Abstract
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.
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Funding
This study was supported by National Institute of Neurological Disorders and Stroke NS086444 (V.Z.), NS093537 (V.Z.), and National Institute on Drug Abuse PPG- POIDAO8227 (V.Z.), NIH T32 5T32DA007135-34 (KP) NIH T32 GM007280 (RAS). Randal A. Serafini is a recipient of the Irene and Eric Simon Brain Research Foundation Summer Fellowship (2019). K. Avrampou is a graduate student in the Molecular Biology and Biomedine program of the University of Crete, Greece.
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Sakloth, F., Manouras, L., Avrampou, K. et al. HDAC6-selective inhibitors decrease nerve-injury and inflammation-associated mechanical hypersensitivity in mice. Psychopharmacology 237, 2139–2149 (2020). https://doi.org/10.1007/s00213-020-05525-9
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DOI: https://doi.org/10.1007/s00213-020-05525-9