Inhibition of histone deacetylase 6 alleviates neuropathic pain via direct regulating post- translation of spinal STAT3 and decreasing downstream C-C Motif Chemokine Ligand 7 synthesis

Journal of Neuroinflammation, 2025 · DOI: https://doi.org/10.1186/s12974-025-03400-y · Published: March 1, 2025

Simple Explanation

Neuropathic pain is a nerve injury-induced condition that poses a significant clinical challenge. The study found that inhibiting HDAC6, an enzyme, with ACY-1215 alleviated pain in mice with nerve injury. ACY-1215 treatment increased acetylated STAT3 and reduced phosphorylated STAT3 in the spinal cord. STAT3 is a protein involved in inflammation and pain signaling. The study suggests that HDAC6 inhibition can mitigate neuropathic pain by affecting STAT3 and reducing the release of CCL7 and cytokines, which are involved in inflammation.

Study Duration

14 days

Participants

Male and female CD-1 mice (6–8 weeks, 20–25 g)

Evidence Level

Not specified

Key Findings

1
ACY-1215 ameliorated SNI-induced pain starting from Day 7 post-SNI operation, achieving relatively stable efficacy by Day 13 in both male and female mice.
2
ACY-1215 increased STAT3 acetylation and reduced STAT3 phosphorylation, while not altering HDAC6 expression.
3
SNI operation increased the interaction between HDAC6 and STAT3, while ACY-1215 administration reversed the SNI-enhanced spinal HDAC6-STAT3 interaction

Research Summary

This study investigates the effects of HDAC6 inhibition on neuropathic pain using a spared nerve injury (SNI) mouse model and demonstrates that the selective HDAC6 inhibitor ACY-1215 significantly alleviated SNI-induced mechanical allodynia and hyperalgesia. ACY-1215 increases STAT3 acetylation while reducing its phosphorylation in the lumbar spinal cord, suggesting that HDAC6 regulates STAT3 post-translational modifications. Neuronal overexpression of STAT3 induced pain hypersensitivity and elevated levels of pro-inflammatory cytokines, including CCL7, TNF-α, and IL-1β, while ACY-1215 was able to suppress these elevations.

Practical Implications

Therapeutic Potential

Targeting the HDAC6/STAT3/CCL axis could offer a new therapeutic approach for neuropathic pain management.

Drug Development

HDAC6 inhibitors, including ACY-1215, may offer advantages in cancer-related pain management, given their therapeutic potential in cancer therapy.

Clinical Trials

Given ACY-1215 exhibits high biosafety and favorable brain permeability, it may benefit the treatment of central nervous system-related disorders

Study Limitations

1
The investigation was primarily confined to the SNI model, which may not fully replicate the complexities of neuropathic pain in human cases.
2
Although we focused on the HDAC6-STAT3 interaction, it is imperative to explore other pathways involved HDAC6’s anti-nociceptive actions.
3
The long-term effects and potential side effects of chronic HDAC6 inhibition on the nervous system have yet to be investigated.

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