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CNS & Neurological Disorders - Drug Targets


ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Review Article

The locus of Action of CGRPergic Monoclonal Antibodies Against Migraine: Peripheral Over Central Mechanisms

Author(s): Abimael González-Hernández, Bruno A. Marichal-Cancino, Enrique García-Boll and Carlos M. Villalón*

Volume 19 , Issue 5 , 2020

Page: [344 - 359] Pages: 16

DOI: 10.2174/1871527319666200618144637

Price: $65


Migraine is a complex neurovascular disorder characterized by attacks of moderate to severe unilateral headache, accompanied by photophobia among other neurological signs. Although an arsenal of antimigraine agents is currently available in the market, not all patients respond to them. As Calcitonin Gene-Related Peptide (CGRP) plays a key role in the pathophysiology of migraine, CGRP receptor antagonists (gepants) have been developed. Unfortunately, further pharmaceutical development (for olcegepant and telcagepant) was interrupted due to pharmacokinetic issues observed during the Randomized Clinical Trials (RCT). On this basis, the use of monoclonal antibodies (mAbs; immunoglobulins) against CGRP or its receptor has recently emerged as a novel pharmacotherapy to treat migraines. RCT showed that these mAbs are effective against migraines producing fewer adverse events. Presently, the U.S. Food and Drug Administration approved four mAbs, namely: (i) erenumab; (ii) fremanezumab; (iii) galcanezumab; and (iv) eptinezumab. In general, specific antimigraine compounds exert their action in the trigeminovascular system, but the locus of action (peripheral vs. central) of the mAbs remains elusive. Since these mAbs have a molecular weight of ∼150 kDa, some studies rule out the relevance of their central actions as they seem unlikely to cross the Blood-Brain Barrier (BBB). Considering the therapeutic relevance of this new class of antimigraine compounds, the present review has attempted to summarize and discuss the current evidence on the probable sites of action of these mAbs.

Keywords: Antibody, antimigraine, CGRP, gepants, headache, pain.

Graphical Abstract
Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 2011; 12(10): 570-84.
[] [PMID: 21931334]
Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev 2017; 97(2): 553-622.
[] [PMID: 28179394]
Uddman R, Tajti J, Hou M, Sundler F, Edvinsson L. Neuropeptide expression in the human trigeminal nucleus caudalis and in the cervical spinal cord C1 and C2. Cephalalgia 2002; 22(2): 112-6.
[] [PMID: 11972578]
Charles A. Migraine: a brain state. Curr Opin Neurol 2013; 26(3): 235-9.
[] [PMID: 23493160]
de Tommaso M, Ambrosini A, Brighina F, et al. Altered processing of sensory stimuli in patients with migraine. Nat Rev Neurol 2014; 10(3): 144-55.
[] [PMID: 24535465]
GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18(5): 459-80.
[] [PMID: 30879893]
GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990-2016: a sys-tematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2018; 17(11): 954-76.
[] [PMID: 30353868]
Tfelt-Hansen P, Lindqvist JK, Do TP. Evaluating the reporting of adverse events in controlled clinical trials conducted in 2010-2015 on migraine drug treatments. Cephalalgia 2018; 38(12): 1885-95.
Villalón CM, Olesen J. The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute an-timigraine drugs. Pharmacol Ther 2009; 124(3): 309-23.
[] [PMID: 19796656]
Olesen J, Burstein R, Ashina M, Tfelt-Hansen P. Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol 2009; 8(7): 679-90.
[] [PMID: 19539239]
Goel D, Un Nisa K, Reza MI, Rahman Z, Aamer S. Aberrant DNA methylation pattern may enhance susceptibility to migraine: a novel perspective. CNS Neurol Disord Drug Targets 2019; 18(7): 504-15.
[] [PMID: 31400273]
Villalón CM, VanDenBrink AM. The role of 5-hydroxytryptamine in the pathophysiology of migraine and its relevance to the design of novel treatments. Mini Rev Med Chem 2017; 17(11): 928-38.
[] [PMID: 27465216]
Bernstein C, Burstein R. Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J Clin Neurol 2012; 8(2): 89-99.
[] [PMID: 22787491]
Goadsby PJ, Hoskin KL. The distribution of trigeminovascular afferents in the nonhuman primate brain Macaca nemestrina: a cfos immunocytochemical study. J Anat 1997; 190(Pt 3): 367-75.
