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Histone Deacetylase Inhibitors Counteract CGRP Signaling and Pronociceptive Sensitization in a Rat Model of Medication Overuse Headache

  • Author Footnotes
    # These authors contributed equally to this work.
    Matteo Urru
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze, Italy
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  • Author Footnotes
    # These authors contributed equally to this work.
    Daniela Buonvicino
    Correspondence
    Address reprint requests to Daniela Buonvicino, PhD. Department of Health Sciences. Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy.
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze, Italy
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  • Alessandra Pistolesi
    Affiliations
    Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze, Italy
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  • Sara Paccosi
    Affiliations
    Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze, Italy
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  • Alberto Chiarugi
    Affiliations
    Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze, Italy
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  • Author Footnotes
    # These authors contributed equally to this work.

      Highlights

      • Chronic exposure of rat to eletriptan induces CGRP and its receptor expression in TG but not in TNc.
      • HDAC inhibitors, Panobinostat and givinostat prevent overexpression of CGRP and its receptor in TG.
      • Both inhibitors counteract photophobic behavior and cephalic allodynia in eletriptan-exposed rats.
      • Both drugs prevent hypersensitivity to capsaicin-induced vasodilatation in eletriptan-exposed rats.
      • Data support the therapeutic potential of HDAC inhibition in preventing migraine chronification.

      Abstract

      Chronic triptan exposure in rodents recapitulates medication overuse headache (MOH), causing cephalic pain sensitization and trigeminal ganglion overexpression of pronociceptive proteins including CGRP. Because of these transcriptional derangements, as well as the emerging role of epigenetics in chronic pain, in the present study, we evaluated the effects of the histone deacetylase inhibitors (HDACis) panobinostat and givinostat, in rats chronically exposed to eletriptan for 1 month. Both panobinostat and givinostat counteracted overexpression of genes coding for CGRP and its receptor subunit RAMP1, having no effects on CLR and RCP receptor subunits in the trigeminal ganglion (TG) of eletriptan-exposed rats. Within the trigeminal nucleus caudalis (TNc), transcripts for these genes were neither upregulated by eletriptan nor altered by concomitant treatment with panobinostat or givinostat. HDACis counteracted hypersensitivity to capsaicin-induced vasodilatation in the trigeminal territory, as well as photophobic behavior and cephalic allodyniain eletriptan-exposed rats. Eletriptan did not affect CGRP, CLR, and RAMP1 expression in cultured trigeminal ganglia, whereas both inhibitors reduced transcripts for CLR and RAMP-1. The drugs, however, increased luciferase expression driven by CGRP promoter in cultured cells. Our findings provide evidence for a key role of HDACs and epigenetics in MOH pathogenesis, highlighting the therapeutic potential of HDAC inhibition in the prevention of migraine chronification.

      Perspective

      The present study highlights a key epigenetic role of HDAC in the rodent model of medication overuse headache, furthering our understanding of the molecular mechanisms responsible for pronociceptive sensitization during headache chronification.

      Key words

      Abbreviations:

      ANOVA (Analysis of Variance), CGRP (Calcitonin Gene-Related Peptide), CLR (Calcitonin-like receptor), CNS (Central nervous system), DIV (days in vitro, HDAC, Histone deacetylase), HDACi (Histone deacetylase inhibitor), MOH (Medication overuse headache), PCR (Polymerase Chain Reaction), RAMP1 (Receptor Activity Modifying Protein 1), RCP (receptor component protein), SEM (Standard error of the mean), TG (trigeminal ganglion), TNc (trigeminal nucleus caudalis)
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      References

