Role of calcitonin gene-related peptide in light-aversive behavior: implications for migraine.
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ABSTRACT:
SUBMITTER: Recober A
PROVIDER: S-EPMC2944225 | biostudies-other | 2009 Jul
REPOSITORIES: biostudies-other
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Project description:Introduction: The neuropeptide calcitonin gene-related peptide (CGRP) is recognized as a critical player in migraine pathophysiology. Excitement has grown regarding CGRP because of the development and clinical testing of drugs targeting CGRP or its receptor. While these drugs alleviate migraine symptoms in half of the patients, the remaining unresponsive half of this population creates an impetus to address unanswered questions that exist in this field.Areas covered: We describe the role of CGRP in migraine pathophysiology and CGRP-targeted therapeutics currently under development and in use. We also discuss how a second CGRP receptor may provide a new therapeutic target.Expert opinion: CGRP-targeting drugs have shown a remarkable safety profile. We speculate that this may reflect the redundancy of peptides within the CGRP family and a second CGRP receptor that may compensate for reduced CGRP activity. Furthermore, we propose that an inherent safety feature of peptide-blocking antibodies is attributed to the fundamental nature of peptide release, which occurs as a large bolus in short bursts of volume transmission. These facts support the development of more refined CGRP therapeutic drugs, as well as drugs that target other neuropeptides. We believe that the future of migraine research is bright with exciting advances on the horizon.
| S-EPMC7050542 | biostudies-literature
Project description:Migraine is the third most common disease in the world (behind dental caries and tension-type headache) with an estimated global prevalence of 15%, yet its etiology remains poorly understood. Recent clinical trials have heralded the potential of therapeutic antibodies that block the actions of the neuropeptide calcitonin gene-related peptide (CGRP) or its receptor to prevent migraine. Calcitonin gene-related peptide is believed to contribute to trigeminal nerve hypersensitivity and photosensitivity in migraine, but a direct role in pain associated with migraine has not been established. In this study, we report that peripherally administered CGRP can act in a light-independent manner to produce spontaneous pain in mice that is manifested as a facial grimace. As an objective validation of the orbital tightening action unit of the grimace response, we developed a squint assay using a video-based measurement of the eyelid fissure, which confirmed a significant squint response after CGRP injection, both in complete darkness and very bright light. These indicators of discomfort were completely blocked by preadministration of a monoclonal anti-CGRP-blocking antibody. However, the nonsteroidal anti-inflammatory drug meloxicam failed to block the effect of CGRP. Interestingly, an apparent sex-specific response to treatment was observed with the antimigraine drug sumatriptan partially blocking the CGRP response in male, but not female mice. These results demonstrate that CGRP can induce spontaneous pain, even in the absence of light, and that the squint response provides an objective biomarker for CGRP-induced pain that is translatable to humans.
| S-EPMC6193822 | biostudies-literature
Project description:Migraine is a neurological disorder that manifests as a debilitating headache associated with altered sensory perception. The neuropeptide calcitonin gene-related peptide (CGRP) is now firmly established as a key player in migraine. Clinical trials carried out during the past decade have proved that CGRP receptor antagonists are effective for treating migraine, and antibodies to the receptor and CGRP are currently under investigation. Despite this progress in the clinical arena, the mechanisms by which CGRP triggers migraine remain uncertain. This review discusses mechanisms whereby CGRP enhances sensitivity to sensory input at multiple levels in both the periphery and central nervous system. Future studies on epistatic and epigenetic regulators of CGRP actions are expected to shed further light on CGRP actions in migraine. In conclusion, targeting CGRP represents an approachable therapeutic strategy for migraine.
| S-EPMC4392770 | biostudies-literature
Project description:BACKGROUND:Migraine prevention with erenumab and migraine induction by calcitonin gene-related peptide (CGRP) both carry notable individual variance. We wanted to explore a possible association between individual efficacy of anti-CGRP treatment and susceptibility to migraine induction by CGRP. METHODS:Thirteen migraine patients, previously enrolled in erenumab anti-CGRP receptor monoclonal antibody trials, received CGRP in a double-blind, placebo-controlled, randomized cross-over design to investigate their susceptibility to migraine induction. A standardized questionnaire was used to assess the efficacy of previous antibody treatment. The patients were stratified into groups of high responders and poor responders. Primary outcomes were incidence of migraine-like attacks and area under the curve of headache intensity after infusion of CGRP and placebo. All interviews and experiments were performed in laboratories at the Danish Headache Center, Copenhagen, Denmark. RESULTS:Ten high responders and three poor responders were included. CGRP induced migraine-like attacks in ten (77%) patients, whereof two were poor responders, compared to none after placebo (p?=?0.002). The area under the curve for headache intensity was greater after CGRP, compared to placebo, at 0-90 min (p?=?0.009), and 2-12 h (p?=?0.014). The median peak headache intensity score was 5 (5-9) after CGRP, compared to 2 (0-4) after placebo (p?=?0.004). CONCLUSIONS:Patients with an excellent effect of erenumab are highly susceptible to CGRP provocation. If an association is evident, CGRP provocation could prove a biomarker for predicting antibody treatment efficacy. TRIAL REGISTRATION:Retrospectively registered at clinicaltrials.gov with identifier: NCT03481400 .