[] [PMID: 9147223]
Bartsch T, Goadsby PJ. Stimulation of the greater occipital nerve induces increased central excitability of dural afferent input. Brain 2002; 125(Pt 7): 1496-509.
[] [PMID: 12077000]
Penfield W, McNaughton FL. Dural headache and the innervation of the dura mater. Arch Neurol Psychiatry 1940; 44: 43-75.
Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol 1988; 23(2): 193-6.
[] [PMID: 2454066.]
Ebersberger A, Averbeck B, Messlinger K, Reeh PW. Release of substance P, calcitonin gene-related peptide and prostaglandin E2 from rat dura mater encephali following electrical and chemical stimulation in vitro. Neuroscience 1999; 89(3): 901-7.
[] [PMID: 10199623]
Williamson DJ, Hargreaves RJ, Hill RG, Shepheard SL. Sumatriptan inhibits neurogenic vasodilation of dural blood vessels in the anaesthetized rat--intravital microscope studies. Cephalalgia 1997; 17(4): 525-31.
[] [PMID: 9209774]
Humphrey PP, Feniuk W, Perren MJ, Beresford IJ, Skingle M, Whalley ET. Serotonin and migraine. Ann N Y Acad Sci 1990; 600: 587-98.
[] [PMID: 2252337]
Goadsby PJ. The vascular theory of migraine--a great story wrecked by the facts. Brain 2009; 132(Pt 1): 6-7.
[] [PMID: 19098031]
Mason BN, Russo AF. Vascular contributions to migraine: time to revisit? Front Cell Neurosci 2018; 12: 233.
[] [PMID: 30127722]
Jacobs B, Dussor G. Neurovascular contributions to migraine: moving beyond vasodilation. Neuroscience 2016; 338: 130-44.
[] [PMID: 27312704]
Kayser V, Aubel B, Hamon M, Bourgoin S. The antimigraine 5-HT 1B/1D receptor agonists, sumatriptan, zolmitriptan and dihydroergotamine, attenuate pain-related behaviour in a rat model of trigeminal neuropathic pain. Br J Pharmacol 2002; 137(8): 1287-97.
[] [PMID: 12466238]
Wolff HG. Headache and other head pain. New York: Oxford Univ. Press 1963.
Feniuk W, Humphrey PPA, Perren MJ, Connor HE, Whalley ET. Rationale for the use of 5-HT1-like agonists in the treatment of migraine. J Neurol 1991; 238(Suppl. 1): S57-61.
[] [PMID: 1646289]
Kaube H, Hoskin KL, Goadsby PJ. Inhibition by sumatriptan of central trigeminal neurones only after blood-brain barrier disruption. Br J Pharmacol 1993; 109(3): 788-92.
[] [PMID: 8395298]
Humphrey PPA, Goadsby PJ. The mode of action of sumatriptan is vascular? A debate. Cephalalgia 1994; 14(6): 401-10.
[] [PMID: 7697699]
Shevel E. The extracranial vascular theory of migraine--a great story confirmed by the facts. Headache 2011; 51(3): 409-17.
[] [PMID: 21352215]
Shevel E. The extracranial vascular theory of migraine: an artificial controversy. J Neural Transm (Vienna) 2011; 118(4): 525-30.
[] [PMID: 21207080]
Messlinger K. MaassenVanDenBrink A. Cardio-and cerebrovascular safety of erenumab, a monoclonal antibody targeting CGRP re-ceptors–important studies on human isolated arteries. Cephalalgia 2019; 39: 1731-4.
[] [PMID: 31526030]
Goadsby PJ. Pathophysiology of migraine. Neurol Clin 2009; 27(2): 335-60.
[] [PMID: 19289219]
Schoonman GG, van der Grond J, Kortmann C, van der Geest RJ, Terwindt GM, Ferrari MD. Migraine headache is not associated with cerebral or meningeal vasodilatation--a 3 T magnetic resonance angiography study. Brain 2008; 131(Pt 8): 2192-200.
[] [PMID: 19407929]
Drummond PD, Lance JW. Extracranial vascular changes and the source of pain in migraine headache. Ann Neurol 1983; 13(1): 32-7.
[] [PMID: 6830162]
Hoffmann J, Baca SM, Akerman S. Neurovascular mechanisms of migraine and cluster headache. J Cereb Blood Flow Metab 2019; 39(4): 573-94.
