Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, United States
Isaac Dripps
Department of Psychiatry, University of Illinois at Chicago, Chicago, United States
Kendra Siegersma
Department of Psychiatry, University of Illinois at Chicago, Chicago, United States
Alycia F Tipton
Department of Psychiatry, University of Illinois at Chicago, Chicago, United States
Wiktor D Witkowski
Department of Psychiatry, University of Illinois at Chicago, Chicago, United States
Zoie Sheets
Department of Psychiatry, University of Illinois at Chicago, Chicago, United States
Pal Shah
Department of Psychiatry, University of Illinois at Chicago, Chicago, United States
Catherine Conway
Department of Psychiatry, University of Illinois at Chicago, Chicago, United States
Elizaveta Mangutov
Department of Psychiatry, University of Illinois at Chicago, Chicago, United States
Mei Ao
Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, United States
Valentina Petukhova
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, United States
Bhargava Karumudi
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, United States
Pavel A Petukhov
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, United States
Serapio M Baca
Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, United States
Mark M Rasenick
Department 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 States
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.
