Calcitonin Gene-related Peptide Receptor Research Articles

Reassessing the adrenomedullin scavenging function of ACKR3 in lymphatic endothelial cells.

Atypical chemokine receptor 3 (ACKR3) is a scavenger of the chemokines CXCL11 and CXCL12 and of several opioid peptides. Additional evidence indicates that ACKR3 binds two other non-chemokine ligands, namely the peptide hormone adrenomedullin (AM) and derivatives of the proadrenomedullin N-terminal 20 peptide (PAMP). AM exhibits multiple functions in the cardiovascular system and is essential for embryonic lymphangiogenesis in mice. Interestingly, AM-overexpressing and ACKR3-deficient mouse embryos both display lymphatic hyperplasia. Moreover, in vitro evidence suggested that lymphatic endothelial cells (LECs), which express ACKR3, scavenge AM and thereby reduce AM-induced lymphangiogenic responses. Together, these observations have led to the conclusion that ACKR3-mediated AM scavenging by LECs serves to prevent overshooting AM-induced lymphangiogenesis and lymphatic hyperplasia. Here, we further investigated AM scavenging by ACKR3 in HEK293 cells and in human primary dermal LECs obtained from three different sources in vitro. LECs efficiently bound and scavenged fluorescent CXCL12 or a CXCL11/12 chimeric chemokine in an ACKR3-dependent manner. Conversely, addition of AM induced LEC proliferation but AM internalization was found to be independent of ACKR3. Similarly, ectopic expression of ACKR3 in HEK293 cells did not result in AM internalization, but the latter was avidly induced upon co-transfecting HEK293 cells with the canonical AM receptors, consisting of calcitonin receptor-like receptor (CALCRL) and receptor activity-modifying protein (RAMP)2 or RAMP3. Together, these findings indicate that ACKR3-dependent scavenging of AM by human LECs does not occur at ligand concentrations sufficient to trigger AM-induced responses mediated by canonical AM receptors.

Zavegepant: First Approval.

Zavegepant is a third generation, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist being developed by Pfizer, under a license from Bristol-Myers Squibb, for the prevention and treatment of chronic and episodic migraine. In March 2023, zavegepant nasal spray (ZAVZPRET™) received its first approval in the USA for the acute treatment of migraine with or without aura in adults. Clinical development of an oral formulation of zavegepant is currently underway. This article summarizes the milestones in the development of zavegepant leading to this first approval for the acute treatment of migraine with or without aura in adults.

Drug therapy of the acute migraine attack and prophylaxis ofmigraine

Migraine has a prevalence of 10 % in Germany, making it the most common neurological disorder. Migraine is a prevalent disorder not only for neurologist, it's an everyday topic for general physicians and internal medicine as well. Acute migraine attacks are treated with analgesics or triptans. In case of frequent migraine attacks, there is an indication for medicinal and non-pharmacological migraine prophylaxis. Medications include beta-blockers, flunarizine, anticonvulsants, amitriptyline or, in the case of chronic migraine, onabotulinumtoxinA. If these drugs are not effective, are not tolerated or contraindicated, monoclonal antibodies against calcitonin gene-related peptide (CGRP) or the CGRP receptor can be used.

TRPV1 activation in human Langerhans cells and T cells inhibits mucosal HIV-1 infection via CGRP-dependent and independent mechanisms

Upon its mucosal transmission, HIV type 1 (HIV-1) rapidly targets genital antigen-presenting Langerhans cells (LCs), which subsequently transfer infectious virus to CD4+ Tcells. We previously described an inhibitory neuroimmune cross talk, whereby calcitonin gene-related peptide (CGRP), a neuropeptide secreted by peripheral pain-sensing nociceptor neurons innervating all mucosal epithelia and associating with LCs, strongly inhibits HIV-1 transfer. As nociceptors secret CGRP following the activation of their Ca2+ ion channel transient receptor potential vanilloid 1 (TRPV1), and as we reported that LCs secret low levels of CGRP, we investigated whether LCs express functional TRPV1. We found that human LCs expressed mRNA and protein of TRPV1, which was functional and induced Ca2+ influx following activation with TRPV1 agonists, including capsaicin (CP). The treatment of LCs with TRPV1 agonists also increased CGRP secretion, reaching its anti-HIV-1 inhibitory concentrations. Accordingly, CP pretreatment significantly inhibited LCs-mediated HIV-1 transfer to CD4+ Tcells, which was abrogated by both TRPV1 and CGRP receptor antagonists. Like CGRP, CP-induced inhibition of HIV-1 transfer was mediated via increased CCL3 secretion and HIV-1 degradation. CP also inhibited direct CD4+ Tcells HIV-1 infection, but in CGRP-independent manners. Finally, pretreatment of inner foreskin tissue explants with CP markedly increased CGRP and CCL3 secretion, and upon subsequent polarized exposure to HIV-1, inhibited an increase in LC-Tcell conjugate formation and consequently Tcell infection. Our results reveal that TRPV1 activation in human LCs and CD4+ Tcells inhibits mucosal HIV-1 infection, via CGRP-dependent/independent mechanisms. Formulations containing TRPV1 agonists, already approved for pain relief, could hence be useful against HIV-1.