        • Andreou AP
        • Edvinsson L
        Mechanisms of migraine as a chronic evolutive condition.
        J Headache Pain. 2019; 20https://doi.org/10.1186/s10194-019-1066-0
        • Becker WJ
        The diagnosis and management of chronic migraine in primary care.
        Headache J Head Face Pain. 2017; 57: 1471-1481https://doi.org/10.1111/head.13089
        • Bertels Z
        • Singh H
        • Dripps I
        • Siegersma K
        • Tipton AF
        • Witkowski W
        • Sheets Z
        • Shah P
        • Conway C
        • Mangutov E
        • Ao M
        • Petukhova V
        • Karumudi B
        • Petukhov PA
        • Baca SM
        • Rasenick MM
        • Pradhan AA
        Neuronal complexity is attenuated in preclinical models of migraine and restored by hdac6 inhibition.
        Elife. 2021; 10https://doi.org/10.7554/ELIFE.63076
        • Bigal ME
        • Serrano D
        • Buse D
        • Scher A
        • Stewart WF
        • Lipton RB
        Acute migraine medications and evolution from episodic to chronic migraine: A longitudinal population-based study.
        Headache. 2008; 48: 1157-1168https://doi.org/10.1111/j.1526-4610.2008.01217.x
        • Broad PM
        • Symes AJ
        • Thakker R.V.
        • Craig RK
        Structure and methylation of the human calcitonin/α-CGRP gene.
        Nucleic Acids Res. 1989; 17: 6999-7011https://doi.org/10.1093/nar/17.17.6999
        • Buntinx L
        • Vermeersch S
        • De Hoon J
        Development of anti-migraine therapeutics using the capsaicin-induced dermal blood flow model.
        Br J Clin Pharmacol. 2015; 80: 992-1000https://doi.org/10.1111/bcp.12704
        • Buonvicino D
        • Mazzola F
        • Zamporlini F
        • Resta F
        • Ranieri G
        • Camaioni E
        • Muzzi M
        • Zecchi R
        • Pieraccini G
        • Dölle C
        • Calamante M
        • Bartolucci G
        • Ziegler M
        • Stecca B
        • Raffaelli N
        • Chiarugi A
        Identification of the nicotinamide salvage pathway as a new toxification route for antimetabolites.
        Cell Chem Biol. 2018; 25 (e7): 471-482https://doi.org/10.1016/j.chembiol.2018.01.012
        • Buonvicino D
        • Ranieri G
        • Pratesi S
        • Guasti D
        • Chiarugi A
        Neuroimmunological characterization of a mouse model of primary progressive experimental autoimmune encephalomyelitis and effects of immunosuppressive or neuroprotective strategies on disease evolution.
        Exp Neurol. 2019; 322https://doi.org/10.1016/j.expneurol.2019.113065
        • Buonvicino D
        • Urru M
        • Muzzi M
        • Ranieri G
        • Luceri C
        • Oteri C
        • Lapucci A
        • Chiarugi A
        Trigeminal ganglion transcriptome analysis in 2 rat models of medication-overuse headache reveals coherent and widespread induction of pronociceptive gene expression patterns.
        Pain. 2018; 159: 1980-1988https://doi.org/10.1097/j.pain.0000000000001291
        • Capi M
        • Curto M
        • Lionetto L
        • De Andrés F
        • Gentile G
        • Negro A
        • Martelletti P
        Eletriptan in the management of acute migraine: An update on the evidence for efficacy, safety, and consistent response.
        Ther Adv Neurol Disord. 2016; 9: 414-423https://doi.org/10.1177/1756285616650619
        • Chifotides HT
        • Bose P
        • Verstovsek S
        Givinostat: an emerging treatment for polycythemia vera.
        Expert Opin Investig Drugs. 2020; 29: 525-536https://doi.org/10.1080/13543784.2020.1761323
        • Colás R
        • Muñoz P
        • Temprano R
        • Gómez C
        • Pascual J
        Chronic daily headache with analgesic overuse.
        Neurology. 2004; 62: 1338-1342https://doi.org/10.1212/01.WNL.0000120545.45443.93
        • Consalvi S
        • Saccone V
        • Mozzetta C
        Histone deacetylase inhibitors: A potential epigenetic treatment for Duchenne muscular dystrophy.
        Epigenomics. 2014; 6: 547-560https://doi.org/10.2217/epi.14.36
        • Crow M
        • Khovanov N
        • Kelleher JH
        • Sharma S
        • Grant AD
        • Bogdanov Y
        • Wood JN
        • McMahon SB
        Denk F: HDAC4 is required for inflammation-associated thermal hypersensitivity.
