NXN-188, a selective nNOS inhibitor and a 5-HT1B/1D receptor agonist, inhibits CGRP release in preclinical migraine models

Cephalalgia ◽  
2012 ◽  
Vol 33 (2) ◽  
pp. 87-100 ◽  
Author(s):  
Deepak K Bhatt ◽  
Saurabh Gupta ◽  
Inger Jansen-Olesen ◽  
John S Andrews ◽  
Jes Olesen
Keyword(s):  
Dura Mater ◽  
Receptor Agonist ◽  
Middle Meningeal Artery ◽  
Cranial Window ◽  
Cgrp Release ◽  
Calcitonin Gene ◽  
Therapeutic Principles ◽  
Oxide Synthase ◽  
Trigeminal Activation ◽  
Nnos Inhibition

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.

Role of ATP-sensitive K+ channels in CGRP-induced dilatation of basilar artery in vivo

1993 ◽  
Vol 265 (2) ◽  
pp. H581-H585 ◽  
Author(s):  
T. Kitazono ◽  
D. D. Heistad ◽  
F. M. Faraci
Keyword(s):  
Basilar Artery ◽  
Minor Component ◽  
K Channels ◽  
Cranial Window ◽  
Calcitonin Gene ◽  
A Minor ◽  
Oxide Synthase ◽  
Camp Levels

Stimulation of adenylate cyclase appears to activate ATP-sensitive K+ channels in the basilar artery. We tested the hypothesis that calcitonin gene-related peptide (CGRP), which increases intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels, activates ATP-sensitive K+ channels and thereby causes vasodilatation. Using a cranial window in anesthetized rats, we examined responses of the basilar artery to CGRP in vivo. We also examined responses of the artery to another vasoactive peptide, vasoactive intestinal peptide (VIP). Topical application of CGRP (10(-11) to 10(-8) M) increased diameter of the basilar artery. Responses of the basilar artery to CGRP were almost abolished by a CGRP1 receptor antagonist, CGRP-(8-37). Vasodilatation in response to VIP was much smaller than that produced by CGRP. Dilator responses of the basilar artery to 10(-9) and 10(-8) M CGRP were inhibited by glibenclamide (10(-6) M), a selective inhibitor of ATP-sensitive K+ channels, by 69 +/- 19 and 41 +/- 9%, respectively. NG-nitro-L-arginine methyl ester (10(-5) M), an inhibitor of nitric oxide synthase, did not attenuate dilator response to 10(-8) M CGRP but inhibited responses to 10(-9) M CGRP by 34 +/- 12%. Indomethacin did not alter dilator responses to CGRP. These findings suggest that a minor component of CGRP-induced dilatation of the basilar artery is mediated by endothelium-derived relaxing factor. Vasodilatation in response to CGRP appears to be mediated primarily by direct activation of CGRP1 receptors on vascular muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Release of Calcitonin Gene-Related Peptide (CGRP) from Guinea Pig Dura Mater in vitro is Inhibited by Sumatriptan But Unaffected by Nitric Oxide

Cephalalgia ◽  
2000 ◽  
Vol 20 (9) ◽  
pp. 838-844 ◽  
Author(s):  
CT Eltorp ◽  
I Jansen-Olesen ◽  
AJ Hansen
Keyword(s):  
Nitric Oxide ◽  
Guinea Pig ◽  
Dura Mater ◽  
Sensory Nerves ◽  
High Potassium ◽  
Cgrp Release ◽  
Calcitonin Gene ◽  
High Potassium Concentration

Migraine attacks can be provoked by administration of nitroglycerin, suggesting a role for nitric oxide (NO). The fact that release of the neuropeptide CGRP from trigeminal sensory nerves occurs during the pain phase of migraine and that NO can augment transmitter release prompted us to study CGRP release from the in situ dura mater in guinea pig skulls. Release of CGRP by capsaicin or by high potassium concentration was concentration-dependent and counteracted in calcium-free medium. The anti-migraine compound, sumatriptan, inhibited CGRP release via the 5-HT1-receptor. The NO donors, nitroglycerin, sodium nitroprusside and S-nitroso-N-acetylpenicillamine did not influence CGRP release, alone or together with the stimulants. We concluded that the skull preparation is well suited for scrutinizing CGRP release from dura mater. The fact that sumatriptan inhibits CGRP release as in migraine patients suggests a use for the present preparation in headache research.