[] [PMID: 28948863]
Dodick DW. Examining the essence of migraine--is it the blood vessel or the brain? A debate. Headache 2008; 48(4): 661-7.
[] [PMID: 18377395]
Frederiksen SD, Haanes KA, Warfvinge K, Edvinsson L. Perivascular neurotransmitters: regulation of cerebral blood flow and role in primary headaches. J Cereb Blood Flow Metab 2019; 39(4): 610-32.
[] [PMID: 29251523]
Strassman AM, Raymond SA, Burstein R. Sensitization of meningeal sensory neurons and the origin of headaches. Nature 1996; 384(6609): 560-4.
[] [PMID: 8955268]
Burstein R, Yamamura H, Malick A, Strassman AM. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J Neurophysiol 1998; 79(2): 964-82.
[] [PMID: 9463456]
Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain 2000; 123(Pt 8): 1703-9.
[] [PMID: 10908199]
Ashina M, Hansen JM, Do TP, Melo-Carrillo A, Burstein R, Moskowitz MA. Migraine and the trigeminovascular system-40 years and counting. Lancet Neurol 2019; 18(8): 795-804.
[] [PMID: 31160203]
Tfelt-Hansen P, De Vries P, Saxena PR. Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy. Drugs 2000; 60(6): 1259-87.
[] [PMID: 11152011]
González-Hernández A, Marichal-Cancino BA. MaassenVanDenBrink A, Villalón CM. Side effects associated with current and prospective antimigraine pharmacotherapies. Expert Opin Drug Metab Toxicol 2018; 14(1): 25-41.
[] [PMID: 29226741]
Rubio-Beltrán E, Labastida-Ramírez A, Villalón CM. MaassenVanDenBrink A. Is selective 5-HT1F receptor agonism an entity apart from that of the triptans in antimigraine therapy? Pharmacol Ther 2018; 186: 88-97.
[] [PMID: 29352859]
Goadsby PJ. The pharmacology of headache. Prog Neurobiol 2000; 62(5): 509-25.
[] [PMID: 10869781]
Bouchelet I, Case B, Olivier A, Hamel E. No contractile effect for 5-HT1D and 5-HT1F receptor agonists in human and bovine cerebral arteries: similarity with human coronary artery. Br J Pharmacol 2000; 129(3): 501-8.
[] [PMID: 10711348]
Färkkilä M, Diener HC, Géraud G, et al. COL MIG-202 study group Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol 2012; 11(5): 405-13.
[] [PMID: 22459549]
Johnson KW, Schaus JM, Durkin MM, et al. 5-HT1F receptor agonists inhibit neurogenic dural inflammation in guinea pigs. Neuroreport 1997; 8(9-10): 2237-40.
[] [PMID: 9243618]
Mitsikostas DD, Sanchez del Rio M, Waeber C. 5-Hydroxytryptamine(1B/1D) and 5-hydroxytryptamine1F receptors inhibit capsaicin-induced c-fos immunoreactivity within mouse trigeminal nucleus caudalis. Cephalalgia 2002; 22(5): 384-94.
[] [PMID: 12110114]
Nelson DL, Phebus LA, Johnson KW, et al. Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan. Cephalalgia 2010; 30(10): 1159-69.
[] [PMID: 20855361]
Phebus LA, Johnson KW, Zgombick JM, et al. Characterization of LY344864 as a pharmacological tool to study 5-HT1F receptors: binding affinities, brain penetration and activity in the neurogenic dural inflammation model of migraine. Life Sci 1997; 61(21): 2117-26.
[] [PMID: 9395253]
Moreno-Ajona D, Chan C, Villar-Martínez MD, Goadsby PJ. Targeting CGRP and 5-HT1F receptors for the acute therapy of migraine: a literature review. Headache 2019; 59(Suppl. 2): 3-19.
[] [PMID: 31291016]
MaassenVanDenBrink A. Meijer J Villalón CM, Ferrari MD. Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol Sci 2016; 37: 779-88.
González-Hernández A, Marichal-Cancino BA, Lozano-Cuenca J, et al. Heteroreceptors modulating CGRP release at neurovascular junction: potential therapeutic implications on some vascular-related diseases. BioMed Res Int 2016.20162056786
[] [PMID: 28116293]
Amrutkar DV, Ploug KB, Hay-Schmidt A, Porreca F, Olesen J, Jansen-Olesen I. mRNA expression of 5-hydroxytryptamine 1B, 1D, and 1F receptors and their role in controlling the release of calcitonin gene-related peptide in the rat trigeminovascular system. Pain 2012; 153(4): 830-8.