        FASEB J. 2015; 29: 3370-3378https://doi.org/10.1096/fj.14-264440
        • Cupini LM
        • Calabresi P
        Medication-overuse headache: Pathophysiological insights.
        J. Headache Pain. 2005; 6: 199-202https://doi.org/10.1007/s10194-005-0184-z
        • D'Amico D
        • Grazzi L
        • Curone M
        • Leonardi M
        • Raggi A
        Cost of medication overuse headache in Italian patients at the time-point of withdrawal: a retrospective study based on real data.
        Neurol Sci. 2017; 38: 3-6https://doi.org/10.1007/S10072-017-2891-Z
        • Da-Silva AN
        • Lake AE
        Clinical aspects of medication overuse headaches.
        Headache. 2014; 54: 211-217https://doi.org/10.1111/head.12223
        • De Felice M
        • Porreca F
        Opiate-induced persistent pronociceptive trigeminal neural adaptations: Potential relevance to opiate-induced medication overuse headache.
        Cephalalgia. 2009; 29: 1277-1284https://doi.org/10.1111/j.1468-2982.2009.01873.x
        • De Felice M
        • Ossipov MH
        • Porreca F
        Persistent medication-induced neural adaptations, descending facilitation, and medication overuse headache.
        Curr Opin Neurol. 2011; 24: 193-196https://doi.org/10.1097/WCO.0b013e328346af25
        • De Felice M
        • Ossipov MH
        • Wang R
        • Dussor G
        • Lai J
        • Meng ID
        • Chichorro J
        • Andrews JS
        • Rakhit S
        • Maddaford S
        • Dodick D
        • Porreca F
        Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal ganglion dural afferents underlies increased responsiveness to potential migraine triggers.
        Brain. 2010; 133: 2475-2488https://doi.org/10.1093/brain/awq159
        • DeFelice M
        • Ossipov MH
        • Wang R
        • Lai J
        • Chichorro J
        • Meng I
        • Dodick DW
        • Vanderah TW
        • Dussor G
        • Porreca F
        Triptan-induced latent sensitization a possible basis for medication overuse headache.
        Ann Neurol. 2010; 67: 325-337https://doi.org/10.1002/ana.21897
        • Denk F
        • Huang W
        • Sidders B
        • Bithell A
        • Crow M
        • Grist J
        • Sharma S
        • Ziemek D
        • Rice ASC
        • Buckley NJ
        • McMahon SB
        HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain.
        Pain. 2013; 154: 1668-1679https://doi.org/10.1016/j.pain.2013.05.021
        • Denk F
        • McMahon SB
        Chronic pain: Emerging evidence for the involvement of epigenetics.
        Neuron. 2012; 73: 435-444https://doi.org/10.1016/j.neuron.2012.01.012
        • Descalzi G
        • Ikegami D
        • Ushijima T
        • Nestler EJ
        • Zachariou V
        • Narita M
        Epigenetic mechanisms of chronic pain.
        Trends in Neurosciences. 2015; 38: 237-246https://doi.org/10.1016/j.tins.2015.02.001
        • Durham PL
        • Dong PX
        • Belasco KT
        • Kasperski J
        • Gierasch WW
        • Edvinsson L
        • Heistad DD
        • Faraci FM
        • Russo AF
        Neuronal expression and regulation of CGRP promoter activity following viral gene transfer into cultured trigeminal ganglia neurons.
        Brain Res. 2004; 997: 103-110https://doi.org/10.1016/j.brainres.2003.11.005
        • Durham PL
        • Sharma R.V.
        • Russo AF
        Repression of the calcitonin gene-related peptide promoter by 5-HT1 receptor activation.
        J Neurosci. 1997; 17: 9545-9553https://doi.org/10.1523/jneurosci.17-24-09545.1997
        • Eleutherakis-Papaiakovou E
        • Kanellias N
        • Kastritis E
        • Gavriatopoulou M
        • Terpos E
        • Dimopoulos MA
        Efficacy of Panobinostat for the Treatment of Multiple Myeloma.
        J Oncol. 2020; 2020: 1-11https://doi.org/10.1155/2020/7131802
        • Evers S
        • Marziniak M
        Clinical features, pathophysiology, and treatment of medication-overuse headache.
        Lancet Neurol. 2010; 9: 391-401https://doi.org/10.1016/S1474-4422(10)70008-9
        • Farajdokht F
        • Babri S
        • Karimi P
        • Alipour MR
        • Bughchechi R
        • Mohaddes G
        Chronic ghrelin treatment reduced photophobia and anxiety-like behaviors in nitroglycerin- induced migraine: role of pituitary adenylate cyclase-activating polypeptide.
