanical hypersensitivity in mice with spared nerve injury (SNI), a model of neuropathic pain.
2
SUM52 was found to reduce microglia-mediated spinal neuroinflammation by decreasing IBA1 immunostaining, iNOS expression, and the phosphorylation of NF-κB and p38 MAPK.
3
SUM52 treatment also resulted in a significant decrease in the levels of proinflammatory cytokines (IL-6 and IL-1ß) in the spinal cord.

Research Summary

This study investigates the efficacy of dual HDAC/BRD4 inhibitors, SUM52 and SUM35, in treating neuropathic pain using a spared nerve injury (SNI) model in mice. The results indicate that both SUM52 and SUM35 can effectively attenuate thermal and mechanical hypersensitivity associated with neuropathic pain, with SUM52 showing a more pronounced effect. The study also highlights that SUM52 reduces spinal neuroinflammation by modulating microglia activation and decreasing the levels of proinflammatory cytokines, suggesting a potential mechanism for its pain-relieving activity.

Practical Implications

Potential for Novel Therapies

The study suggests that dual HDAC/BRD4 inhibitors could be a promising approach for developing new treatments for neuropathic pain.

Targeting Neuroinflammation

The findings indicate that reducing neuroinflammation, particularly by modulating microglia activation, is a key therapeutic strategy for neuropathic pain relief.

Multi-Target Approach

The research supports the idea that targeting multiple disease-relevant mechanisms with a single molecule can be more effective than traditional single-target therapies.

Study Limitations

1
The study is limited to a mouse model of neuropathic pain, and further research is needed to confirm these findings in humans.
2
The study focuses on specific HDAC and BRD4 isoforms, and the roles of other isoforms may warrant further investigation.
3
The long-term effects and potential side effects of dual HDAC/BRD4 inhibitors require additional evaluation.

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