Neuronal Complexity is Attenuated in Preclinical Models of Migraine and Restored by HDAC6 Inhibition

Overview

Journal Elife

Specialty Biology

Date 2021 Apr 15

PMID 33856345

Citations 15

Authors

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

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Effect of acupuncture combined with auricular beanembedding on autonomic nervous system function, heart rate variability and mental state of migraine patients.

Lu Y, Sun Z, Huang P, Wang Y Am J Transl Res. 2024; 16(10):6148-6158.

PMID: 39544727 PMC: 11558419. DOI: 10.62347/MJPK6664.

White matter and cortical gray matter microstructural abnormalities in new daily persistent headache: a NODDI study.

Li Z, Mei Y, Wang W, Wang L, Wu S, Zhang K J Headache Pain. 2024; 25(1):110.

PMID: 38977951 PMC: 11232337. DOI: 10.1186/s10194-024-01815-1.

Glial activation in pain and emotional processing regions in the nitroglycerin mouse model of chronic migraine.

Cropper H, Conway C, Wyche W, Pradhan A Headache. 2024; 64(8):973-982.

PMID: 38899347 PMC: 11864597. DOI: 10.1111/head.14740.

Histone deacetylase inhibitor decreases hyperalgesia in a mouse model of alcohol withdrawal-induced hyperalgesia.

Aguilar J, De Carvalho L, Chen H, Condon R, Lasek A, Pradhan A Alcohol Clin Exp Res (Hoboken). 2024; 48(3):478-487.

PMID: 38378262 PMC: 10940188. DOI: 10.1111/acer.15273.

Alterations in DNA methylation associate with reduced migraine and headache days after medication withdrawal treatment in chronic migraine patients: a longitudinal study.

Mehta D, de Boer I, Sutherland H, Pijpers J, Bron C, Bainomugisa C Clin Epigenetics. 2023; 15(1):190.

PMID: 38087366 PMC: 10717674. DOI: 10.1186/s13148-023-01604-8.

References

Long T, He W, Pan Q, Zhang S, Zhang Y, Liu C . Microglia P2X4 receptor contributes to central sensitization following recurrent nitroglycerin stimulation. J Neuroinflammation. 2018; 15(1):245. PMC: 6117935. DOI: 10.1186/s12974-018-1285-3. View

Steffensen A, Sword J, Croom D, Kirov S, MacAulay N . Chloride Cotransporters as a Molecular Mechanism underlying Spreading Depolarization-Induced Dendritic Beading. J Neurosci. 2015; 35(35):12172-87. PMC: 4556786. DOI: 10.1523/JNEUROSCI.0400-15.2015. View

Portran D, Schaedel L, Xu Z, Thery M, Nachury M . Tubulin acetylation protects long-lived microtubules against mechanical ageing. Nat Cell Biol. 2017; 19(4):391-398. PMC: 5376231. DOI: 10.1038/ncb3481. View

Liu Y, Zhou L, Wang J, Li D, Ren W, Peng J . TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury. J Neurosci. 2017; 37(4):871-881. PMC: 5296781. DOI: 10.1523/JNEUROSCI.2235-16.2016. View

Abdelkarim H, Neelarapu R, Madriaga A, Vaidya A, Kastrati I, Karumudi B . Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Amine-based Histone Deacetylase Inhibitors. ChemMedChem. 2017; 12(24):2030-2043. PMC: 5881582. DOI: 10.1002/cmdc.201700449. View

Brennan K, Bates E, Shapiro R, Zyuzin J, Hallows W, Huang Y . Casein kinase iδ mutations in familial migraine and advanced sleep phase. Sci Transl Med. 2013; 5(183):183ra56, 1-11. PMC: 4220792. DOI: 10.1126/scitranslmed.3005784. View

Basarsky T, Duffy S, Andrew R, MacVicar B . Imaging spreading depression and associated intracellular calcium waves in brain slices. J Neurosci. 1998; 18(18):7189-99. PMC: 6793239. View

Zhang X, Levy D, Kainz V, Noseda R, Jakubowski M, Burstein R . Activation of central trigeminovascular neurons by cortical spreading depression. Ann Neurol. 2011; 69(5):855-65. PMC: 3174689. DOI: 10.1002/ana.22329. View

dYdewalle C, Bogaert E, Van Den Bosch L . HDAC6 at the Intersection of Neuroprotection and Neurodegeneration. Traffic. 2012; 13(6):771-9. DOI: 10.1111/j.1600-0854.2012.01347.x. View

10.

Dripps I, Bertels Z, Moye L, Tipton A, Siegersma K, Baca S . Forebrain delta opioid receptors regulate the response of delta agonist in models of migraine and opioid-induced hyperalgesia. Sci Rep. 2020; 10(1):17629. PMC: 7573615. DOI: 10.1038/s41598-020-74605-9. View

11.

Greco R, Demartini C, Zanaboni A, Tassorelli C . Chronic and intermittent administration of systemic nitroglycerin in the rat induces an increase in the gene expression of CGRP in central areas: potential contribution to pain processing. J Headache Pain. 2018; 19(1):51. PMC: 6043463. DOI: 10.1186/s10194-018-0879-6. View

12.

. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015; 386(9995):743-800. PMC: 4561509. DOI: 10.1016/S0140-6736(15)60692-4. View

13.

Janke C, Bulinski J . Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions. Nat Rev Mol Cell Biol. 2011; 12(12):773-86. DOI: 10.1038/nrm3227. View

14.

Jochems J, Teegarden S, Chen Y, Boulden J, Challis C, Ben-Dor G . Enhancement of stress resilience through histone deacetylase 6-mediated regulation of glucocorticoid receptor chaperone dynamics. Biol Psychiatry. 2014; 77(4):345-55. PMC: 4297530. DOI: 10.1016/j.biopsych.2014.07.036. View

15.

Chen S, Ayata C . Novel Therapeutic Targets Against Spreading Depression. Headache. 2017; 57(9):1340-1358. DOI: 10.1111/head.13154. View

16.

Charles A, Baca S . Cortical spreading depression and migraine. Nat Rev Neurol. 2013; 9(11):637-44. DOI: 10.1038/nrneurol.2013.192. View

17.

Filiz A, Tepe N, Eftekhari S, Boran H, Dilekoz E, Edvinsson L . CGRP receptor antagonist MK-8825 attenuates cortical spreading depression induced pain behavior. Cephalalgia. 2017; 39(3):354-365. DOI: 10.1177/0333102417735845. View

18.

Descalzi G, Ikegami D, Ushijima T, Nestler E, Zachariou V, Narita M . Epigenetic mechanisms of chronic pain. Trends Neurosci. 2015; 38(4):237-46. PMC: 4459752. DOI: 10.1016/j.tins.2015.02.001. View

19.

Bates E, Nikai T, Brennan K, Fu Y, Charles A, Basbaum A . Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice. Cephalalgia. 2009; 30(2):170-8. PMC: 4854191. DOI: 10.1111/j.1468-2982.2009.01864.x. View

20.

Schytz H, Schoonman G, Ashina M . What have we learnt from triggering migraine?. Curr Opin Neurol. 2010; 23(3):259-65. DOI: 10.1097/WCO.0b013e328337b884. View