[] [PMID: 22305629]
Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993; 33(1): 48-56.
[] [PMID: 8388188]
Tso AR, Goadsby PJ. Anti-CGRP monoclonal antibodies: the next era of migraine prevention? Curr Treat Options Neurol 2017; 19(8): 27.
[] [PMID: 28653227]
Mitsikostas DD, Rapoport AM. New players in the preventive treatment of migraine. BMC Med 2015; 13: 279.
[] [PMID: 26555040]
Diener HC, Charles A, Goadsby PJ, Holle D. New therapeutic approaches for the prevention and treatment of migraine. Lancet Neurol 2015; 14(10): 1010-22.
[] [PMID: 26376968]
Charles A, Pozo-Rosich P. Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet 2019; 394(10210): 1765-74.
[] [PMID: 31668411]
Xu H, Han W, Wang J, Li M. Network meta-analysis of migraine disorder treatment by NSAIDs and triptans. J Headache Pain 2016; 17(1): 113.
[] [PMID: 27957624]
Ong JJY, De Felice M. Migraine treatment: current acute medications and their potential mechanisms of action. Neurotherapeutics 2018; 15(2): 274-90.
[] [PMID: 29235068]
Silberstein SD. The pharmacology of ergotamine and dihydroergotamine. Headache 1997; 37(Suppl. 1): S15-25.
[PMID: 9009470]
Rothlin E. The specific action of ergot alkaloids on the sympathetic nervous system. J Pharmacol Exp Ther 1929; 36: 657-83.
Garrett WJ. The effects of adrenaline noradrenaline and dihydroergotamine on excised human myometrium. Br J Pharmacol Chemother 1955; 10(1): 39-44.
[] [PMID: 14351684]
Lennox WG. The use of ergotamine tartrate in migraine. N Engl J Med 1934; 210: 1061-5.
Lennox WG, Von Storch TJC. Experience with ergotamine tartrate in 120 patients with migraine. JAMA 1935; 105: 169-71.
González-Hernández A, Marichal-Cancino BA, Lozano-Cuenca J. MaassenVanDenBrink A, Villalón CM. MaassenVanDenBrink A, Villalón CM. Functional characterization of the prejunctional receptors mediating the inhibition by ergotamine of the rat perivascular sensory peptidergic drive. ACS Chem Neurosci 2019; 10(7): 3173-82.
[] [PMID: 30695640]
Chan KY, Vermeersch S, de Hoon J, Villalón CM, Maassenvandenbrink A. Potential mechanisms of prospective antimigraine drugs: a focus on vascular (side) effects. Pharmacol Ther 2011; 129(3): 332-51.
[] [PMID: 21130807]
Soveyd N, Abdolahi M, Djalali M, et al. The combined effects of ω -3 fatty acids and nano-curcumin supplementation on intercellular adhesion molecule-1 (ICAM-1) gene expression and serum levels in migraine patients. CNS Neurol Disord Drug Targets 2018; 16(10): 1120-6.
[] [PMID: 29237386]
Abdolahi M, Sarraf P, Javanbakht MH, et al. A novel combination of ω-3 fatty acids and nano-curcumin modulates interleukin-6 gene expression and high sensitivity c-reactive protein serum levels in patients with migraine: a randomized clinical trial study. CNS Neurol Disord Drug Targets 2018; 17(6): 430-8.
[] [PMID: 29938621]
Abdolahi M, Tafakhori A, Togha M, et al. The synergistic effects of ω-3 fatty acids and nano-curcumin supplementation on Tumor Necrosis Factor (TNF)-α gene expression and serum level in migraine patients. Immunogenetics 2017; 69(6): 371-8.
[] [PMID: 28478481]
Villalón CM, Centurión D, Valdivia LF, De Vries P, Saxena PR. An introduction to migraine: from ancient treatment to functional pharmacology and antimigraine therapy. Proc West Pharmacol Soc 2002; 45: 199-210.
[PMID: 12434581]
Dodick DW, Martin VT, Smith T, Silberstein S. Cardiovascular tolerability and safety of triptans: a review of clinical data. Headache 2004; 44(S1)(Suppl. 1): S20-30.
