The chicken and egg problem: CGRP release due to trigeminal activation or vice versa?

Background NXN-188 is a combined neuronal nitric oxide synthase (nNOS) inhibitor and 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Using preclinical models, we evaluated whether these two unique therapeutic principles have a synergistic effect in attenuating stimulated calcitonin gene-related peptide (CGRP) release, a marker of trigeminal activation. Methods We examined the effect of NXN-188 on: (1) KCl-, capsaicin- and resiniferatoxin (RTX)-induced immunoreactive CGRP (iCGRP) release from isolated preparation of rat dura mater, trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC); and (2) capsaicin- and electrical stimulation (ES)-induced middle meningeal artery (MMA) dilation in a rat closed-cranial window. Results NXN-188 inhibited: (1) KCl-stimulated iCGRP release from dura mater (% decrease mean ± SEM, lowest effective concentration) (35 ± 6%, 30 µM), TG (24 ± 11 %, 10 µM) and TNC (40 ± 8%, 10 µM); (2) capsaicin- and RTX-induced iCGRP release from dura mater; and (3) capsaicin- and ES-induced increase in dural artery diameter (32 ± 5%, 3 mg kg−1 intravenous (i.v.) and 36 ± 1%, 10 mg kg−1 i.v.). Conclusions NXN-188 inhibits CGRP release from migraine-relevant cephalic tissues. Its effect is most likely mediated via a combination of nNOS-inhibition and 5-HT1B/1D receptor agonism in dura mater while the mechanisms of action for inhibition of CGRP release from TG and TNC have to be investigated further.

Download Full-text

Petasin and isopetasin reduce CGRP release from trigeminal afferents indicating an inhibitory effect on TRPA1 and TRPV1 receptor channels

The Journal of Headache and Pain ◽

10.1186/s10194-021-01235-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Johanna Kleeberg-Hartmann ◽

Birgit Vogler ◽

Karl Messlinger

Keyword(s):

Inhibitory Effect ◽

Transient Receptor Potential Channels ◽

Mustard Oil ◽

Root Extract ◽

Dependent Manner ◽

Trpv1 Receptor ◽

Cgrp Release ◽

Ganglion Neurons ◽

Sites Of Action ◽

The Impact

Abstract Background Butterbur root extract with its active ingredients petasin and isopetasin has been used in the prophylactic treatment of migraine for years, while its sites of action are not completely clear. Calcitonin gene-related peptide (CGRP) is known as a biomarker and promoting factor of migraine. We set out to investigate the impact of petasins on the CGRP release from trigeminal afferents induced by activation of the calcium conducting transient receptor potential channels (TRPs) of the subtypes TRPA1 and TRPV1. Methods We used well-established in vitro preparations, the hemisected rodent skull and dissected trigeminal ganglia, to examine the CGRP release from rat and mouse cranial dura mater and trigeminal ganglion neurons, respectively, after pre-incubation with petasin and isopetasin. Mustard oil and capsaicin were used to stimulate TRPA1 and TRPV1 receptor channels. CGRP concentrations were measured with a CGRP enzyme immunoassay. Results Pre-incubation with either petasin or isopetasin reduced mustard oil- and capsaicin-evoked CGRP release compared to vehicle in an approximately dose-dependent manner. These results were validated by additional experiments with mice expressing functionally deleted TRPA1 or TRPV1 receptor channels. Conclusions Earlier findings of TRPA1 receptor channels being involved in the site of action of petasin and isopetasin are confirmed. Furthermore, we suggest an important inhibitory effect on TRPV1 receptor channels and assume a cooperative action between the two TRP receptors. These mechanisms may contribute to the migraine prophylactic effect of petasins.

Download Full-text

Trigeminal satellite cells modulate neuronal responses to triptans: relevance for migraine therapy

Neuron Glia Biology ◽

10.1017/s1740925x11000172 ◽

2011 ◽

Vol 7 (2-4) ◽

pp. 109-116 ◽

Cited By ~ 4

Author(s):

Alice de Corato ◽

Alessandro Capuano ◽

Diego Currò ◽

Giuseppe Tringali ◽

Pierluigi Navarra ◽

...

