LOS FENOMENOS INFLAMATORIOS NEUROGENICOS SON UN NUEVO BLANCO TERAPEUTICO EN LA MIGRAÑA





LOS FENOMENOS INFLAMATORIOS NEUROGENICOS SON UN NUEVO BLANCO TERAPEUTICO EN LA MIGRAÑA

(especial para SIIC © Derechos reservados)
Uno de los principales mecanismos patogénicos de las crisis migrañosas es la activación de las vías trigeminovasculares, que constituyen el blanco terapéutico de diversos fármacos efectivos para tratar la migraña. Algunos datos recientes sustentan la presencia de eventos inflamatorios transitorios, autolimitados, de origen neurogénico, subsiguientes a la activación trigeminovascular, los que pueden ser antagonizados mediante opciones terapéuticas establecidas o experimentales para la migraña aguda.
sarchielli9.jpg Autor:
Paola Sarchielli
Columnista Experto de SIIC
Artículos publicados por Paola Sarchielli
Coautores
Francesca Coppola* Cristiana Rossi* Antonio Baldi* Ilenia Corbelli* Katiuscia Nardi* Monica Acciarresi* 
Doctor of Medicine, Perugia, Italia*
Recepción del artículo
26 de Septiembre, 2006
Aprobación
13 de Diciembre, 2006
Primera edición
27 de Abril, 2007
Segunda edición, ampliada y corregida
7 de Junio, 2021

Resumen
Se considera que la activación de las vías trigeminovasculares desempeña un papel crucial en la inducción y el mantenimiento de la crisis migrañosa y se ha propuesto que la inflamación neurogénica, consecutiva a dicha activación, es uno de los mecanismos patogénicos principales de la cefalea. La liberación del péptido relacionado con el gen de calcitonina (CGRP) y la producción de óxido nítrico (NO) son los eventos más importantes del proceso inflamatorio neurogénico subyacente a la fase de dolor de la migraña. Los hallazgos firmes provenientes de modelos animales y de la investigación clínica se centran en los agentes antimigrañosos que limitan los eventos inducidos por la activación de las neuronas trigeminales, en particular, la liberación de CGRP y la vasodilatación a nivel meníngeo. Tales compuestos incluyen fármacos efectivos para el tratamiento agudo de la migraña, como los triptanos, los derivados del cornezuelo de centeno, los agentes antiinflamatorios no esteroides o los inhibidores de la ciclooxigenasa 2 (COX-2), y también los medicamentos preventivos antimigrañosos, como el valproato, el topiramato y la toxina botulínica tipo A. Además, algunos compuestos que eliminan la crisis migrañosa al actuar específicamente sobre el CGRP mostraron resultados promisorios en ensayos clínicos recientes. Existen datos crecientes sobre la presencia de fenómenos inflamatorios transitorios, secundarios a la activación trigeminovascular, que comprenden el aumento temporal de algunas citoquinas proinflamatorias, moléculas de adhesión e interleuquina 8 (IL-8), el incremento del factor nuclear kappa B (NFκB) y el aumento de la sintasa de óxido nítrico inducible (iNOS). De acuerdo con estos hallazgos, los fármacos con efecto sobre la respuesta inflamatoria, que inhiban selectivamente la transcripción mediada por el NFκB o la expresión de genes proinflamatorios, representan estrategias promisorias para el tratamiento de la migraña.

Palabras clave
activación trigeminovascular, inflamación neurogénica, péptido relacionado genéticamente con la calcitonina, eventos inflamatorios mediados por el factor nuclear kB


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Abstract
Activation of the trigeminovascular system is thought to play a pivotal role in the induction and maintenance of migraine attack. Neurogenic inflammation consequent to its activation has been proposed as a central pathogenic mechanism for migraine. Calcitonin gene-related peptide (CGRP) release and nitric oxide (NO) production are the most relevant events in neurogenic inflammation underlying the headache phase of migraine. Strong evidence in animal models and clinical investigation have focused on anti-migraine compounds that limit events induced by activation of trigeminal neurons, in particular, CGRP release and meningeal vasodilation. They include effective drugs for acute migraine treatment, such as triptans, ergot derivatives, non-steroidal anti-inflammatory drugs, cyclooxygenase (COX)-2 inhibitors, and also anti-migraine preventive drugs, such as valproate, topiramate and botulinum toxin type A. Moreover, compounds that abort migraine attack by precisely targeting CGRP have recently shown promising results in clinical trials. Accumulating data support the occurrence of transitory inflammatory events consequent to trigeminovascular activation involving a transient increase of some proinflammatory cytokines, adhesion molecules and interleukin (IL)-8, the enhancement of nuclear factor kappa B (NFκB) activity and up-regulation of inducible NO synthase (iNOS). Based on these findings, drugs targeting the inflammatory response by selective inhibition of NFκB-driven transcription or downstream proinflammatory gene expression offer promising approaches to the treatment of migraine.

