Parthenolide inhibits nociception and neurogenic vasodilatation in the trigeminovascular system by targeting the TRPA1 channel

Abstract

While 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, which are known to trigger migraine or cluster headache attacks, as TRPA1 simulants. A major constituent of feverfew, parthenolide, may interact with TRPA1 nucleophilic sites, suggesting that feverfew 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.

A Combination of Tanacetum parthenium, Griffonia simplicifolia and Magnesium (Aurastop) as Symptomatic Acute Treatment for Migraine Aura: A Retrospective Cohort Study

“…For Tanacetum parthenium (and its derivate Parthenolide) the inhibition of nitric oxide synthesis, NF-kB activation and proinflammatory cytokines synthesis represented key mechanisms [26]. Moreover, Tanacetum parthenium seems to act as partial agonist of transient receptor potential ankyrin 1 channel (TRPA1), causing its desensitization and defunctionalization, with a consequent inhibition of calcitonin gene-related peptide (CGRP) release in trigeminovascular system actually considered as a key mechanism in the genesis of migraine [27] [28]. From this point of view, Pathenolide could exert its antimigraine effect toward a TPRA1-mediated reduction of neurogenic vasodilatation in the trigeminovascular system.…”

Diet and nutraceutical interventions for headache management: A review of the evidence

“…Parthenolide, a sesquiterpene lactone, appears to be feverfew's active ingredient and has multiple actions in the central nervous system. Several of its properties suggest a potential mechanism of action in migraine prevention, including evidence to suggest that parthenolide inhibits Fos-induced 8 Cephalalgia 0(0) activation of the nucleus trigeminalis caudalis (57), a nucleus central to migraine pathogenesis, and evidence for partial agonist activity of parthenolide at TRPA1 channels (58), which have been implicated in migraine pathogenesis (59). Feverfew is one of the best-studied nutraceutical agents for migraine prophylaxis in adults.…”

Migraine in the era of precision medicine

“…Parthenolide, a bioactive compound contained in the antimigraine preparations from Tanacetum parthenium (also known as feverfew), has been very recently shown to act as a partialagonist at TRPA1 channels (101). Although TRP channels appear a promising target for migraine treatment, there are no other products of this class in current development in clinical trials.…”