| S-EPMC6755614 | biostudies-literature
Project description:This article seeks to analyze the clinical trials concerning the newly approved eptinezumab to assess its efficacy, safety, and application to current clinical practice. The Institute of Health US National Library of Medicine Clinical Trials, PubMed, and Cochrane Library databases were searched for relevant abstracts, journal articles, and other published sources. Search terms included eptinezumab, Vyepti®, and ALD403. Relevant English-language articles were evaluated and included in the narrative. Two randomized controlled trials compared quarterly infusions of eptinezumab 100 mg, eptinezumab 300 mg, and placebo in chronic and episodic migraine sufferers. In episodic migraine, eptinezumab resulted in a reduction of approximately 4 monthly migraine days, which was significant compared to placebo. In chronic migraine, eptinezumab reduced monthly migraine days by approximately 8 days, also significant compared to placebo. More patients who received eptinezumab experienced at least 75% reduction in monthly migraine days compared to placebo, resulting in a number needed to treat as low as 6, depending on the study population and the dose. The preventive impact was noticed day one post-infusion. The most common treatment-emergent adverse events were nausea and fatigue, and there was a low incidence of hypersensitivity or study withdrawal. Eptinezumab is the fourth Calcitonin Gene-related Peptide monoclonal antibody to receive Federal Drug Administration approval. Its delivery as a quarterly infusion sets it apart from the other agents in this class. As an infusion, eptinezumab has a quick onset of action that may prove especially beneficial to those with severe or refractory episodic or chronic migraines, despite the perceived increased direct and indirect cost of an infusion.
| S-EPMC8511911 | biostudies-literature
Project description:ObjectiveTo summarize the pharmacology of the calcitonin peptide family of receptors and explore their relationship to migraine and current migraine therapies.BackgroundTherapeutics that dampen calcitonin gene-related peptide (CGRP) signaling are now in clinical use to prevent or treat migraine. However, CGRP belongs to a broader peptide family, including the peptides amylin and adrenomedullin. Receptors for this family are complex, displaying overlapping pharmacologic profiles. Despite the focus on CGRP and the CGRP receptor in migraine research, recent evidence implicates related peptides and receptors in migraine.MethodsThis narrative review summarizes literature encompassing the current pharmacologic understanding of the calcitonin peptide family, and the evidence that links specific members of this family to migraine and migraine-like behaviors.ResultsRecent work links amylin and adrenomedullin to migraine-like behavior in rodent models and migraine-like attacks in individuals with migraine. We collate novel information that suggests females may be more sensitive to amylin and CGRP in the context of migraine-like behaviors. We report that drugs designed to antagonize the canonical CGRP receptor also antagonize a second CGRP-responsive receptor and speculate as to whether this influences therapeutic efficacy. We also discuss the specificity of current drugs with regards to CGRP isoforms and how this may influence therapeutic profiles. Lastly, we emphasize that receptors related to, but distinct from, the canonical CGRP receptor may represent underappreciated and novel drug targets.ConclusionMultiple peptides within the calcitonin family have been linked to migraine. The current focus on CGRP and its canonical receptor may be obscuring pathways to further therapeutics. Drug discovery schemes that take a wider view of the receptor family may lead to the development of new anti-migraine drugs with favorable clinical profiles. We also propose that understanding these related peptides and receptors may improve our interpretation regarding the mechanism of action of current drugs.
| S-EPMC9613588 | biostudies-literature
Project description:The calcitonin gene-related peptide (CGRP) is implicated in the pathogenesis of several pain-related syndromes, including migraine. Targeting CGRP and its receptor by their antagonists and antibodies was a breakthrough in migraine therapy, but the need to improve efficacy and limit the side effects of these drugs justify further studies on the regulation of CGRP in migraine. The expression of the CGRP encoding gene, CALCA, is modulated by epigenetic modifications, including the DNA methylation, histone modification, and effects of micro RNAs (miRNAs), circular RNAs, and long-coding RNAs (lncRNAs). On the other hand, CGRP can change the epigenetic profile of neuronal and glial cells. The promoter of the CALCA gene has two CpG islands that may be specifically methylated in migraine patients. DNA methylation and lncRNAs were shown to play a role in the cell-specific alternative splicing of the CALCA primary transcript. CGRP may be involved in changes in neural cytoarchitecture that are controlled by histone deacetylase 6 (HDAC6) and can be related to migraine. Inhibition of HDAC6 results in reduced cortical-spreading depression and a blockade of the CGRP receptor. CGRP levels are associated with the expression of several miRNAs in plasma, making them useful peripheral markers of migraine. The fundamental role of CGRP in inflammatory pain transmission may be epigenetically regulated. In conclusion, epigenetic connections of CGRP should be further explored for efficient and safe antimigraine therapy.