Key words
trigeminovascular activation, neurogenic inflammation, calcitonin gene-related peptide, nuclear factor kB mediated inflammatory events


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Clasificación en siicsalud
Artículos originales > Expertos del Mundo >
página   www.siicsalud.com/des/expertocompleto.php/

Especialidades
Principal: Neurología
Relacionadas: Bioquímica, Diagnóstico por Laboratorio, Medicina Interna



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Enviar correspondencia a:
Paola Sarchielli, Neurologic Clinic, Department of Medical and Surgical Specialties and Public Health, University of Perugia, Ospedale S. Maria della Misericordia, 06156, Sant'Andrea delle Fratte, Perugia, Italia
Patrocinio y reconocimiento:
A John A. Toomey, por la edición de la versión en inglés, y a Marisa M. Morson por su ayuda técnica.
Bibliografía del artículo
1. Silberstein SD. Migraine pathophysiology and its clinical implications. Cephalalgia 24(Suppl 2):2-7, 2004.
2. Buzzi MG, Moskowitz MA.The trigemino-vascular system and migraine. Pathol Biol (Paris) 40(4):313-7, 1992.
3. May A, Goadsby PJ. The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 19(2):115-27, 1999.
4. Williamson DJ, Hargreaves RJ. Neurogenic inflammation in the context of migraine. Microsc Res Tech 53(3):167-78, 2001.
5. Geppetti P, Capone JG, Trevisani M, Nicoletti P, Zagli G, Tola MR. CGRP and migraine: neurogenic inflammation revisited. J Headache Pain 6(2):61-70, 2005.
6. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28(2):183-7, 1990.
7. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 33(1):48-56, 1193.
8. Goadsby P. Neuropeptides and migraine: a useful biological marker? Cephalalgia 15(5):333-4, 1995.
9. Gallai V, Sarchielli P, Floridi A, et al. Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia 15(5):384-90, 1995.
10. Sarchielli P, Alberti A, Codini M, Floridi A, Gallai V. Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. Cephalalgia 20(10):907-18, 2000.
11. Ashina M, Bendtsen L, Jensen R, Schifter S, Olesen J. Evidence for increased plasma levels of calcitonin gene-related peptide in migraine outside of attacks. Pain 86(1-2):133-8, 2000.
12. Tvedskov JF, Lipka K, Ashina M, Iversen HK, Schifter S, Olesen J. No increase of calcitonin gene-related peptide in jugular blood during migraine. Ann Neurol 58(4):561-8, 2005.
13. Edvinsson L. New therapeutic target in primary headaches - blocking the CGRP receptor. Expert Opin Ther Targets 7(3):377-83, 2003.
14. Edvinsson L. Clinical data on the CGRP antagonist BIBN4096BS for treatment of migraine attacks. CNS Drug Rev 11(1):69-76, 2005.
15. Sarchielli P, Pini LA, Zanchin G, et al. Clinical-biochemical correlates of migraine attacks in rizatriptan responders and non-responders. Cephalalgia 26(3):257-65, 2006.
16. Barbanti P, Fabbrini G, Pesare M, Vanacore N, Cerbo R. Unilateral cranial autonomic symptoms in migraine. Cephalalgia 22(4):256-9, 2002.
17 Barbanti P, Fabbrini G, Vanacore N, Pesare M, Buzzi MG. Sumatriptan in migraine with unilateral cranial autonomic symptoms: an open study. Headache 43(4):400-3, 2003.
18. Thomsen LL, Olesen J. Nitric oxide in primary headaches. Curr Opin Neurol 14(3):315-21, 2001.
19. Akerman S, Williamson DJ, Kaube H, Goadsby PJ. Nitric oxide synthase inhibitors can antagonize neurogenic and calcitonin gene-related peptide induced dilation of dural meningeal vessels. Br J Pharmacol 137(1):62-8, 2002.
20. Bellamy J, Bowen EJ, Russo AF, Durham PL. Nitric oxide regulation of calcitonin gene-related peptide gene expression in rat trigeminal ganglia neurons. Eur J Neurosci 23(8):2057-66, 2006.
21. Iversen HK. Experimental headache in humans. Cephalalgia 15(4):281-7, 1995.