Rimegepant for migraine: acute efficacy beyond the USA

The safety and efficacy of rimegepant, a synthetic molecule that competes with calcitonin gene-related peptide (CGRP) for binding to its receptor, have been shown in two phase 3 studies on symptomatic treatment 1 Lipton RB Croop R Stock EG et al. Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine. N Engl J Med. 2019; 381: 142-149 Crossref PubMed Scopus (177) Google Scholar , 2 Croop R Goadsby PJ Stock DA et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. Lancet. 2019; 394: 737-745 Summary Full Text Full Text PDF PubMed Scopus (172) Google Scholar and one on prophylactic treatment 3 Croop R Lipton RB Kudrow D et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet. 2021; 397: 51-60 Summary Full Text Full Text PDF PubMed Scopus (106) Google Scholar of migraine, all done in the USA. On the basis of these data, rimegepant was the first CGRP antagonist (gepant) to be approved by the US Food and Drug Administration and European Medicines Agency for both symptomatic and prophylactic treatment of migraine, giving it a unique and innovative role in the treatment of headaches. Rimegepant is available as a pill for oral administration as needed by people with migraine (ie, whenever they have a migraine attack 4 Mitsikostas DD Belesioti I Arvaniti C et al. Patients' preferences for headache acute and preventive treatment. J Headache Pain. 2017; 18: 102 Crossref PubMed Scopus (26) Google Scholar ), possibly without the risk of developing medication overuse headache, and without the need to take another medication for migraine prophylaxis. Until the development of the anti-CGRP treatments, all prophylactic anti-migraine medications had been repurposed from other diseases; these older treatments have little evidence of efficacy in migraine prophylaxis and have well known side-effects, which increases the likelihood that individuals have adverse events, reducing adherence and benefit. 5 Charles A Pozo-Rosich P Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet. 2019; 394: 1765-1774 Summary Full Text Full Text PDF PubMed Scopus (157) Google Scholar By contrast, CGRP-pathway-targeting drugs are mechanism-based, are migraine-specific, and have very good evidence of tolerability and safety. 6 Hepp Z Dodick DW Varon SF Gillard P Hansen RN Devine EB Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015; 35: 478-488 Crossref PubMed Scopus (254) Google Scholar Safety and efficacy of rimegepant orally disintegrating tablet for the acute treatment of migraine in China and South Korea: a phase 3, double-blind, randomised, placebo-controlled trialAmong adults living in China or South Korea, a single dose of 75 mg rimegepant was effective for the acute treatment of migraine. Safety and tolerability were similar to placebo. Our findings suggest that rimegepant might be a useful new addition to the range of medications for the acute treatment of migraine in China and South Korea, but further studies are needed to support long-term efficacy and safety and to compare rimegepant with other medications for the acute treatment of migraine in this population. Full-Text PDF

Assessment of Functional Characteristics of Small Arterioles and Capillaries Using an Intact Dura Mater Preparation

The dura mater, a protective layer surrounding the brain and spinal cord, plays a crucial role in maintaining homeostatic function of the central nervous system. The large arteries and veins of the dura mater are relatively sparse and have been extensively studied with respect to their contribution to pain sensation, with unclear and controversial contributions to headache and migraine pathology. Small arterioles and capillaries exhibit nearly ubiquitous coverage of the entire dura, yet their physiological and pathophysiological functions remain largely unexplored. Here, using ex vivo mouse dura, we examined the electrical (membrane potential recordings), Ca2+ signaling properties (GCaMP or Cal-520 AM imaging), and vasomotor behavior (pressurized dura vessels with diameter measurement) of these exquisitely small vessels. Furthermore, we show electrical and Ca2+ responses in smooth muscle and pericytes in response to calcitonin gene-related peptide (CGRP) receptor and transient receptor potential V1 (TRPV1) channel activation, which are two principal targets in headache and migraine pathology. Last, we highlight unique anatomical interactions between nerves and arterioles in the dura mater using immunostaining techniques. In conclusion, we hypothesize that microvessels consisting of arterioles and capillaries are a logical and unexplored region for studying homeostatic and pathological roles of the dura mater. Funding Provided by the Totman Medical Trust This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of rimegepant 75 mg daily on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate in healthy female participants.

