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https://www.readbyqxmd.com/read/29869205/cgrp-and-migraine-the-role-of-blocking-calcitonin-gene-related-peptide-ligand-and-receptor-in-the-management-of-migraine
#1
Kasra Maasumi, Rebecca L Michael, Alan M Rapoport
Migraine is a highly prevalent, complex neurological disorder. The burden of disease and the direct/indirect annual costs are enormous. Thus far, treatment options have been inadequate and mostly based on trial and error, leaving a significant unmet need for effective therapies. While the underlying pathophysiology of migraine is incompletely understood, blocking the calcitonin gene-related peptide (CGRP) using monoclonal antibodies targeting CGRP or its receptor and small molecule CGRP receptor antagonists (gepants) have emerged as a promising therapeutic opportunity for the management of migraine...
June 4, 2018: Drugs
https://www.readbyqxmd.com/read/29848264/the-therapeutic-impact-of-new-migraine-discoveries
#2
Melinda Lukács, Janos Tajti, Ferenc Fülöp, Jozsef Toldi, Lars Edvinsson, Laszlo Vécsei
BACKGROUND: Migraine is one the most disabling neurological conditions and associates with high socio-economic costs. Though certain aspects of the pathomechanism of migraine are still incompletely understood, the leading hypothesis implicates the role of the activation of the trigeminovascular system. Triptans are considered the current gold standard therapy for migraine attacks; however, their use in clinical practice is limited. Prophylactic treatment includes non-specific approaches for migraine prevention...
May 29, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29802544/dihydroergotamine-inhibits-the-vasodepressor-sensory-cgrpergic-outflow-by-prejunctional-activation-of-%C3%AE-2-adrenoceptors-and-5-ht-1-receptors
#3
Abimael González-Hernández, Jair Lozano-Cuenca, Bruno A Marichal-Cancino, Antoinette MaassenVanDenBrink, Carlos M Villalón
BACKGROUND: Dihydroergotamine (DHE) is an antimigraine drug that produces cranial vasoconstriction and inhibits trigeminal CGRP release; furthermore, it inhibits the vasodepressor sensory CGRPergic outflow, but the receptors involved remain unknown. Prejunctional activation of α2A/2C -adrenergic, serotonin 5-HT1B/1F , or dopamine D2 -like receptors results in inhibition of this CGRPergic outflow. Since DHE displays affinity for these receptors, this study investigated the pharmacological profile of DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow...
May 25, 2018: Journal of Headache and Pain
https://www.readbyqxmd.com/read/29802484/characterization-of-the-trigeminovascular-actions-of-several-adenosine-a-2a-receptor-antagonists-in-an-in-vivo-rat-model-of-migraine
#4
Kristian A Haanes, Alejandro Labastida-Ramírez, Kayi Y Chan, René de Vries, Brian Shook, Paul Jackson, Jimmy Zhang, Christopher M Flores, Alexander H J Danser, Carlos M Villalón, Antoinette MaassenVanDenBrink
BACKGROUND: Migraine is considered a neurovascular disorder, but its pathophysiological mechanisms are not yet fully understood. Adenosine has been shown to increase in plasma during migraine attacks and to induce vasodilation in several blood vessels; however, it remains unknown whether adenosine can interact with the trigeminovascular system. Moreover, caffeine, a non-selective adenosine receptor antagonist, is included in many over the counter anti-headache/migraine treatments. METHODS: This study used the rat closed cranial window method to investigate in vivo the effects of the adenosine A2A receptor antagonists with varying selectivity over A1 receptors; JNJ-39928122, JNJ-40529749, JNJ-41942914, JNJ-40064440 or JNJ-41501798 (0...
May 25, 2018: Journal of Headache and Pain
https://www.readbyqxmd.com/read/29730242/potentiation-of-capsaicin-induced-neurogenic-inflammation-by-5-ht7-receptors-in-the-rat-hind-paw-involvement-of-calcitonin-gen-related-peptide
#5
Luis D Arreola-Peralta, Frida Altamirano-Reyna, Deni M Galindo-González, Jessica G Solis-Anguiano, Enza Lacivita, Marcello Leopoldo, José A Terrón
A decrease in the activation threshold of primary sensory neurons to transient receptor potential V1 (TRPV1) stimulation by serotonin 5-HT7 receptors has been reported but no confirmation if this might translate into facilitation of neurogenic inflammation has been provided. We analysed the modulation of capsaicin (CAP)-induced neurogenic inflammation in the rat hind paw by the selective 5-HT7 receptor agonist, LP-44, and the involvement of calcitonin gen-related peptide (CGRP) in this effect. Animals received intra-plantar injections (30 μl) of vehicle, CAP (0...