22. Thomsen LL. Investigations into the role of nitric oxide and the large intracranial arteries in migraine headache. Cephalalgia 17(8):873-95, 1997.
23. Juhasz G, Zsombok T, Modos EA, et al. NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain 106(3):461-70, 2003.
24. D'Amico D, Ferraris A, Leone M, et al. Increased plasma nitrites in migraine and cluster headache patients in interictal period: basal hyperactivity of L-arginine-NO pathway? Cephalalgia 22(1):33-6, 2002.
25. Shukla R, Barthwal MK, Srivastava N, et al. Blood nitrite levels in patients with migraine during headache-free period. Headache 41(5):475-81, 2001.
26. Lassen LH, Ashina M, Christiansen I, Ulrich V, Olesen J. Nitric oxide synthase inhibition in migraine. Lancet 349(9049):401-2, 1997.
27. Krymchantowski AV, Barbosa JS. Rizatriptan combined with rofecoxib vs. rizatriptan for the acute treatment of migraine: an open label pilot study: Cephalalgia 22(4):309-12, 2002.
28. Krymchantowski AV, Bigal ME. Rizatriptan versus rizatriptan plus rofecoxib versus rizatriptan plus tolfenamic acid in the acute treatment of migraine. BMC Neurol 4:10, 2004.
29. Saper J, Dahlof C, So Y, et al; Rofecoxib Protocol 162 Study Group. Rofecoxib in the acute treatment of migraine: a randomized controlled clinical trial. Headache 46(2):264-75, 2006.
30. Krymchantowski AV, Bigal ME. Rofecoxib in migraine. Expert Rev Neurother 5(1):55-61, 2005.
31. Schuh-Hofer S, Tayefeh M, Reuter U, Dirnagl U, Arnold G. Effects of parecoxib on plasma protein extravasation and c-fos expression in the rat. Headache 46(2):276-85, 2006.
32. Durham PL, Russo AF. Stimulation of the calcitonin gene-related peptide enhancer by mitogen-activated protein kinases and repression by an antimigraine drug in trigeminal ganglia neurons. J Neurosci 23(3):807-15, 2003.
33. Edvinsson L, Uddman R. Neurobiology in primary headaches. Brain Res Brain Res Rev 48(3):438-56, 2005.
34. Reuter U, Bolay H, Jansen-Olesen I, et al. Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 124(Pt 12):2490-2502, 2001.
35. Reuter U, Chiarugi A, Bolay H, Moskowitz MA. Nuclear factor-kappaB as a molecular target for migraine therapy. Ann Neurol 51(4):507-16, 2002.
36. Sarchielli P, Floridi A, Mancini M, et al. NF-kappaB activity and iNOS expression in monocytes from internal jugular blood of migraine without aura patients during attacks. Cephalalgia 26(9):1071-79, 2006.
37. Chen F, Demers LM, Shi X. Upstream signal transduction of NF-kappaB activation. Curr Drug Targets Inflamm Allergy 1(2):137-49, 2002.
38. Tian B, Brasier AR. Identification of a nuclear factor kappa B-dependent gene network. Recent Prog Horm Res 58:95-130, 2003.
39. Connelly L, Palacios-Callender M, Ameixa C, Moncada S, Hobbs AJ. Biphasic regulation of NF-kappa B activity underlies the pro- and anti-inflammatory actions of nitric oxide. J Immunol 166(6):3873-81, 2001.
40. Sarchielli P, Alberti A, Baldi A, et al. Proinflammatory cytokines, adhesion molecules, and lymphocyte integrin expression in the internal jugular blood of migraine patients without aura assessed ictally. Headache 46(2):200-7, 2006.
41. Sarchielli P, Alberti A, Vaianella L, et al. Chemokine levels in the jugular venous blood of migraine without aura patients during attacks. Headache 44(10):961-8, 2004.
42. Tran MT, Ritchie MH, Lausch RN, Oakes JE. Calcitonin gene-related peptide induces IL-8 synthesis in human corneal epithelial cells. J Immunol 164(8):4307-12, 2000.
43. Amann R, Peskar BA. Anti-inflammatory effects of aspirin and sodium salicylate. Eur J Pharmacol 447(1):1-9, 2002.
44. Vogler BK, Pittler MH, Ernst E. Feverfew as a preventive treatment for migraine: a systematic review. Cephalalgia 18:704-8, 1998.