The nitric oxide synthase inhibitor and serotonin-receptor agonist NXN-188 during the aura phase of migraine with aura: A randomized, double-blind, placebo-controlled cross-over study

2013 ◽  
Vol 4 (1) ◽  
pp. 48-52 ◽  
Author(s):  
Anders Hougaard ◽  
Anne Werner Hauge ◽  
Song Guo ◽  
Peer Tfelt-Hansen
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Acute Treatment ◽  
Receptor Agonist ◽  
Drop Out ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Drop Out Rate ◽  
Oxide Synthase ◽  
Nnos Inhibition

AbstractBackground and aimsNXN-188 is a combined neuronal nitric oxide synthase (nNOS) inhibitor and 5HT-1B/1D receptor agonist which has previously shown efficacy in the acute treatment of migraine. Nitric oxide (NO) is involved in the pathogenesis of migraine pain and is formed after cortical spreading depression. Therefore NXN-188 could perhaps prevent the development of the headache phase in migraine with aura if taken during the aura. The aims of the present study were to evaluate the efficacy and safety of 600mg NXN-188 in the acute treatment of migraine when dosed during the aura.MethodsA single-centre, randomized, double-blind, placebo-controlled, two-way crossover trial. The study medication was taken during the aura and the patients kept a study diary for 48h post-dose.ResultsOf 615 patients screened, 50 patients were included in the study and randomized. Only 18 patients completed both treatments in compliance with the study procedures. 22% of patients reported freedom of headache at 2h after intake of NXN-188 compared with only 11% of patients after placebo.ConclusionsThe dual-action drug NXN-188 with 5HT-1B/1D agonism and nNOS inhibition, taken orally during the aura phase did not have a statistically substantial effect on migraine headache in this study. This study was limited by a high drop-out rate and small sample of included patients who were able to complete the cross-over protocol. Therefore, efficacy of the treatment cannot be refuted with certainty.ImplicationsThis study illustrates the difficulties of doing well controlled studies in migraine patients with aura. nNOS inhibition is expected to be effective mostly in the aura phase, i.e. the oral administration may have had too slow pharmacokinetics to have effect. Parenteral administration may overcome this obstacle. 5HT-1B/1D agonism is not effective when dosed during migraine aura. Repeated dosing of the NXN-188 during and immediately following the aura may have exploited more the dualaction. The high drop-out rate may be reduced in future studies by having the patients familiarize themselves with the study procedure by filling out the attack report form while treating one attack with their own medication before entering the trial. A parallel group comparison may be a more effective trial design for treatment during an aura.

PACAP-38 infusion causes sustained vasodilation of the middle meningeal artery in the rat: Possible involvement of mast cells

Cephalalgia ◽  
2014 ◽  
Vol 34 (11) ◽  
pp. 877-886 ◽  
Author(s):  
Deepak K Bhatt ◽  
Saurabh Gupta ◽  
Jes Olesen ◽  
Inger Jansen-Olesen
Keyword(s):  
Mast Cells ◽  
Receptor Antagonist ◽  
Middle Meningeal Artery ◽  
Healthy Human ◽  
Cranial Window ◽  
Arterial Blood ◽  
Calcitonin Gene ◽  
Human Volunteers ◽  
Pituitary Adenylate Cyclase ◽  
Meningeal Artery