[] [PMID: 15149490]
Doenicke A, Brand J, Perrin VL. Possible benefit of GR43175, a novel 5-HT1-like receptor agonist, for the acute treatment of severe migraine. Lancet 1988; 1(8598): 1309-11.
[] [PMID: 2897560]
Patten JP. Oral Sumatriptan Dose-defining Study Group Clinical experience with oral sumatriptan: a placebo-controlled, dose-ranging study. J Neurol 1991; 238(S1)(Suppl. 1): S62-5.
[] [PMID: 1646290]
Ferrari MD, Goadsby PJ, Roon KI, Lipton RB. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 2002; 22(8): 633-58.
[] [PMID: 12383060]
Pini LA, Brovia D. Different characteristics of triptans. J Headache Pain 2004; 5: S109-11.
Diener HC, Limmroth V. Advances in pharmacological treatment of migraine. Expert Opin Investig Drugs 2001; 10(10): 1831-45.
[] [PMID: 11772289]
Burger-Mulder I, Li M, Quin T, et al. Anti-migraine CGRP antagonists (gepants) worsen cerebral ischemia outcome in mice. Cephalalgia 2019; 39(1S): 398.
Do TP, Guo S, Ashina M. Therapeutic novelties in migraine: new drugs, new hope? J Headache Pain 2019; 20(1): 37.
[] [PMID: 30995909]
Olesen J, Diener HC, Husstedt IW, et al. BIBN 4096 BS Clinical Proof of Concept Study Group. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 2004; 350(11): 1104-10.
[] [PMID: 15014183]
Ho TW, Mannix LK, Fan X, et al. MK-0974 Protocol 004 study Group. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 2008; 70(16): 1304-12.
[] [PMID: 17914062]
Voss T, Lipton RB, Dodick DW, et al. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia 2016; 36(9): 887-98.
[] [PMID: 27269043]
Tepper SJ. Anti-calcitonin gene-related peptide (CGRP) therapies: Update on a previous review after the American Headache Society 60th Scientific Meeting, San Francisco, June 2018. Headache 2018; 58(Suppl. 3): 276-90.
[] [PMID: 30403405]
Negro A, Martelletti P. Gepants for the treatment of migraine. Expert Opin Investig Drugs 2019; 28(6): 555-67.
[] [PMID: 31081399]
Martelletti P, Giamberardino MA. Advances in orally administered pharmacotherapy for the treatment of migraine. Expert Opin Pharmacother 2019; 20(2): 209-18.
[] [PMID: 30475090]
Hostetler ED, Joshi AD, Sanabria-Bohórquez S, et al. In vivo quantification of calcitonin gene-related peptide receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography tracer [11C]MK-4232. J Pharmacol Exp Ther 2013; 347(2): 478-86.
[] [PMID: 23975906]
Dodick DW, Goadsby PJ, Silberstein SD, et al. ALD403 study investigators. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 2014; 13(11): 1100-7.
[] [PMID: 25297013]
Bigal ME, Edvinsson L, Rapoport AM, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 2015; 14(11): 1091-100.
[] [PMID: 26432181]
Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 2014; 13(9): 885-92.
[] [PMID: 25127173]
Detke HC, Goadsby PJ, Wang S, Friedman DI, Selzler KJ, Aurora SK. Galcanezumab in chronic migraine: the randomized, double-blind, placebo-controlled REGAIN study. Neurology 2018; 91(24): e2211-21.
[] [PMID: 30446596]
Skljarevski V, Oakes TM, Zhang Q, et al. Effect of different doses of galcanezumab vs placebo for episodic migraine prevention: a randomized clinical trial. JAMA Neurol 2018; 75(2): 187-93.
[] [PMID: 29255900]
Camporeale A, Kudrow D, Sides R, et al. A phase 3, long-term, open-label safety study of galcanezumab in patients with migraine. BMC Neurol 2018; 18(1): 188.
[] [PMID: 30413151]
Holzmann B. Modulation of immune responses by the neuropeptide CGRP. Amino Acids 2013; 45(1): 1-7.
[] [PMID: 22113645]
Holzmann B. Antiinflammatory activities of CGRP modulating innate immune responses in health and disease. Curr Protein Pept Sci 2013; 14(4): 268-74.
[] [PMID: 23745695]
Rochlitzer S, Veres TZ, Kühne K, et al. The neuropeptide calcitonin gene-related peptide affects allergic airway inflammation by modulating dendritic cell function. Clin Exp Allergy 2011; 41(11): 1609-21.
