HDAC6-selective inhibitors decrease nerve-injury and inflammation-associated mechanical hypersensitivity in mice

Sakloth, Farhana; Manouras, Lefteris; Avrampou, Kleopatra; Mitsi, Vasiliki; Serafini, Randal A.; Pryce, Kerri D.; Cogliani, Valeria; Berton, Olivier; Jarpe, Matthew; Zachariou, Venetia

doi:10.1007/s00213-020-05525-9

Cited by 20 publications

(27 citation statements)

References 47 publications

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“…In addition, both groups found that chemotherapy blunted mitochondrial transport in sensory neurons, an effect that was restored by HDAC6 inhibition. A recent study also found that HDAC6 inhibition was effective in models of inflammatory and neuropathic pain [72]. Together with our study, these data further demonstrate the importance of HDAC6 in regulating acetylated α-tubulin and how tubulin acetylation state can regulate sensory dysfunction; thus supporting the potential of HDAC6 inhibitors for the treatment for chronic pain conditions.…”

Section: Discussionsupporting

confidence: 86%

Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

Bertels

Grewal

Dripps

et al. 2020

Preprint

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Migraine is the third most prevalent disease worldwide and current therapies provide only partial relief. Greater insight into molecular migraine mechanisms would create novel therapies. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on microtubule dynamicity. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated models of chronic migraine to show that HDAC6-inhibition is an effective migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in pain-processing regions, and these were reversed by HDAC6 inhibition.Cortical spreading depression (CSD), a physiological correlate of migraine aura, also caused decreased cortical neurite growth, while administration of HDAC6-inhibitor restored neuronal complexity and decreased CSD. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and evolving migraine therapies might include agents that restore microtubule stability and neuronal plasticity.

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Section: Discussionsupporting

confidence: 86%

Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

Bertels

Grewal

Dripps

et al. 2020

Preprint

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“…It should be noted that other HDACs, such as HDAC3, may be involved in neuropathic pain development and resolution, as illustrated by studies with pan-HDAC inhibitors ( Cho and Cavalli, 2014 ). With that said, many studies point to HDAC6 as a major player in mechanisms that underlie peripheral neuropathy development ( d’Ydewalle et al, 2012 ; Benoy et al, 2017 ; Krukowski et al, 2017 ; Ma et al, 2018b ; Prior et al, 2018 ; Sakloth et al, 2020 ). Moreover, HDAC6-specific inhibitors are being investigated as targeted therapeutics for peripheral neuropathy, in comparison to other HDAC inhibitors, especially in light of observations of HDAC6 regulation of neuronal microtubule stability ( Rivieccio et al, 2009 ; d’Ydewalle et al, 2012 ; Simões-Pires et al, 2013 ; Wang et al, 2016 ).…”

Section: Histone Modifications Are Important For Neuronal Microtubule Stabilitymentioning

confidence: 99%

“…Histone deacetylase 6 is a cytoplasmic Class II histone deacetylase, known to target and enzymatically remove acetyl groups from post-translationally modified non-histone proteins, such as microtubules, and significantly alter target protein function ( Hubbert et al, 2002 ). Dysregulated HDAC6 correlates with peripheral neuropathy development, neuronal microtubule instability, and decreased axonal transport of mitochondria ( Chen et al, 2010 ; Picci et al, 2020 ; Sakloth et al, 2020 ). Therefore, therapies targeting HDAC6 may restore balanced mitochondrial activity, mediate potential repair of peripheral neuropathy, and alleviate neuropathic pain ( Adalbert et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

HDAC6: A Key Link Between Mitochondria and Development of Peripheral Neuropathy

English

Barton

2021

Front. Mol. Neurosci.

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Peripheral neuropathy, which is the result of nerve damage from lesions or disease, continues to be a major health concern due to the common manifestation of neuropathic pain. Most investigations into the development of peripheral neuropathy focus on key players such as voltage-gated ion channels or glutamate receptors. However, emerging evidence points to mitochondrial dysfunction as a major player in the development of peripheral neuropathy and resulting neuropathic pain. Mitochondrial dysfunction in neuropathy includes altered mitochondrial transport, mitochondrial metabolism, as well as mitochondrial dynamics. The mechanisms that lead to mitochondrial dysfunction in peripheral neuropathy are poorly understood, however, the Class IIb histone deacetylase (HDAC6), may play an important role in the process. HDAC6 is a key regulator in multiple mechanisms of mitochondrial dynamics and may contribute to mitochondrial dysregulation in peripheral neuropathy. Accumulating evidence shows that HDAC6 inhibition is strongly associated with alleviating peripheral neuropathy and neuropathic pain, as well as mitochondrial dysfunction, in in vivo and in vitro models of peripheral neuropathy. Thus, HDAC6 inhibitors are being investigated as potential therapies for multiple peripheral neuropathic disorders. Here, we review emerging studies and integrate recent advances in understanding the unique connection between peripheral neuropathy and mitochondrial dysfunction through HDAC6-mediated interactions.

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“…Furthermore, this effect of ACY-738 appeared to be short lasting and was no longer present at the 24 h timepoint. Other groups using ACY-738 or other HDAC6 inhibitors also did not observe general disruption in mechanical or temperature sensitivity with HDAC6 inhibition [15,[73][74][75]. Additionally, constitutive knockout of HDAC6 produces viable offspring with few phenotypic changes [76].…”

Section: Discussionmentioning

confidence: 93%

“…In addition, both groups found that chemotherapy blunted mitochondrial transport in sensory neurons, an effect that was restored by HDAC6 inhibition. Another study also found that HDAC6 inhibitors were effective in models of inflammatory and neuropathic pain ( Sakloth et al, 2020 ). Together, these studies highlight the importance of cytoarchitectural dynamics in relation to pain sensation and the ability of HDAC6 inhibition to promote relief from allodynia/hyperalgesia.…”

Section: Discussionmentioning

confidence: 98%

Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition

Bertels

Singh

Dripps

et al. 2021

eLife

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Migraine is the third most prevalent disease worldwide but the mechanisms that underlie migraine chronicity are poorly understood. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on dynamic microtubules. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated mouse models of migraine to show that HDAC6-inhibition is a promising migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in headache-processing regions, which were reversed by HDAC6 inhibition. Cortical spreading depression (CSD), a physiological correlate of migraine aura, also decreased cortical neurite growth, while HDAC6-inhibitor restored neuronal complexity and decreased CSD. Importantly, a calcitonin gene-related peptide receptor antagonist also restored blunted neuronal complexity induced by nitroglycerin. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and effective migraine therapies might include agents that restore microtubule/neuronal plasticity.

show abstract

HDAC6-selective inhibitors decrease nerve-injury and inflammation-associated mechanical hypersensitivity in mice

Cited by 20 publications

References 47 publications

Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

HDAC6: A Key Link Between Mitochondria and Development of Peripheral Neuropathy

Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition

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