        Eur J Neurosci. 2017; 45: 763-772https://doi.org/10.1111/ejn.13486
        • Finocchi C
        • Strada L
        Sex-related differences in migraine.
        Neurol Sci. 2014; 35https://doi.org/10.1007/S10072-014-1772-Y
        • Franco-Cereceda A
        • Rudehill A
        Capsaicin-induced vasodilatation of human coronary arteries in vitro is mediated by calcitonin gene-related peptide rather than substance P or neurokinin A.
        Acta Physiol Scand. 1989; 136: 575-580https://doi.org/10.1111/J.1748-1716.1989.TB08704.X
        • Freeland K
        • Liu YZ
        • Latchman DS
        Distinct signalling pathways mediate the cAMP response element (CRE)-dependent activation or the calcitonin gene-related peptide gene promoter by cAMP and nerve growth factor.
        Biochem J. 2000; 345: 233-238https://doi.org/10.1042/0264-6021:3450233
        • Hitomi S
        • Kross K
        • Kurose M
        • Porreca F
        • Meng ID
        Activation of dura-sensitive trigeminal neurons and increased c-Fos protein induced by morphine withdrawal in the rostral ventromedial medulla.
        Cephalalgia. 2017; 37: 407-417https://doi.org/10.1177/0333102416648655
        • Ho TW
        • Edvinsson L
        • Goadsby PJ
        CGRP and its receptors provide new insights into migraine pathophysiology.
        Nature Reviews Neurology. 2010; 6: 573-582https://doi.org/10.1038/nrneurol.2010.127
        • Kim YJ
        • Greer CB
        • Cecchini KR
        • Harris LN
        • Tuck DP
        • Kim TH
        HDAC inhibitors induce transcriptional repression of high copy number genes in breast cancer through elongation blockade.
        Oncogene. 2013; 32: 2828-2835https://doi.org/10.1038/onc.2013.32
        • Kopruszinski CM
        • Xie JY
        • Eyde NM
        • Remeniuk B
        • Walter S
        • Stratton J
        • Bigal M
        • Chichorro JG
        • Dodick D
        • Porreca F
        Prevention of stress- or nitric oxide donor-induced medication overuse headache by a calcitonin gene-related peptide antibody in rodents.
        Cephalalgia. 2017; 37: 560-570https://doi.org/10.1177/0333102416650702
        • Levy D
        • Jakubowski M
        • Burstein R
        Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT 1B/1D receptor agonists.
        Proc Natl Acad Sci U. S. A. 2004; 101: 4274-4279https://doi.org/10.1073/pnas.0306147101
        • Lewis EC
        • Blaabjerg L
        • StØrling J
        • Ronn SG
        • Mascagni P
        • Dinarello CA
        Mandrup-Poulsen T: The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet β cells in vivo and in vitro.
        Mol Med. 2011; 17: 369-377https://doi.org/10.2119/molmed.2010.00152
        • Mason BN
        • Kaiser EA
        • Kuburas A
        • Loomis MCM
        • Latham JA
        • Garcia-Martinez LF
        • Russo AF
        Induction of migraine-like photophobic behavior in mice by both peripheral and central CGRP mechanisms.
        J Neurosci. 2017; 37: 204-216https://doi.org/10.1523/JNEUROSCI.2967-16.2016
        • Matthews GM
        • Lefebure M
        • Doyle MA
        • Shortt J
        • Ellul J
        • Chesi M
        • Banks KM
        • Vidacs E
        • Faulkner D
        • Atadja P
        • Bergsagel PL
        • Johnstone RW
        Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma.
        Cell Death Dis. 2013; 4: e798https://doi.org/10.1038/cddis.2013.306
        • Mauro A
        • Rigante D
        • Cimaz R
        Investigational drugs for treatment of juvenile idiopathic arthritis.
        Expert Opin Investigat Drugs. 2017; 26: 381-387https://doi.org/10.1080/13543784.2017.1301929
        • Melo-Carrillo A
        • Strassman AM
        • Nir R-R
        • Schain AJ
        • Noseda R
        • Stratton J
        • Burstein R
        Fremanezumab-A Humanized Monoclonal Anti-CGRP Antibody-Inhibits Thinly Myelinated (Aδ) But Not Unmyelinated (C) Meningeal Nociceptors.
        J Neurosci. 2017; 37: 10587-10596https://doi.org/10.1523/JNEUROSCI.2211-17.2017
        • Meng ID
        • Dodick D
        • Ossipov MH
        • Porreca F
        Pathophysiology of medication overuse headache: Insights and hypotheses from preclinical studies.
        Cephalalgia. 2011; 31: 851-860https://doi.org/10.1177/0333102411402367
        • Nusinzon I