To assess the effect of single and multiple doses of rimegepant 75 mg dose on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol (EE)/norgestimate (NGM) in healthy females of childbearing potential or non-menopausal females with tubal ligation. Females of childbearing age experience the highest prevalence of migraine and frequently inquire about the concomitant use of anti-migraine medications and contraceptives. Rimegepant, a calcitonin gene-related peptide receptor antagonist, demonstrated efficacy and safety for treating an acute migraine attack and preventing migraine. This open-label, single-center, phase 1, drug-drug interaction study explored the effects of rimegepant 75 mg daily dose on the pharmacokinetics of an oral contraceptive containing EE/NGM 0.035 mg/0.25 mg in healthy females of childbearing potential or non-menopausal females with tubal ligation. During cycles 1 and 2, participants received EE/NGM once daily for 21 days followed by placebo tablets with inactive ingredients for 7 days. Rimegepant was administered during only cycle 2 for 8 days, from days 12 through 19. The primary endpoint was the effect of single and multiple doses of rimegepant on the pharmacokinetics of EE and norelgestromin (NGMN), an active metabolite of NGM, at steady state, including area under the concentration-time curve for 1 dosing interval (AUC0-τ,ss ) and maximum observed concentration (Css[max] ). The study enrolled 25 participants, with pharmacokinetic data assessed for 20 participants. A single 75 mg dose of rimegepant co-administered with EE/NGM increased exposures of EE and NGMN by ≤16% (geometric mean ratio [GMR], 1.03; 90% confidence interval [CI], 1.01-1.06; and GMR, 1.16; 90% CI, 1.13-1.20, respectively). After 8 days of co-administering EE/NGM with rimegepant, EE pharmacokinetic parameters, AUC0-τ,ss and Css(max) , increased by 20% (GMR, 1.20; 90% CI, 1.16-1.25) and 34% (GMR, 1.34; 90% CI, 1.23-1.46), respectively, and NGMN pharmacokinetic parameters increased by 46% (GMR, 1.46; 90% CI, 1.39-1.52) and 40% (GMR, 1.40; 90% CI, 1.30-1.51), respectively. The study identified modest elevations in overall EE and NGMN exposures after multiple doses of rimegepant, but these elevations are unlikely to be clinically relevant in healthy females with migraine.

Acetaldehyde via CGRP receptor and TRPA1 in Schwann cells mediates ethanol-evoked periorbital mechanical allodynia in mice: relevance for migraine

BackgroundIngestion of alcoholic beverages is a known trigger of migraine attacks. However, whether and how ethanol exerts its pro-migraine action remains poorly known. Ethanol stimulates the transient receptor potential vanilloid 1 (TRPV1) channel, and its dehydrogenized metabolite, acetaldehyde, is a known TRP ankyrin 1 (TRPA1) agonist.MethodsPeriorbital mechanical allodynia following systemic ethanol and acetaldehyde was investigated in mice after TRPA1 and TRPV1 pharmacological antagonism and global genetic deletion. Mice with selective silencing of the receptor activated modifying protein 1 (RAMP1), a component of the calcitonin gene-related peptide (CGRP) receptor, in Schwann cells or TRPA1 in dorsal root ganglion (DRG) neurons or Schwann cells, were used after systemic ethanol and acetaldehyde.ResultsWe show in mice that intragastric ethanol administration evokes a sustained periorbital mechanical allodynia that is attenuated by systemic or local alcohol dehydrogenase inhibition, and TRPA1, but not TRPV1, global deletion, thus indicating the implication of acetaldehyde. Systemic (intraperitoneal) acetaldehyde administration also evokes periorbital mechanical allodynia. Importantly, periorbital mechanical allodynia by both ethanol and acetaldehyde is abrogated by pretreatment with the CGRP receptor antagonist, olcegepant, and a selective silencing of RAMP1 in Schwann cells. Periorbital mechanical allodynia by ethanol and acetaldehyde is also attenuated by cyclic AMP, protein kinase A, and nitric oxide inhibition and pretreatment with an antioxidant. Moreover, selective genetic silencing of TRPA1 in Schwann cells or DRG neurons attenuated periorbital mechanical allodynia by ethanol or acetaldehyde.ConclusionsResults suggest that, in mice, periorbital mechanical allodynia, a response that mimics cutaneous allodynia reported during migraine attacks, is elicited by ethanol via the systemic production of acetaldehyde that, by releasing CGRP, engages the CGRP receptor in Schwann cells. The ensuing cascade of intracellular events results in a Schwann cell TRPA1-dependent oxidative stress generation that eventually targets neuronal TRPA1 to signal allodynia from the periorbital area.