Background: In healthy human volunteers and in migraineurs, pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) infusion caused sustained vasodilation of the middle meningeal artery (MMA) and an immediate as well as a delayed headache. All the study subjects experienced facial flushing. Mast cells (MCs) might have a role in the long-lasting effect of PACAP-38 infusion. We hypothesized that in mast cell-depleted (MCD) rats the vascular responses to PACAP-38 would be lesser than in control rats because of a lack of vasodilatory products released during MC degranulation. Methods: MCs were depleted by chronic treatment with compound 48/80. The effect of 20 minutes' intravenous (i.v.) infusion of calcitonin gene-related peptide (CGRP), PACAP-38, PACAP(6-38) (PAC-1 receptor antagonist) and PACAP-27 on the diameter of the MMA and on mean arterial blood pressure (MABP) in control and MCD rats was recorded by using the genuine closed-cranial window (CCW) model. Vasoactive intestinal polypeptide (VIP) infusion was given only in control rats. A combination of the histamine H1 receptor antagonist mepyramine (4 mg kg−1 i.v.) and the H2 receptor antagonist famotidine (1 mg kg−1 i.v.) was given 10 minutes prior to PACAP-38 infusion. Increasing doses of PACAP-38, PACAP-27 and VIP were infused through the intracarotid artery (i.c.) in control and MCD rats to see the direct effects of these peptides on MMA diameter change. Results: There was no significant change in CGRP-induced MMA diameter increase in control and MCD rats, and the dilated MMA immediately returned back to baseline after stopping the infusion. The delayed MMA dilation induced by PACAP-38 was abolished in MCD and antihistamine (AH)-pretreated rats. Compared to PACAP-38, the PACAP-27 i.v. infusion gave smaller peak dilation of MMA in control rats. In MCD rats, PACAP-27 did not induce any significant dilation. VIP i.v. infusion reduced MABP but did not dilate MMA significantly. PACAP(6-38), which is a potent MC degranulator, also gave a significant delayed dilation of MMA. PACAP-38 i.c. responses (direct receptor mediated response) were not affected by MC depletion. Only the maximum response (% Emax) value of PACAP-27 (i.c.) was significantly lower in MCD rats compared to control rats. Conclusions: The delayed MMA dilatory responses to PACAP-38 infusion were attenuated in MCD and AH-pretreated rats, indicating a role of the MC mediator-histamine in PACAP-38-induced delayed dilation of MA.

Miconazole represses CO2-induced pial arteriolar dilation only under selected circumstances

1999 ◽  
Vol 277 (4) ◽  
pp. H1484-H1490 ◽  
Author(s):  
Dale A. Pelligrino ◽  
Roberto A. Santizo ◽  
Qiong Wang
Keyword(s):  
Adult Rats ◽  
Cyclic Monophosphate ◽  
Cranial Window ◽  
Window System ◽  
Cgmp Analog ◽  
Cerebral Vasodilation ◽  
Experimental Findings ◽  
Oxide Synthase ◽  
Permissive Role ◽  
Nnos Inhibition

Previous experimental findings have led to the suggestion that guanosine 3′,5′-cyclic monophosphate (cGMP) plays a permissive role in hypercapnic cerebral vasodilation. However, we recently reported that the technique used to reveal a permissive role for cGMP [cGMP repletion in the presence of nitric oxide synthase (NOS) inhibition] created a situation where CO2 reactivity was normalized but where different mechanisms (i.e., K+ channels) participated in the response. In the present study, we examined whether that nascent K+-channel dependence is related in any way to an increase in the influence of the miconazole-inhibitable cytochrome P-450 epoxygenase pathway. Using intravital microscopy and a closed cranial window system in adult rats, we measured pial arteriolar diameters during normo- and hypercapnia, first in the absence and then in the presence of a neuronal NOS (nNOS) inhibitor [7-nitroindazole (7-NI)]. This was followed by suffusion of a cGMP analog and then cGMP plus miconazole. Separate groups of rats were used to evaluate whether miconazole either alone or in the presence of 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP) or its vehicle (0.1% ethanol) had any effect on CO2 reactivity and whether miconazole affected K+-channel opener-induced dilations. Hypercapnic (arterial[Formula: see text], ≅65 mmHg) pial arteriolar dilations, as expected, were reduced by 70–80% with 7-NI and restored with cGMP repletion. CO2reactivity was again attenuated after miconazole introduction. Miconazole, with and without 8-BrcGMP, and its vehicle had no influence on pial arteriolar CO2 reactivity in the absence of nNOS inhibition combined with cGMP repletion. Miconazole alone also did not affect vasodilatory responses to K+-channel openers. Thus present results suggest that the nascent K+-channel dependence of the hypercapnic response found in our earlier study may be related to increased epoxygenase activity. The specific reasons why the pial arteriolar CO2 reactivity gains a K+-channel and epoxygenase dependence only under conditions of nNOS inhibition and cGMP restoration remain to be identified. These findings again call into question the interpretations applied to data collected in studies evaluating potential permissive actions of cGMP or NO.

