Parthenolide inhibits nociception and neurogenic vasodilatation in the trigeminovascular system by targeting the TRPA1 channel.
Although feverfew has been used for centuries to treat pain and headaches and is recommended for migraine treatment, the mechanism for its protective action remains unknown. Migraine is triggered by calcitonin gene-related peptide (CGRP) release from trigeminal neurons. Peptidergic sensory neurons express a series of transient receptor potential (TRP) channels, including the ankyrin 1 (TRPA1) channel. Recent findings have identified agents either inhaled from the environment or produced endogenously that are known to trigger migraine or cluster headache attacks, such as TRPA1 simulants. A major constituent of feverfew, parthenolide, may interact with TRPA1 nucleophilic sites, suggesting that feverfew's antimigraine effect derives from its ability to target TRPA1. We found that parthenolide stimulates recombinant (transfected cells) or natively expressed (rat/mouse trigeminal neurons) TRPA1, where it, however, behaves as a partial agonist. Furthermore, in rodents, after initial stimulation, parthenolide desensitizes the TRPA1 channel and renders peptidergic TRPA1-expressing nerve terminals unresponsive to any stimulus. This effect of parthenolide abrogates nociceptive responses evoked by stimulation of peripheral trigeminal endings. TRPA1 targeting and neuronal desensitization by parthenolide inhibits CGRP release from trigeminal neurons and CGRP-mediated meningeal vasodilatation, evoked by either TRPA1 agonists or other unspecific stimuli. TRPA1 partial agonism, together with desensitization and nociceptor defunctionalization, ultimately resulting in inhibition of CGRP release within the trigeminovascular system, may contribute to the antimigraine effect of parthenolide.
Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy Headache Center, Florence University Hospital, Florence, Italy Department of Chemistry "U. Schiff", University of Florence, Florence, Italy King's College, London, UK Department of Pharmacology, University of Arizona, Tucson, AZ, USA Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy Pharmacology Department, Chiesi Farmaceutici SpA, Parma, Italy.
Serena
S
Materazzi
Silvia
S
Benemei
Camilla
C
Fusi
Roberta
R
Gualdani
Gaetano
G
De Siena
Nisha
N
Vastani
David A
DA
Andersson
Gabriela
G
Trevisan
Maria Rosa
MR
Moncelli
Xiaomei
X
Wei
Gregory
G
Dussor
Federica
F
Pollastro
Riccardo
R
Patacchini
Giovanni
G
Appendino
Pierangelo
P
Geppetti
Romina
R
Nassini
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016503:Drug Delivery Systems / Q000379:methods*; D035264:Flowers; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059225:Nociception / Q000187:drug effects* / Q000502:physiology; D010936:Plant Extracts / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000008:administration & dosage*; D000074025:TRPA1 Cation Channel; D020903:Tanacetum parthenium; D050051:Transient Receptor Potential Channels / Q000819:agonists* / Q000096:biosynthesis; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000378:metabolism; D014276:Trigeminal Nerve / Q000187:drug effects* / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010936:Plant Extracts; D012717:Sesquiterpenes; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C002669:parthenolide
CGRP; Migraine; Parthenolide; TRPA1