Keyword(s):

Neuronal Excitability ◽

Primary Cultures ◽

Neuronal Cultures ◽

Neuronal Responses ◽

Satellite Glial Cells ◽

Cgrp Release ◽

Trigeminal Neurons ◽

Trigeminal Neuron ◽

Anti Migraine Drug

In the present paper, we have further developed an in vitro model to study neuronal–glial interaction at trigeminal level by characterizing the effects of conditioned medium (CM) collected from activated primary cultures of satellite glial cells (SGCs) on calcitonin gene-related peptide (CGRP) release from rat trigeminal neurons. Moreover, we investigated whether such release is inhibited by a clinically relevant anti-migraine drug, sumatriptan. CM effects were tested on trigeminal neuronal cultures in different conditions of activation and at different time points. Long-term exposures of trigeminal neurons to CM increased directly neuronal CGRP release, which was further enhanced by the exposure to capsaicin. In this framework, the anti-migraine drug sumatriptan was able to inhibit the evoked CGRP release from naïve trigeminal neuron cultures, as well as from trigeminal cultures pre-exposed for 30 min to CM. On the contrary, sumatriptan failed to inhibit evoked CGRP release from trigeminal neurons after prolonged (4 and 8 h) pre-exposures to CM. These findings were confirmed in co-culture experiments (neurons and SGCs), where activation of SGCs or a bradykinin priming were used. Our data demonstrate that SGCs activation could influence neuronal excitability, and that this event affects the neuronal responses to triptans.

Download Full-text

Comparative effects of traditional Chinese and Western migraine medicines in an animal model of nociceptive trigeminovascular activation

Cephalalgia ◽

10.1177/0333102417728245 ◽

2017 ◽

Vol 38 (7) ◽

pp. 1215-1224 ◽

Cited By ~ 7

Author(s):

Yonglie Zhao ◽

Margarida Martins-Oliveira ◽

Simon Akerman ◽

Peter J Goadsby

Keyword(s):

Clinical Trial Data ◽

Preventive Treatment ◽

Pharmacokinetic Profile ◽

Neuronal Firing ◽

Migraine Treatment ◽

Traditional Chinese Medicines ◽

Chinese Medicines ◽

Potential Efficacy ◽

Trigeminal Activation

Background Migraine is a highly prevalent and disabling disorder of the brain with limited therapeutic options, particularly for preventive treatment. There is a need to identify novel targets and test their potential efficacy in relevant preclinical migraine models. Traditional Chinese medicines have been used for millennia and may offer avenues for exploration. Methods We evaluated two traditional Chinese medicines, gastrodin and ligustrazine, and compared them to two Western approaches with propranolol and levetiracetam, one effective and one ineffective, in an established in vivo rodent model of nociceptive durovascular trigeminal activation. Results Intravenous gastrodin (30 and 100 mg/kg) significantly inhibited nociceptive dural-evoked neuronal firing in the trigeminocervical complex. Ligustrazine (10 mg/kg) and propranolol (3 mg/kg) also significantly inhibited dural-evoked trigeminocervical complex responses, although the timing of responses of ligustrazine does not match its pharmacokinetic profile. Levetiracetam had no effects on trigeminovascular responses. Conclusion Our data suggest gastrodin has potential as an anti-migraine treatment, whereas ligustrazine seems less promising. Interestingly, in line with clinical trial data, propranolol was effective and levetiracetam not. Exploration of the mechanisms and modelling effects of Chinese traditional therapies offers novel route for drug discovery in migraine.

Download Full-text

The role of transient receptor potential ankyrin 1 (TRPA1) receptors in the H2S-evoked calcitonin gene-related peptide (CGRP) release from isolated rat trachea

Frontiers in Neuroscience ◽

10.3389/conf.fnins.2011.84.00022 ◽

2011 ◽

Vol 5 ◽

Author(s):

Pintér E.

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Cgrp Release ◽

Calcitonin Gene ◽

Transient Receptor ◽

Rat Trachea ◽

Isolated Rat

Download Full-text

Noxious heat-induced CGRP release from rat sciatic nerve axonsin vitro

European Journal of Neuroscience ◽

10.1046/j.0953-816x.2001.01741.x ◽

2001 ◽

Vol 14 (8) ◽

pp. 1203-1208 ◽

Cited By ~ 37

Author(s):

S. K. Sauer ◽

P. W. Reeh ◽

G. M. Bove

Keyword(s):

Sciatic Nerve ◽

Noxious Heat ◽

Rat Sciatic Nerve ◽

Cgrp Release

Download Full-text

Triggers for Trigeminal Activation: Clinical Abstracts and Commentary

Headache Currents ◽

10.1111/j.1743-5013.2005.00018.x ◽

2005 ◽

Vol 2 (5) ◽

pp. 104-107

Author(s):

Manjit S. Matharu ◽

Peter J. Goadsby

Keyword(s):

Trigeminal Activation

Download Full-text

Clinical-Biochemical Correlates of Migraine Attacks in Rizatriptan Responders and Non-Responders

Cephalalgia ◽

10.1111/j.1468-2982.2005.01016.x ◽

2006 ◽

Vol 26 (3) ◽

pp. 257-265 ◽

Cited By ~ 38

Author(s):

P Sarchielli ◽

LA Pini ◽

G Zanchin ◽

A Alberti ◽

F Maggioni ◽

...