May 3, 2018: Peptides
https://www.readbyqxmd.com/read/29719223/the-transient-receptor-potential-ankyrin-type-1-plays-a-critical-role-in-cortical-spreading-depression
#6
Liwen Jiang, Yan Wang, Yuewei Xu, Dongqing Ma, Minyan Wang
The transient receptor potential ankyrin type-1 (TRPA1) channels have been proposed as a potential target for migraine therapy. Yet the role of cortical TRPA1 channels in migraine mechanism has not been fully understood. Cortical spreading depression (CSD) is known as an underlying cause of migraine aura. The aim of this study is to investigate if cortical TRPA1 activity is required for CSD genesis and propagation. A mouse brain slice CSD model with intrinsic optical imaging was applied for TRPA1 signaling pharmacology...
April 29, 2018: Neuroscience
https://www.readbyqxmd.com/read/29691490/cgrp-as-the-target-of-new-migraine-therapies-successful-translation-from-bench-to-clinic
#7
REVIEW
Lars Edvinsson, Kristian Agmund Haanes, Karin Warfvinge, Diana N Krause
Treatment of migraine is on the cusp of a new era with the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are expected to receive approval for use in migraine headache in 2018 and 2019. CGRP-related therapies offer considerable improvements over existing drugs as they are the first to be designed specifically to act on the trigeminal pain system, they are more specific and they seem to have few or no adverse effects...
June 2018: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/29653090/vascular-and-molecular-pharmacology-of-the-metabolically-stable-cgrp-analogue-sax
#8
Majid Sheykhzade, Bahareh Abdolalizadeh, Cassandra Koole, Darryl Scott Pickering, Karin Dreisig, Sara Ellinor Johansson, Balsam Kadri Abboud, Rasmus Dreier, Jais Oliver Berg, Jørgen Lykke Jeppesen, Patrick M Sexton, Lars Edvinsson, Denise Wootten, Anette Sams
The main purpose of this study was to compare in vitro pharmacological properties of human αCGRP (CGRP) and a recently discovered metabolically stable CGRP analogue, SAX, in isolated rat and human artery segments. In rat, CGRP and SAX induced similar vasodilatory responses in isolated mesenteric artery with the potency of SAX being lower than that of CGRP (vasodilatory pEC50 8.2 ± 0.12 and 9.0 ± 0.11, respectively). A corresponding difference in receptor binding affinity of SAX and CGRP was determined in rat cerebral membranes (pKi 8...
June 15, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29617678/increased-asics-expression-via-the-camkii-creb-pathway-in-a-novel-mouse-model-of-trigeminal-pain
#9
Yan Wang, Xiujuan Fu, Lifang Huang, Xi Wang, Zuneng Lu, Fan Zhu, Zheman Xiao
BACKGROUND/AIMS: Migraine is a disabling condition that severely impacts socioeconomic function and quality of life. The focus of this study was to develop a mouse model of trigeminal pain that mimics migraine. METHODS: After undergoing dural cannulation surgery, mice were treated with repeated dural doses of an acidic solution to induce trigeminal pain. RESULTS: The method elicited intermittent, head-directed wiping and scratching as well as the expression of both the c-FOS gene in the spinal trigeminal nucleus caudalis and calcitonin gene related peptide (CGRP) in the periaqueductal grey matter...
2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29616830/cgrp-a-target-for-acute-therapy-in-migraine-clinical-data
#10
Roberta Messina, Peter J Goadsby
Background A better understanding of the mechanisms underlying the migraine attack has reinforced the concept that migraine is a complex brain disease, and has paved the way for the development of new migraine specific acute treatments. In recent years, targeting the calcitonin gene-related peptide and its receptors has been one of the most promising pharmacological strategies for both acute and preventive treatment of migraine. Findings Randomized double-blind placebo-controlled trials have demonstrated the superiority of small molecule calcitonin gene-related peptide receptor antagonists (gepants) over placebo in treating acute migraine attacks measured as the two-hour pain free endpoint...
