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

Z Bertels, H Singh, I Dripps, K Siegersma, AF Tipton… - bioRxiv, 2020 - biorxiv.org
Z Bertels, H Singh, I Dripps, K Siegersma, AF Tipton, W Witkowski, Z Sheets, P Shah…
bioRxiv, 2020biorxiv.org
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 models of migraine to show that HDAC6-inhibition is a promising migraine
treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The …
Abstract
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 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.
biorxiv.org
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