Calcitonin receptors in GtoPdb v.2023.1

This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [131, 74, 71]) are generated by the genes CALCR (which codes for the CT receptor, CTR) and CALCRL (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 150 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CTR; these in turn produce variants of AMY receptors [131], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin, α-CGRP (formerly known as CGRP-I), β-CGRP (formerly known as CGRP-II), amylin (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin and adrenomedullin 2/intermedin. There are species differences in peptide sequences, particularly for the CTs. CTR-stimulating peptide (CRSP) is another member of the family with selectivity for the CTR but it is not expressed in humans [93]. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin. There are several approved drugs that target this receptor family, such as pramlintide, erenumab, and the "gepant" class of CGRP receptor antagonists. There are also species differences in agonist pharmacology; for example, CGRP displays potent activity at multiple rat and mouse receptors [58, 15]. The summary table only reflects human receptor pharmacology.

Real-Life Experience with Erenumab Therapy in the Episodic and Chronic Migraine. (P12-12.004)

<h3>Objective:</h3> The study aims to confirm the efficacy and safety of erenumab in migraine patients. <h3>Background:</h3> Migraine prevention with erenumab is approved in Kuwait. It is a fully human monoclonal antibody inhibiting the calcitonin gene-related peptide receptor (CGRPr). <h3>Design/Methods:</h3> This is a prospective, real-life, cohort study. In our tertiary hospital in Kuwait, we selected patients with a ICHD-3 diagnosis of migraine who received erenumab monthly between May 2019 and April 2022. The study included migraine patients aged 18 to 65 years treated with erenumab in the Headache clinic. Primary endpoint of this analysis was the mean change in monthly headache days from the baseline until the end of observational period. Secondary endpoints were changes days with acute headache medication in the treatment period, severity of headache pain and change of quality of after treatment. <h3>Results:</h3> A total of 151 migraine patients were identified to the study, 123 (81.5%) were female, with a mean age of 20.23±11.74 years. Erenumab decreased mean headache days frequency from 15.05 ± 8.93 to 6.08± 6.05; p&lt;0.002; mean monthly days of analgesic use from 15.48 ±8.77 to 6.30± 6.83; P &lt; 0.001), and mean severity of headache pain from 8.75± 1.67 to 5.46 ±2.90. Constipation (6%) was the most frequent adverse events reported. <h3>Conclusions:</h3> At the end of study, we reported a statistically significant reduction in the mean number of monthly headache days, acute medication use per month, and improvement of quality of life. Results of this real-world setting are comparable to results of clinical trials. <b>Disclosure:</b> Dr. Alshawaf has nothing to disclose. Dr. Ahmed has nothing to disclose. Dr. Alroughani has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen, Bayer, Novartis, Merck, Roche, Sanofi. Dr. Alroughani has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen, Novartis, Merck, Roche, Sanofi. Dr. Al-Hashel has nothing to disclose.

Assessment of the Potential for Drug–Drug Interactions Between INP104 and Gepants for Migraine Management Using a Model-based Approach (P12-12.008)

Assessment of the Potential for Drug–Drug Interactions Between INP104 and Gepants for Migraine Management Using a Model-based Approach (P12-12.008)

Investigating the Risk of Hypertension After Initiation of Erenumab in the Post-Market Setting (S47.009)

Investigating the Risk of Hypertension After Initiation of Erenumab in the Post-Market Setting (S47.009)

Efficacy and Safety of Rimegepant for the Acute Treatment of Migraine in Black and African American Adults: Results From 3 Randomized, Placebo-Controlled Clinical Trials (P9-12.009)

Efficacy and Safety of Rimegepant for the Acute Treatment of Migraine in Black and African American Adults: Results From 3 Randomized, Placebo-Controlled Clinical Trials (P9-12.009)