January 1, 2018: Cephalalgia: An International Journal of Headache
https://www.readbyqxmd.com/read/29616344/novel-pharmacological-nonopioid-therapies-in-chronic-pain
#11
REVIEW
Alan David Kaye, Elyse M Cornett, Brendon Hart, Shilpadevi Patil, Andrew Pham, Matthew Spalitta, Kenneth F Mancuso
PURPOSE OF REVIEW: Opioid use and abuse has led to a worldwide opioid epidemic. And while opioids are clinically useful when appropriately indicated, they are associated with a wide range of dangerous side effects and whether they are effective at treating or eliminating chronic pain is controversial. There has long been a need for the development of nonopioid alternative treatments for patients that live in pain, and until recently, only a few effective treatments were available. Today, there are a wide range of nonopioid treatments available including NSAIDs, acetaminophen, corticosteroids, nerve blocks, SSRIs, neurostimulators, and anticonvulsants...
April 3, 2018: Current Pain and Headache Reports
https://www.readbyqxmd.com/read/29588250/a-novel-role-for-lymphotactin-xcl1-signaling-in-the-nervous-system-xcl1-acts-via-its-receptor-xcr1-to-increase-trigeminal-neuronal-excitability
#12
Emma V Bird, Tommaso Iannitti, Claire R Christmas, Ilona Obara, Veselin I Andreev, Anne E King, Fiona M Boissonade
Chemokines are known to have a role in the nervous system, influencing a range of processes including the development of chronic pain. To date there are very few studies describing the functions of the chemokine lymphotactin (XCL1) or its receptor (XCR1) in the nervous system. We investigated the role of the XCL1-XCR1 axis in nociceptive processing, using a combination of immunohistochemical, pharmacological and electrophysiological techniques. Expression of XCR1 in the rat mental nerve was elevated 3 days following chronic constriction injury (CCI), compared with 11 days post-CCI and sham controls...
May 21, 2018: Neuroscience
https://www.readbyqxmd.com/read/29572067/independent-roles-of-cgrp-in-cardioprotection-and-hemodynamic-regulation-in-ischemic-postconditioning
#13
Zheng Guo, Na Liu, Lu Chen, Xin Zhao, Mu-Rong Li
Calcitonin gene-related peptide (CGRP) may participate in ischemic post-conditioning (IPost) attenuating myocardial ischemia/reperfusion injury. However, the molecular mechanism underlying the effect of CGRP is still elusive. In this study, we evaluated the difference in hemodynamics, infarct size and CGRP in myocardium and serum of rats after acute myocardial ischemia/reperfusion with and without IPost. A specific antagonist of CGRP receptor, CGRP8-37 was employed to testify the role of endogenous CGRP in IPost...
June 5, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29556965/targeted-cgrp-small-molecule-antagonists-for-acute-migraine-therapy
#14
REVIEW
Philip R Holland, Peter J Goadsby
Migraine is a highly prevalent, severe, and disabling neurological condition with a significant unmet need for effective acute therapies. Patients (~50%) are dissatisfied with their currently available therapies. Calcitonin gene-related peptide (CGRP) has emerged as a key neuropeptide involved in the pathophysiology of migraines. As reviewed in this manuscript, a number of small molecule antagonists of the CGRP receptor have been developed for migraine therapy. Incredibly, the majority of the clinical trials conducted have proven positive, demonstrating the importance of this signalling pathway in migraine...
April 2018: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
https://www.readbyqxmd.com/read/29535050/trpa1-and-cgrp-antagonists-counteract-vesicant-induced-skin-injury-and-inflammation
#15
Satyanarayana Achanta, Narendranath Reddy Chintagari, Marian Brackmann, Shrilatha Balakrishna, Sven-Eric Jordt
The skin is highly sensitive to the chemical warfare agent in mustard gas, sulfur mustard (SM) that initiates a delayed injury response characterized by erythema, inflammation and severe vesication (blistering). Although SM poses a continuing threat, used as recently as in the Syrian conflict, no mechanism-based antidotes against SM are available. Recent studies demonstrated that Transient Receptor Potential Ankyrin 1 (TRPA1), a chemosensory cation channel in sensory nerves innervating the skin, is activated by SM and 2-chloroethyl ethyl sulfide (CEES), an SM analog, in vitro, suggesting it may promote vesicant injury...