[] [PMID: 21752117]
Overeem LH, Neeb L, Reuter U. Erenumab for episodic migraine prophylaxis. Expert Rev Neurother 2019; 19(8): 751-7.
[] [PMID: 30614741]
Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 2017; 16(6): 425-34.
[] [PMID: 28460892]
Reuter U, Goadsby PJ, Lanteri-Minet M, et al. Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study. Lancet 2018; 392(10161): 2280-7.
[] [PMID: 30360965]
Sun H, Dodick DW, Silberstein S, et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 2016; 15(4): 382-90.
[] [PMID: 26879279]
Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med 2017; 377(22): 2123-32.
[] [PMID: 29171821]
Raffaelli B, Mussetto V, Israel H, Neeb L, Reuter U. Erenumab and galcanezumab in chronic migraine prevention: effects after treatment termination. J Headache Pain 2019; 20(1): 66.
[] [PMID: 31159727]
Mathew PG, Klein BC. Getting to the heart of the matter: migraine, triptans, DHE, ditans, CGRP antibodies, firs/second-generation gepants, and cardiovascular risk. Headache 2019; 59(8): 1421-6.
[] [PMID: 31318457]
Raffaelli B, Reuter U. The biology of monoclonal antibodies: focus on calcitonin gene-related peptide for prophylactic migraine therapy. Neurotherapeutics 2018; 15(2): 324-35.
[] [PMID: 29616494]
Dodick DW. CGRP ligand and receptor monoclonal antibodies for migraine prevention: evidence review and clinical implications. Cephalalgia 2019; 39(3): 445-58.
[] [PMID: 30661365]
Depre C, Antalik L, Starling A, et al. A randomized, double-blind, placebo-controlled study to evaluate the effect of erenumab on exercise time during a treadmill test in patients with stable angina. Headache 2018; 58(5): 715-23.
[] [PMID: 29878340]
Maassen van den Brink A, Rubio-Beltrán E, Duncker D, Villalón CM. Is CGRP receptor blockade cardiovascularly safe? Appropriate studies are needed. Headache 2018; 58(8): 1257-8.
[] [PMID: 30289181]
Denekas T, Tröltzsch M, Vater A, Klussmann S, Messlinger K. Inhibition of stimulated meningeal blood flow by a calcitonin gene-related peptide binding mirror-image RNA oligonucleotide. Br J Pharmacol 2006; 148(4): 536-43.
[] [PMID: 16633354]
Kumar A, Potts JD, DiPette DJ. Protective role of α-calcitonin gene-related peptide in cardiovascular diseases. Front Physiol 2019; 10: 821.
[] [PMID: 31312143]
Homma S, Kimura T, Sakai S, et al. Calcitonin gene-related peptide protects the myocardium from ischemia induced by endothelin-1: intravital microscopic observation and (31)P-MR spectroscopic studies. Life Sci 2014; 118(2): 248-54.
[] [PMID: 24607775]
Lozano-Cuenca J, González-Hernández A, Muñoz-Islas E, et al. Effect of some acute and prophylactic antimigraine drugs on the vasodepressor sensory CGRPergic outflow in pithed rats. Life Sci 2009; 84(5-6): 125-31.
[] [PMID: 19041880]
González-Hernández A, Manrique-Maldonado G, Lozano-Cuenca J, et al. The 5-HT(1) receptors inhibiting the rat vasodepressor sensory CGRPergic outflow: further involvement of 5-HT(1F), but not 5-HT(1A) or 5-HT(1D), subtypes. Eur J Pharmacol 2011; 659(2-3): 233-43.
[] [PMID: 21473863]
Prado MS, Bendtzen K, Andrade LEC. Biological anti-TNF drugs: immunogenicity underlying treatment failure and adverse events. Expert Opin Drug Metab Toxicol 2017; 13(9): 985-95.
[] [PMID: 28772079]
LiverTox Clinical and Research Information on Drug-Induced Liver Injury Bethesda. MD: National Institute of Diabetes and Digestive and Kidney Diseases 2012. Available from
Taylor FR. CGRP, amylin, immunology, and headache medicine. Headache 2019; 59(1): 131-50.
[] [PMID: 30390312]
Vu T, Ma P, Chen JS, et al. Pharmacokinetic pharmacodynamic relationship of erenumab (AMG 334) and capsaicin-induced dermal blood flow in healthy and migraine subjects. Pharm Res 2017; 34(9): 1784-95.