        • Horvath CM
        Histone Deacetylases as Transcriptional Activators?.
        Role Reversal Inducible Gene Regulation. Sci Signal. 2005; 2005: re11https://doi.org/10.1126/stke.2962005re11
        • Park KY
        • Fletcher JR
        • Raddant AC
        • Russo AF
        Epigenetic regulation of the calcitonin gene-related peptide gene in trigeminal glia.
        Cephalalgia. 2011; 31: 614-624https://doi.org/10.1177/0333102410391487
        • Park KY
        • Russo AF
        Control of the calcitonin gene-related peptide enhancer by upstream stimulatory factor in trigeminal ganglion neurons.
        J Biol Chem. 2008; 283: 5441-5451https://doi.org/10.1074/jbc.M708662200
        • Pisanu C
        • Caproni S
        • Congiu D
        • Cupini LM
        • Squassina A
        • Patrinos GP
        • Corbelli I
        • Calabresi P
        • Del Zompo M
        • Sarchielli P
        HDAC3 role in medication consumption in medication overuse headache patients: a pilot study.
        Hum Genomics. 2015; 9: 30https://doi.org/10.1186/s40246-015-0051-1
        • Probyn K
        • Bowers H
        • Caldwell F
        • Mistry D
        • Underwood M
        • Matharu M
        • Pincus T
        Prognostic factors for chronic headache.
        Neurology. 2017; 89: 291-301https://doi.org/10.1212/WNL.0000000000004112
        • Russell MB
        • Lundqvist C
        Prevention and management of medication overuse headache.
        Curr Opin Neurol. 2012; 25: 290-295https://doi.org/10.1097/WCO.0b013e328352c431
        • Tassorelli C
        • Jensen R
        • Allena M
        • De Icco R
        • Sances G
        • Katsarava Z
        • Lainez M
        • Leston J
        • Fadic R
        • Spadafora S
        • Pagani M
        • Nappi G
        A consensus protocol for the management of medication-overuse headache: Evaluation in a multicentric, multinational study.
        Cephalalgia. 2014; 34: 645-655https://doi.org/10.1177/0333102414521508
        • Tverberg LA
        • Russo AF
        Cell-specific glucocorticoid repression of calcitonin/calcitonin gene- related peptide transcription. Localization to an 18-base pair basal enhancer element.
        J Biol Chem. 1992; 267: 17567-17573https://doi.org/10.1016/s0021-9258(19)37080-2
        • Urru M
        • Muzzi M
        • Coppi E
        • Ranieri G
        • Buonvicino D
        • Camaioni E
        • Coppini R
        • Pugliese AM
        • Tanaka B
        • Estacion M
        • Waxman SG
        • Dib-Hajj SD
        • Chiarugi A
        Dexpramipexole blocks Nav1.8 sodium channels and provides analgesia in multiple nociceptive and neuropathic pain models.
        Pain. 2020; 161: 831-841https://doi.org/10.1097/J.PAIN.0000000000001774
        • Viney TJ
        • Schmidt TW
        • Gierasch W
        • Sattar AW
        • Yaggie RE
        • Kuburas A
        • Quinn JP
        • Coulson JM
        • Russo AF
        Regulation of the cell-specific calcitonin/calcitonin gene-related peptide enhancer by USF and the Foxa2 forkhead protein.
        J Biol Chem. 2004; 279: 49948-49955https://doi.org/10.1074/JBC.M406659200
        • Wan D
        • Hou L
        • Zhang X
        • Han X
        • Chen M
        • Tang W
        • Liu R
        • Dong Z
        • Yu S
        DNA methylation of RAMP1 gene in migraine: an exploratory analysis.
        J Headache Pain. 2015; 16https://doi.org/10.1186/s10194-015-0576-7
        • Watson A
        • Ensor E
        • Symes A
        • Winter J
        • Kendall G
        • Latchman D
        A minimal CGRP gene promoter is inducible by nerve growth factor in adult rat dorsal root ganglion neurons but not in PC12 phaeochromocytoma cells.
        Eur J Neurosci. 1995; 7: 394-400https://doi.org/10.1111/j.1460-9568.1995.tb00335.x
        • Xu C
        • Wang X
        • Wang S
        Effect of soybean protein and high calcium intake on the concentration of serum lipids in hypercholesterolemic rats.
        Zhonghua Yu Fang Yi Xue Za Zhi. 2001; 35: 318-321https://doi.org/10.1111/bph.13783
        • Zhang Z
        • Winborn CS
        • De Prado BM
        • Russo AF
        Sensitization of calcitonin gene-related peptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion.
        J Neurosci. 2007; 27: 2693-2703https://doi.org/10.1523/JNEUROSCI.4542-06.2007