| S-EPMC9181031 | biostudies-literature
Project description:ObjectiveCalcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRP-mediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia.MethodsMiddle cerebral artery was occluded for 12 to 60 minutes in mice. We compared infarct risk and volumes, collateral flow, and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1-1mg/kg) or rimegepant (single doses of 10-100mg/kg) versus vehicle. We also determined their potency on CGRP-induced relaxations in mouse and human vessels, in vitro.ResultsOlcegepant (1mg/kg, single dose) increased infarct risk after 12- to 20-minute occlusions mimicking transient ischemic attacks (14/19 vs 6/18 with vehicle, relative risk = 2.21, p < 0.022), and doubled infarct volumes (p < 0.001) and worsened neurological deficits (median score = 9 vs 5 with vehicle, p = 0.008) after 60-minute occlusion. Ten daily doses of 0.1 to 1mg/kg olcegepant yielded similar results. Rimegepant 10mg/kg increased infarct volumes by 60% after 20-minute ischemia (p = 0.03); 100mg/kg caused 75% mortality after 60-minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1mg/kg increased infarct size after 30-minute occlusion (1.6-fold, p = 0.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10-fold more potent than rimegepant on CGRP-induced relaxations in mouse aorta.InterpretationGepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition. ANN NEUROL 2020;88:771-784.
| S-EPMC7540520 | biostudies-literature
Project description:Migraine is a common neurologic disorder characterized by attacks consisting of unilateral, throbbing headache accompanied by photophobia, phonophobia, and nausea which remarkably reduces the patients' quality of life. Not migraine-specific non-steroidal anti-inflammatory drugs (NSAIDs) are effective in patients affected by mild episodic migraine whilst in moderate or severe episodic migraine and in chronic migraineurs triptans and preventative therapies are needed. Since these treatments are endowed with serious side effects and have limited effectiveness new pharmacological approaches have been investigated. The demonstrated pivotal role of calcitonin gene-related peptide (CGRP) has fostered the development of CGRP antagonists, unfortunately endowed with liver toxicity, and monoclonal antibodies (mAbs) toward circulating CGRP released during migraine attack or targeting its receptor. Currently, four mAbs, eptinezumab, fremanezumab, galcanezumab for CGRP and erenumab for CGRP canonical receptor, have been studied in clinical trials for episodic and chronic migraine. Apart from the proven effectiveness, these antibodies have resulted well tolerated and could improve the compliance of the patients due to their long half-lives allowing less frequent administrations. This study aims at investigating the still poorly clear pathogenesis of migraine and the potential role of anti-CGRP mAbs in the scenario of prophylaxis of migraine.
| S-EPMC6465320 | biostudies-literature
Project description:?-Calcitonin gene-related peptide (?-CGRP) is a regulatory neuropeptide of 37 amino acids. It is widely distributed in the central and peripheral nervous system, predominantly in cell bodies of the dorsal root ganglion (DRG). It is the most potent vasodilator known to date and has inotropic and chronotropic effects. Using pharmacological and genetic approaches, our laboratory and other research groups established the protective role of ?-CGRP in various cardiovascular diseases such as heart failure, experimental hypertension, myocardial infarction, and myocardial ischemia/reperfusion injury (I/R injury). ?-CGRP acts as a depressor to attenuate the rise in blood pressure in three different models of experimental hypertension: (1) DOC-salt, (2) subtotal nephrectomy-salt, and (3) L-NAME-induced hypertension during pregnancy. Subcutaneous administration of ?-CGRP lowers the blood pressure in hypertensive and normotensive humans and rodents. Recent studies also demonstrated that an ?-CGRP analog, acylated ?-CGRP, with extended half-life (~7 h) reduces blood pressure in Ang-II-induced hypertensive mouse, and protects against abdominal aortic constriction (AAC)-induced heart failure. Together, these studies suggest that ?-CGRP, native or a modified form, may be a potential therapeutic agent to treat patients suffering from cardiac diseases.
| S-EPMC6614340 | biostudies-literature