[] [PMID: 28593473]
Grell AS, Haanes KA, Johansson SE, Edvinsson L, Sams A. Fremanezumab inhibits vasodilatory effects of CGRP and capsaicin in rat cerebral artery - Potential role in conditions of severe vasoconstriction. Eur J Pharmacol 2019; 864172726
[] [PMID: 31589869]
Bullard DE, Bourdon M, Bigner DD. Comparison of various methods for delivering radiolabeled monoclonal antibody to normal rat brain. J Neurosurg 1984; 61(5): 901-11.
[] [PMID: 6436447]
Brightman MW. Morphology of blood-brain interfaces. Exp Eye Res 1977; 25(Suppl.): 1-25.
[] [PMID: 73470]
Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache 2017; 57(Suppl. 2): 47-55.
[] [PMID: 28485848]
Edvinsson L, Tfelt-Hansen P. The blood-brain barrier in migraine treatment. Cephalalgia 2008; 28(12): 1245-58.
[] [PMID: 18727638]
Eftekhari S, Salvatore CA, Johansson S, Chen T-B, Zeng Z, Edvinsson L. Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier. Brain Res 2015; 1600: 93-109.
[] [PMID: 25463029]
Hoskin KL, Goadsby PJ. Comparison of more and less lipophilic serotonin (5HT1B/1D) agonists in a model of trigeminovascular nociception in cat. Exp Neurol 1998; 150(1): 45-51.
[] [PMID: 9514827]
Muñoz-Islas E, Gupta S, Jiménez-Mena LR, et al. Donitriptan, but not sumatriptan, inhibits capsaicin-induced canine external carotid vasodilatation via 5-HT1B rather than 5-HT1D receptors. Br J Pharmacol 2006; 149(1): 82-91.
[] [PMID: 16880765]
Muñoz-Islas E, Lozano-Cuenca J, González-Hernández A, et al. Spinal sumatriptan inhibits capsaicin-induced canine external carotid vasodilatation via 5-HT1B rather than 5-HT1D receptors. Eur J Pharmacol 2009; 615(1-3): 133-8.
[] [PMID: 19460365]
Hougaard A, Amin FM, Christensen CE, et al. Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks of migraine with aura. Brain 2017; 140(6): 1633-42.
[] [PMID: 28430860]
Amin FM, Hougaard A, Cramer SP, et al. Intact blood-brain barrier during spontaneous attacks of migraine without aura: a 3T DCE-MRI study. Eur J Neurol 2017; 24(9): 1116-24.
[] [PMID: 28727225]
Schankin CJ, Maniyar FH, Seo Y, et al. Ictal lack of binding to brain parenchyma suggests integrity of the blood-brain barrier for 11C-dihydroergotamine during glyceryl trinitrate-induced migraine. Brain 2016; 139(Pt 7): 1994-2001.
[] [PMID: 27234268]
McCulloch J, Uddman R, Kingman TA, Edvinsson L. Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci USA 1986; 83(15): 5731-5.
[] [PMID: 3488550]
Noseda R, Schain AJ, Melo-Carrillo A, et al. Fluorescently-labeled fremanezumab is distributed to sensory and autonomic ganglia and the dura but not to the brain of rats with uncompromised blood brain barrier. Cephalalgia 2020; 40(3): 229-40.
[] [PMID: 31856583]
Johnson KW, Morin SM, Wroblewski VJ, Johnson MP. Peripheral and central nervous system distribution of the CGRP neutralizing antibody [125I] galcanezumab in male rats. Cephalalgia 2019; 39(10): 1241-8.
[] [PMID: 31003588]
Edvinsson JCA, Warfvinge K, Krause DN, et al. C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system. J Headache Pain 2019; 20(1): 105.
[] [PMID: 31718551]
Melo-Carrillo A, Strassman AM, Nir RR, et al. Fremanezumab-A humanized monoclonal anti-CGRP antibody-inhibits thinly myelinated (Aδ) but not unmyelinated (C) meningeal nociceptors. J Neurosci 2017; 37(44): 10587-96.
[] [PMID: 28972120]
Melo-Carrillo A, Schain AJ, Stratton J, Strassman AM, Burstein R. Fremanezumab and its isotype slow propagation rate and shorten cortical recovery period but do not prevent occurrence of cortical spreading depression in rats with compromised blood-brain barrier. Pain 2020; 161(5): 1037-43.