Improvement in Patient-Reported Outcomes When Ubrogepant Is Administered During the Migraine Prodrome (Premonitory Phase): Results From the PRODROME Trial (P9-12.001)

Improvement in Patient-Reported Outcomes When Ubrogepant Is Administered During the Migraine Prodrome (Premonitory Phase): Results From the PRODROME Trial (P9-12.001)

Efficacy of Ubrogepant for the Treatment of Migraine Symptoms During the Prodrome (Premonitory Phase): Results From the PRODROME Trial (S47.002)

Efficacy of Ubrogepant for the Treatment of Migraine Symptoms During the Prodrome (Premonitory Phase): Results From the PRODROME Trial (S47.002)

Ubrogepant for the Acute Treatment of Migraine When Administered During the Prodrome (Premonitory Phase): Results From a Phase 3, Randomized, Double-blind, Placebo-Controlled, Crossover Study (S47.001)

Ubrogepant for the Acute Treatment of Migraine When Administered During the Prodrome (Premonitory Phase): Results From a Phase 3, Randomized, Double-blind, Placebo-Controlled, Crossover Study (S47.001)

Benefit-Risk Assessment of Atogepant: A Post Hoc Analysis of the ADVANCE Trial (P12-12.001)

Benefit-Risk Assessment of Atogepant: A Post Hoc Analysis of the ADVANCE Trial (P12-12.001)

Safety and Efficacy of Oral Calcitonin Gene-Related Peptide Receptor Antagonists for the Acute Treatment of Migraine in the Pediatric Population (P9-12.010)

<h3>Objective:</h3> To evaluate the safety and efficacy of gepants for the acute treatment of migraine in pediatric patients. <h3>Background:</h3> Calcitonin gene-related peptide (CGRP) has been found to be elevated during migraine attacks. Gepants are oral CGRP receptor antagonists, which have been shown to be effective for acute and preventive treat of migraine in adults. Generally, they are well tolerated with limited side effects. Currently, they are FDA approved in adults for migraine, however, there is limited data on their use in pediatrics. <h3>Design/Methods:</h3> Retrospective chart review of patients &lt; 18 years old who were prescribed a gepant (rimegepant or ubrogepant) for acute migraine treatment at a single institution from 1/1/2020 to 1/1/2023. Data was collected through chart review for all patients that used ≥ 1 dose of a gepant. Safety and tolerability were assessed through reported side effects, laboratory data and vital signs pre- and post-gepant use. The data was evaluated using descriptive statistics and compared using paired t-tests. <h3>Results:</h3> Thirteen patients were identified. Median (range) age was 16 years (13 to 17). There were 10 females and 3 males. Five (38%) had episodic migraine, 5 (38%) had chronic migraine and 3 (23%) had hemiplegic migraine. At baseline, median (range) headache days per month was 10 (0 to 30). Patients tried on median (range) 5 (1 to 8) acute medications before being prescribed a gepant. At the follow-up visit, 11 (85%) had reported any improvement or resolution of their migraine attack with use of a gepant. Zero patients reported side effects and there were no significant laboratory, height or weight changes seen after gepant use. <h3>Conclusions:</h3> The results indicate that gepants may be an effective acute treatment for migraine in pediatric patients. They appear to be safe and well-tolerated. However, larger prospective and randomized trials need to be conducted to confirm these results. <b>Disclosure:</b> Dr. Tourlas has stock in Axonics Modulation Technologies (AXNX). Dr. Tourlas has stock in Biote (BTMD). An immediate family member of Dr. Pavitt has received personal compensation for serving as an employee of Lundbeck.

Long-Term Safety and Tolerability of Zavegepant 10 mg Nasal Spray During Concomitant Use of CGRP Monoclonal Antibodies: Results From a 1-Year Open-label Safety Trial (P10-12.009)

Long-Term Safety and Tolerability of Zavegepant 10 mg Nasal Spray During Concomitant Use of CGRP Monoclonal Antibodies: Results From a 1-Year Open-label Safety Trial (P10-12.009)

Efficacy and Safety of Zavegepant Nasal Spray for the Acute Treatment of Migraine: Results of a Phase 3 Double-Blind, Randomized, Placebo Controlled Trial (PL5.002)

Efficacy and Safety of Zavegepant Nasal Spray for the Acute Treatment of Migraine: Results of a Phase 3 Double-Blind, Randomized, Placebo Controlled Trial (PL5.002)