45. Pfaffenrath V, Diener HC, Fischer M, Friede M, Henneicke-von Zepelin HH; Investigators. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis--a double-blind, multicentre, randomized placebo-controlled dose-response study. Cephalalgia 22(7):523-32, 2002.
46. Diener HC, Pfaffenrath V, Schnitker J, Friede M, Henneicke-von Zepelin HH. Efficacy and safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in migraine prevention--a randomized, double-blind, multicentre, placebo-controlled study. Cephalalgia 25(11):1031-41, 2005.
47. Bremner P, Heinrich M. Natural products as targeted modulators of the nuclear factor-kappaB pathway. J Pharm Pharmacol 54(4):453-72, 2002.
48. Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 8(2):136-42, 2002.
49. Dalkara T, Zervas NT, Moskowitz MA. From spreading depression to the trigeminovascular system. Neurol Sci 27 Suppl 2:S86-90, 2006.
50. Arulmani U, Maassenvandenbrink A, Villalon CM, Saxena PR. Calcitonin gene-related peptide and its role in migraine pathophysiology. Eur J Pharmacol 500(1-3):315-30, 2004.
51. Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache 46 Suppl 1:S3-8, 2006.
52. Durham P, Russo A. New insights into the molecular actions of serotonergic antimigraine drugs. Pharmacol Ther 94(1-2):77-92, 2002.
53. Peroutka SJ. Neurogenic inflammation and migraine: implications for the therapeutics. Mol Interv 5(5):304-11, 2005.
54. Cutrer FM, Moskowitz MA. Wolff Award 1996. The actions of valproate and neurosteroids in a model of trigeminal pain. Headache 36(10):579-85, 1996.
55. Akerman S, Goadsby PJ. Topiramate inhibits trigeminovascular activation: an intravital microscopy study. Br J Pharmacol 146(1):7-14, 2005.
56. Akerman S, Williamson DJ, Kaube H, Goadsby PJ. The effect of anti-migraine compounds on nitric oxide-induced dilation of dural meningeal vessels. Eur J Pharmacol 452(2):223-8, 2002.
57. Goldstein DJ, Offen WW, Klein EG, et al. Lanepitant, an NK-1 antagonist, in migraine prevention. Cephalalgia 21(2):102-6, 2001.
58. Diener HC; RPR100893 Study Group. RPR100893, a substance-P antagonist, is not effective in the treatment of migraine attacks. Cephalalgia 23(3):183-5, 2003.
59. May A, Gijsman HJ, Wallnofer A, Jones R, Diener HC, Ferrari MD. Endothelin antagonist bosentan blocks neurogenic inflammation, but is not effective in aborting migraine attacks. Pain 67(2-3):375-8, 1996.
60. Durham PL, Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache 44(1):35-42, 2004.
61. Edvinsson L. Calcitonin gene-related peptide (CGRP) and the pathophysiology of headache: therapeutic implications. CNS Drugs 15(10):745-53, 2001.
62. Taylor CK, Smith DD, Hulce M, Abel PW. Pharmacological characterization of novel CGRP receptor peptide antagonists that are selective for human CGRP receptors. J Pharmacol Exp Ther 2006 Jul 27 [Epub ahead of print]. DOI: 10.1124/jpet.106.108316.
63. Doods H, Hallermayer G, Wu D, et al. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br J Pharmacol 129(3):420-3, 2000.
64. Hay DL, Poyner D. The preclinical pharmacology of BIBN4096BS, a CGRP antagonist. Cardiovasc Drug Rev 23(1):31-42, 2005.
65. Brain SD. Calcitonin gene-related peptide (CGRP) antagonists: blockers of neuronal transmission in migraine. Br J Pharmacol 142(7):1053-4, 2004.
66. 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 350(11):1104-10, 2004.
67. Goadsby PJ. Calcitonin gene-related peptide antagonists as treatments of migraine and other primary headaches. Drugs 65(18):2557-67, 2005.
68. Levy D, Burstein R, Strassman AM. Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann Neurol 58(5):698-705, 2005.

 
 
 
 
 
 
 
 
 
 
 
 
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