[] [PMID: 31895266]
Pascual J. CGRP antibodies: the Holy Grail for migraine prevention? Lancet Neurol 2015; 14(11): 1066-7.
[] [PMID: 26432183]
Girotra P, Singh SK. Multivariate optimization of rizatriptan benzoate-loaded solid lipid nanoparticles for brain targeting and migraine management. AAPS PharmSciTech 2017; 18(2): 517-28.
[] [PMID: 27126007]
Hansraj GP, Singh SK, Kumar P. Sumatriptan succinate loaded chitosan solid lipid nanoparticles for enhanced anti-migraine potential. Int J Biol Macromol 2015; 81: 467-76.
[] [PMID: 26299709]
Girotra P, Singh SK. A comparative study of orally delivered PBCA and ApoE coupled BSA nanoparticles for brain targeting of sumatriptan succinate in therapeutic management of migraine. Pharm Res 2016; 33(7): 1682-95.
[] [PMID: 27003706]
Girotra P, Singh SK, Kumar G. Development of zolmitriptan loaded PLGA/poloxamer nanoparticles for migraine using quality by design approach. Int J Biol Macromol 2016; 85: 92-101.
[] [PMID: 26724690]
Girotra P, Thakur A, Kumar A, Singh SK. Identification of multi-targeted anti-migraine potential of nystatin and development of its brain targeted chitosan nanoformulation. Int J Biol Macromol 2017; 96: 687-96.
[] [PMID: 28041915]
Kassem AA. Formulation approaches of triptans for management of migraine. Curr Drug Deliv 2016; 13(6): 882-98.
[] [PMID: 27109335]
Warfvinge K, Edvinsson L. Distribution of CGRP and CGRP receptor components in the rat brain. Cephalalgia 2019; 39(3): 342-53.
[] [PMID: 28856910]
Rubio-Beltrán E, Correnti E, Deen M, et al. PACAP38 and PAC1 receptor blockade: a new target for headache? J Head Pain 2018; 19: 64.
Karatas H, Yemisci M, Eren-Kocak E, Dalkara T. Brain peptides for the treatment of neuropsychiatric disorders. Curr Pharm Des 2018; 24(33): 3905-17.
[] [PMID: 30417776]
Alder BioPharmaceuticals® Announces first-in-human dosing in phase 1 ald1910 study for preventive treatment of migraine available from
Reglodi D, Vaczy A, Rubio-Beltran E. MaassenVanDenBrink A. Protective effects of PACAP in ischemia. J Head Pain 2018; 19: 19.
Tzabazis A, Kori S, Mechanic J, et al. Oxytocin and migraine headache. Headache 2017; 57(Suppl. 2): 64-75.
[] [PMID: 28485846]
García-Boll E, Martínez-Lorenzana G, Condés-Lara M, González-Hernández A. Inhibition of nociceptive dural input to the trigemi-nocervical complex through oxytocinergic transmission. Exp Neurol 2020; •••323113079
[] [PMID: 31678349]
Strother LC, Srikiatkhachorn A, Supronsinchai W. Targeted orexin and hypothalamic neuropeptides for migraine. Neurotherapeutics 2018; 15(2): 377-90.
[] [PMID: 29442286]
González-Hernández A, Condés-Lara M. The multitarget drug approach in migraine treatment: the new challenge to conquer. Headache 2014; 54(1): 197-9.
[] [PMID: 24400769]
Goadsby PJ. Primary headache disorders: five new things. Neurol Clin Pract 2019; 9(3): 233-40.
[] [PMID: 31341711]
Edvinsson L. The CGRP pathway in migraine as a viable target for therapies. Headache 2018; 58(Suppl. 1): 33-47.
[] [PMID: 29697153]
Shi L, Lehto SG, Zhu DX, et al. Pharmacologic characterization of AMG 334, a potent and selective human monoclonal antibody against the calcitonin gene-related peptide receptor. J Pharmacol Exp Ther 2016; 356(1): 223-31.
[] [PMID: 26559125]
Benschop RJ, Gehlert DR, Merchant KM, Shanafelt AB. Treatment of migraine with anti-CGRP antibodies Patent number: WO2007076336 A1, 2007.
Zeller J, Poulsen KT, Abdiche YN, Pons J, Collier SJ, Rosenthal A. Antagonist antibodies directed against calcitonin gene-related peptide and methods using same Patent number: WO2007054809, 2007.

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