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HDAC6-selective inhibitors decrease nerve-injury and inflammation-associated mechanical hypersensitivity in mice
Farhana Sakloth1, Lefteris Manouras1, Kleopatra Avrampou1
1Nash Family Department of Neuroscience, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Box 10-65, New York, NY, 10029, USA.
Background:
HDAC6 is a class IIB histone deacetylase expressed at many levels of the nociceptive pathway. This study tested the ability of novel and selective HDAC6 inhibitors to alleviate sensory hypersensitivity behaviors in mouse models of peripheral nerve injury and peripheral inflammation.
Methods:
We utilized the murine spared nerve injury (SNI) model for peripheral nerve injury and the Complete Freund's Adjuvant (CFA) model of peripheral inflammation. We applied the Von Frey assay to monitor mechanical allodynia.
Results:
Using the SNI model, we demonstrate that daily administration of the brain-penetrant HDAC6 inhibitor, ACY-738, abolishes mechanical allodynia in male and in female mice. Importantly, there is no tolerance to the antiallodynic actions of these compounds as they produce a consistent increase in Von Frey thresholds for several weeks. We observed a similar antiallodynic effect when utilizing the HDAC6 inhibitor, ACY-257, which shows limited brain expression when administered systemically. We also demonstrate that ACY-738 and ACY-257 attenuate mechanical allodynia in the CFA model of peripheral inflammation.
Conclusions:
Overall, our findings suggest that inhibition of HDAC6 provides a promising therapeutic avenue for the alleviation of mechanical allodynia associated with peripheral nerve injury and peripheral inflammation.
Insights
Novel HDAC6 inhibitors, ACY-738 and ACY-257, effectively reduced pain hypersensitivity in mouse models of nerve injury and inflammation. These findings suggest HDAC6 inhibition as a promising strategy for pain relief.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Histone deacetylase 6 (HDAC6) is implicated in pain pathways.
- Novel selective HDAC6 inhibitors were investigated for therapeutic potential.
Purpose of the Study:
- To evaluate the efficacy of HDAC6 inhibitors in alleviating pain behaviors.
- To assess the therapeutic potential of HDAC6 inhibition for nerve injury and inflammation-induced pain.
Main Methods:
- Murine spared nerve injury (SNI) and Complete Freund's Adjuvant (CFA) models were used.
- Mechanical allodynia was measured using the Von Frey assay.
Main Results:
- Brain-penetrant ACY-738 abolished mechanical allodynia in SNI mice (male and female) without tolerance.
- Non-brain-penetrant ACY-257 also showed antiallodynic effects in SNI and CFA models.
- Both compounds attenuated mechanical allodynia in CFA-induced peripheral inflammation.
Conclusions:
- HDAC6 inhibition demonstrates significant potential for treating pain associated with peripheral nerve injury.
- HDAC6 inhibition offers a promising therapeutic approach for managing pain from peripheral inflammation.