Lack of Effect of the Adenosine A1 Receptor Agonist, GR79236, on Capsaicin-Induced CGRP Release in Anaesthetized Pigs

Cephalalgia ◽  
2005 ◽  
Vol 25 (11) ◽  
pp. 1082-1090 ◽  
Author(s):  
U Arulmani ◽  
JPC Heiligers ◽  
D Centurión ◽  
IM Garrelds ◽  
CM Villalón ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Sensory Nerves ◽  
Cgrp Release ◽  
Calcitonin Gene ◽  
Adenosine A1 ◽  
Potent Vasodilator ◽  
Haemodynamic Changes ◽  
A1 Receptor ◽  
The Difference ◽  
Prejunctional Inhibition

Migraine is a common neurological disorder that is associated with an increase in plasma calcitonin gene-related peptide (CGRP) levels. CGRP, a potent vasodilator released from the activated trigeminal sensory nerves, dilates intracranial blood vessels and transmits vascular nociception. Hence, inhibition of trigeminal CGRP release may prevent neurotransmission and, thereby, ameliorate migraine headache. Therefore, the present study in anaesthetized pigs investigates the effects of a selective adenosine A1 receptor agonist, GR79236 (3, 10 and 30 μg/kg, i.v.) on capsaicin-induced carotid haemodynamic changes and on plasma CGRP release. Intracarotid (i.c.) infusion of capsaicin (10 μg/kg/min, i.c.) increased the total carotid blood flow and conductance as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. These responses to capsaicin were dose-dependently attenuated by GR79236. However, the increases in the plasma CGRP concentrations by capsaicin remained essentially unmodified after GR79236 treatment. The above results suggest that GR79236 may have an antimigraine potential due to its postjunctional effects (carotid vasoconstriction) rather than to prejunctional inhibition of trigeminal CGRP release.

Calcitonin gene-related peptide receptors in rat trigeminal ganglion do not control spinal trigeminal activity

2012 ◽  
Vol 108 (2) ◽  
pp. 431-440 ◽  
Author(s):  
Oana Covasala ◽  
Sören L. Stirn ◽  
Stephanie Albrecht ◽  
Roberto De Col ◽  
Karl Messlinger
Keyword(s):  
Trigeminal Ganglion ◽  
Dura Mater ◽  
Calcitonin Gene Related Peptide ◽  
Afferent Input ◽  
Nitric Oxide Donor ◽  
Cgrp Receptor ◽  
Related Peptide ◽  
Trigeminal Neurons ◽  
Calcitonin Gene ◽  
Evoked Activity

Calcitonin gene-related peptide (CGRP) is regarded as a key mediator in the generation of primary headaches. CGRP receptor antagonists reduce migraine pain in clinical trials and spinal trigeminal activity in animal experiments. The site of CGRP receptor inhibition causing these effects is debated. Activation and inhibition of CGRP receptors in the trigeminal ganglion may influence the activity of trigeminal afferents and hence of spinal trigeminal neurons. In anesthetized rats extracellular activity was recorded from neurons with meningeal afferent input in the spinal trigeminal nucleus caudalis. Mechanical stimuli were applied at regular intervals to receptive fields located in the exposed cranial dura mater. α-CGRP (10−5 M), the CGRP receptor antagonist olcegepant (10−3 M), or vehicle was injected through the infraorbital canal into the trigeminal ganglion. The injection of volumes caused transient discharges, but vehicle, CGRP, or olcegepant injection was not followed by significant changes in ongoing or mechanically evoked activity. In animals pretreated intravenously with the nitric oxide donor glyceryl trinitrate (GTN, 250 μg/kg) the mechanically evoked activity decreased after injection of CGRP and increased after injection of olcegepant. In conclusion, the activity of spinal trigeminal neurons with meningeal afferent input is normally not controlled by CGRP receptor activation or inhibition in the trigeminal ganglion. CGRP receptors in the trigeminal ganglion may influence neuronal activity evoked by mechanical stimulation of meningeal afferents only after pretreatment with GTN. Since it has previously been shown that olcegepant applied to the cranial dura mater is ineffective, trigeminal activity driven by meningeal afferent input is more likely to be controlled by CGRP receptors located centrally to the trigeminal ganglion.

