Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition
Migraine is the sixth 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...
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doaj-7606ea99f0624f14a360122dad4954792021-05-19T18:36:20ZengeLife Sciences Publications LtdeLife2050-084X2021-04-011010.7554/eLife.63076Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibitionZachariah Bertels0Harinder Singh1https://orcid.org/0000-0002-0160-1575Isaac Dripps2Kendra Siegersma3Alycia F Tipton4Wiktor D Witkowski5Zoie Sheets6Pal Shah7Catherine Conway8Elizaveta Mangutov9Mei Ao10Valentina Petukhova11Bhargava Karumudi12Pavel A Petukhov13Serapio M Baca14Mark M Rasenick15Amynah A Pradhan16https://orcid.org/0000-0001-9691-2976Department of Psychiatry, University of Illinois at Chicago, Chicago, United StatesDepartment of Physiology and Biophysics, University of Illinois at Chicago, Chicago, United StatesDepartment of Psychiatry, University of Illinois at Chicago, Chicago, United StatesDepartment of Psychiatry, University of Illinois at Chicago, Chicago, United StatesDepartment of Psychiatry, University of Illinois at Chicago, Chicago, United StatesDepartment of Psychiatry, University of Illinois at Chicago, Chicago, United StatesDepartment of Psychiatry, University of Illinois at Chicago, Chicago, United StatesDepartment of Psychiatry, University of Illinois at Chicago, Chicago, United StatesDepartment of Psychiatry, University of Illinois at Chicago, Chicago, United StatesDepartment of Psychiatry, University of Illinois at Chicago, Chicago, United StatesDepartment of Physiology and Biophysics, University of Illinois at Chicago, Chicago, United StatesDepartment of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, United StatesDepartment of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, United StatesDepartment of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, United StatesDepartment of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, United StatesDepartment of Psychiatry, University of Illinois at Chicago, Chicago, United States; Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, United States; Jesse Brown VAMC, Chicago, United StatesDepartment of Psychiatry, University of Illinois at Chicago, Chicago, United StatesMigraine is the sixth 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.https://elifesciences.org/articles/63076migrainepainauraallodyniatubulincytoskeleton |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zachariah Bertels Harinder Singh Isaac Dripps Kendra Siegersma Alycia F Tipton Wiktor D Witkowski Zoie Sheets Pal Shah Catherine Conway Elizaveta Mangutov Mei Ao Valentina Petukhova Bhargava Karumudi Pavel A Petukhov Serapio M Baca Mark M Rasenick Amynah A Pradhan |
spellingShingle |
Zachariah Bertels Harinder Singh Isaac Dripps Kendra Siegersma Alycia F Tipton Wiktor D Witkowski Zoie Sheets Pal Shah Catherine Conway Elizaveta Mangutov Mei Ao Valentina Petukhova Bhargava Karumudi Pavel A Petukhov Serapio M Baca Mark M Rasenick Amynah A Pradhan Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition eLife migraine pain aura allodynia tubulin cytoskeleton |
author_facet |
Zachariah Bertels Harinder Singh Isaac Dripps Kendra Siegersma Alycia F Tipton Wiktor D Witkowski Zoie Sheets Pal Shah Catherine Conway Elizaveta Mangutov Mei Ao Valentina Petukhova Bhargava Karumudi Pavel A Petukhov Serapio M Baca Mark M Rasenick Amynah A Pradhan |
author_sort |
Zachariah Bertels |
title |
Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition |
title_short |
Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition |
title_full |
Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition |
title_fullStr |
Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition |
title_full_unstemmed |
Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition |
title_sort |
neuronal complexity is attenuated in preclinical models of migraine and restored by hdac6 inhibition |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2021-04-01 |
description |
Migraine is the sixth 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. |
topic |
migraine pain aura allodynia tubulin cytoskeleton |
url |
https://elifesciences.org/articles/63076 |
work_keys_str_mv |
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