Keyword(s):

Venous Blood ◽

Poor Response ◽

Neurokinin A ◽

Parasympathetic System ◽

Number Of Patients ◽

Calcitonin Gene ◽

System Activation ◽

Radio Immunoassay ◽

Accompanying Symptoms ◽

Trigeminal Activation

The present study was aimed at verifying the clinical characteristics of a typical attack in 20 migraine patients, 10 responders and 10 non-responders to rizatriptan, and at investigating any differences in the levels of neuropeptides of the trigeminovascular or parasympathetic systems [calcitonin gene-related peptide (CGRP), neurokinin A (NKA) and vasoactive intestinal peptide (VIP) measured by radio-immunoassay methods in external jugular blood] between responders and nonresponders. In all responders to rizatriptan, pain was unilateral, severe, and pulsating, and in five of them at least one sign suggestive of parasympathetic system activation was recorded. Five patients who were non-responders to rizatriptan referred bilateral and non-pulsating pain, even though severe in most of them. CGRP and NKA levels measured before rizatriptan administration were significantly higher in responders than in non-responders ( P < 0.0001 and P < 0.002, respectively). In the five patients with autonomic signs among rizatriptan responders, detectable VIP levels were found at baseline. One hour after rizatriptan administration, a decrease in CGRP and NKA levels was evident in the external jugular venous blood of rizatriptan responders, and this corresponded to a significant pain relief and alleviation of accompanying symptoms. VIP levels were also significantly reduced at the same time in the five patients with autonomic signs. After rizatriptan administration, CGRP and NKA levels in non-responder patients showed less significant variations at all time points after rizatriptan administration compared with rizatriptan responders. The present study, although carried out on a limited number of patients, supports recent clinical evidence of increased trigeminal activation associated with a better triptan response in migraine patients accompanied by parasympathetic activation in a subgroup of patients with autonomic signs. In contrast, the poor response seems to be correlated with a lesser degree of trigeminal activation, lower variations of trigeminal neuropeptides after triptan administration, and no evidence of parasympathetic activation at baseline.

Download Full-text

Danaparoid sodium reduces ischemia/reperfusion-induced liver injury in rats by attenuating inflammatory responses

Thrombosis and Haemostasis ◽

10.1160/th06-04-0226 ◽

2007 ◽

Vol 97 (01) ◽

pp. 81-87 ◽

Cited By ~ 11

Author(s):

Naoaki Harada ◽

Hidefumi Kohmura ◽

Mitsuhiro Uchiba ◽

Tsutomu Tomita ◽

Kenji Okajima

Keyword(s):

Liver Injury ◽

Rat Model ◽

Inflammatory Responses ◽

Ischemia Reperfusion ◽

Hepatic Tissue ◽

Therapeutic Effects ◽

Danaparoid Sodium ◽

Cgrp Release ◽

Neuron Activation

SummaryThis study was undertaken to examine the mechanism by which danaparoid sodium (DS), a heparinoid that contains mainly heparan sulfate, prevents reperfusion-induced hepatic damage in a rat model of ischemia/reperfusion (I/R)-induced liver injury. Administration of DS significantly reduced liver injury and inhibited the decrease in hepatic tissue blood flow in rats. DS attenuated hepatic I/R-induced increases in hepatic tissue levels of tumor necrosis factor (TNF) and myeloperoxidase (MPO) in vivo. In contrast, neither monocytic TNF production nor neutrophil activation was inhibited by DS in vitro. DS enhanced I/R-induced increases in levels of calcitonin-gene related peptide (CGRP), a neuropeptide released from sensory neurons, and of 6-ketoprostaglandin (PG) F1α, a stable metabolite of PGI2, in liver tissues. The therapeutic effects of DS were not seen in animals pretreated with capsazepine, an inhibitor of sensory neuron activation. The distribution of heparan sulfate in the perivascular area was significantly increased by DS administration in this rat model. DS significantly increased CGRP release from isolated rat dorsal root ganglion neurons (DRG) in vitro, while DX-9065a, a selective inhibitor of activated factor X, did not. DS enhanced anandamide-induced CGRP release from DRG in vitro. These observations strongly suggested that DS might reduce I/R-induced liver injury in rats by attenuating inflammatory responses. These therapeutic effects of DS might be at least partly explained by its enhancement of sensory neuron activation, leading to the increase the endothelial production of PGI2.

Download Full-text