Release of Histamine from Dural Mast Cells by Substance P and Calcitonin Gene-Related Peptide

Cephalalgia ◽  
1997 ◽  
Vol 17 (3) ◽  
pp. 166-174 ◽  
Author(s):  
A Ottosson ◽  
L Edvinsson
Keyword(s):  
Mast Cells ◽  
Substance P ◽  
Histamine Release ◽  
Dura Mater ◽  
Neurogenic Inflammation ◽  
Calcitonin Gene Related Peptide ◽  
Sampling Procedure ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Peritoneal Mast Cells

The aim of the present study was to examine if the neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) can stimulate histamine release from mast cells in the dura mater and thereby play a role in cranial vasoregulation and local neurogenic inflammation. Dura mater mast cells were compared with peritoneal mast cells in the rat. Histamine was released from dura mater mast cells by compound 48/80, SP and CGRP but from peritoneal mast cells only by compound 8/80 and SP. NPY and VIP released quite small amounts of histamine from dural mast cells. The release on SP and CGRP from rat dura mater mast cells was blocked by the receptor antagonists FK888 and CGRP8-37 respectively, suggesting receptor mediated release mechanisms. None of the stimuli released histamine from human or porcine dural mast cells, possibly because the sampling procedure injures and incapacitates the cells.

scholarly journals Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia: Targets and anti-migraine mechanisms

Cephalalgia ◽  
2016 ◽  
Vol 37 (13) ◽  
pp. 1272-1284 ◽  
Author(s):  
Rosaria Greco ◽  
Chiara Demartini ◽  
Anna Maria Zanaboni ◽  
Elisa Redavide ◽  
Selena Pampalone ◽  
...  
Keyword(s):  
Kynurenic Acid ◽  
Formalin Injection ◽  
Major Mechanism ◽  
Trigeminal Nociception ◽  
Acid Analogue ◽  
Calcitonin Gene ◽  
Pain Models ◽  
Increased Sensitivity ◽  
Kynurenic Acid Analogue ◽  
Oxide Synthase

Background Trigeminal sensitization represents a major mechanism underlying migraine attacks and their recurrence. Nitroglycerin (NTG) administration provokes spontaneous migraine-like headaches and in rat, an increased sensitivity to the formalin test. Kynurenic acid (KYNA), an endogenous regulator of glutamate activity and its analogues attenuate NTG-induced neuronal activation in the nucleus trigeminalis caudalis (NTC). The anti-hyperalgesic effect of KYNA analogue 1 (KYNA-A1) was investigated on animal models specific for migraine pain. Aim Rats made hyperalgesic by NTG administration underwent the plantar or orofacial formalin tests. The effect of KYNA-A1 was evaluated in terms of nocifensive behavior and of neuronal nitric oxide synthase (nNOS), calcitonin gene-related peptide (CGRP) and cytokines expression in areas involved in trigeminal nociception. Results KYNA-A1 abolished NTG-induced hyperalgesia in both pain models; NTG alone or associated to formalin injection induced an increased mRNA expression of CGRP, nNOS and cytokines in the trigeminal ganglia and central areas, which was reduced by KYNA-A1. Additionally, NTG caused a significant increase in nNOS immunoreactivity in the NTC, which was prevented by KYNA-A1. Conclusion Glutamate activity is likely involved in mediating hyperalgesia in an animal model specific for migraine. Its inhibition by means of a KYNA analogue modulates nNOS, CGRP and cytokines expression at peripheral and central levels.

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