March 10, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29532195/the-big-cgrp-flood-sources-sinks-and-signalling-sites-in-the-trigeminovascular-system
#16
REVIEW
Karl Messlinger
BACKGROUND: Calcitonin gene-related peptide (CGRP) has long been a focus of migraine research, since it turned out that inhibition of CGRP or CGRP receptors by antagonists or monoclonal IgG antibodies was therapeutic in frequent and chronic migraine. This contribution deals with the questions, from which sites CGRP is released, where it is drained and where it acts to cause its headache proliferating effects in the trigeminovascular system. RESULTS: The available literature suggests that the bulk of CGRP is released from trigeminal afferents both in meningeal tissues and at the first synapse in the spinal trigeminal nucleus...
March 12, 2018: Journal of Headache and Pain
https://www.readbyqxmd.com/read/29492510/-effect-of-different-concentrations-of-calcitonin-gene-related-peptide-on-the-long-term-potentiation-in-hippocampus-of-mice
#17
Xin Wu, Wan-Jun Zheng, Ming-Hui Lv, Shao-Hua Su, Song-Jiang Zhang, Jian-Feng Gao
The purpose of this study was to explore the effects of different concentrations of calcitonin gene-related peptide (CGRP) on long-term potentiation (LTP) in the hippocampus of mice. C57BL/6J mice (30 days old) were randomly divided into control group, three CGRP groups, and CGRP + CGRP8-37 group (10 mice for each group). Different concentrations of CGRP (50, 100 and 200 nmol/L) were given to the hippocampal slices of mice. The presynaptic release of neurotransmitters and the induction of LTP were measured by extracellular field recording techniques...
February 25, 2018: Sheng Li Xue Bao: [Acta Physiologica Sinica]
https://www.readbyqxmd.com/read/29465314/endogenously-generated-arachidonate-derived-ligands-for-trpv1-induce-cardiac-protection-in-sepsis
#18
Jianmin Chen, Alexander J P Hamers, Michaela Finsterbusch, Gianmichele Massimo, Maleeha Zafar, Roger Corder, Romain A Colas, Jesmond Dalli, Christoph Thiemermann, Amrita Ahluwalia
The severity of cardiac dysfunction predicts mortality in sepsis. Activation of transient receptor potential vanilloid receptor type (TRPV)-1, a predominantly neuronal nonselective cation channel, has been shown to improve outcome in sepsis and endotoxemia. However, the role of TRPV1 and the identity of its endogenous ligands in the cardiac dysfunction caused by sepsis and endotoxemia are unknown. Using TRPV1-/- and TRPV1+/+ mice, we showed that endogenous activation of cardiac TRPV1 during sepsis is key to limiting the ensuing cardiac dysfunction...
February 20, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29435045/the-protective-effects-of-rutaecarpine-on-acute-pancreatitis
#19
Lu Yan, Qing-Fu Li, Yan-Ting Rong, Yong-Heng Chen, Zhao-Hong Huang, Zhi-Zhi Wang, Jie Peng
Acute pancreatitis (AP) is the acute inflammation of the pancreas. The morbidity of AP has increased in recent years. Certain patients eventually develop severe AP (SAP), which rapidly progresses to multiple organ dysfunction; the incidence of this occurring in patients with AP is 20-30%. To date, no specific drugs or methods exist to treat this disease. Rutaecarpine relaxes vascular smooth muscle by stimulating calcitonin gene-related peptide (CGRP) release via activation of vanilloid receptor subtype 1 (VR1)...
March 2018: Oncology Letters
https://www.readbyqxmd.com/read/29430561/the-cgrp-receptor-antagonist-bibn4096-inhibits-prolonged-meningeal-afferent-activation-evoked-by-brief-local-k-stimulation-but-not-cortical-spreading-depression-induced-afferent-sensitization
#20
Jun Zhao, Dan Levy
Introduction: Cortical spreading depression (CSD) is believed to promote migraine headache by enhancing the activity and mechanosensitivity of trigeminal intracranial meningeal afferents. One putative mechanism underlying this afferent response involves an acute excitation of meningeal afferents by cortical efflux of K+ and the ensuing antidromic release of proinflammatory sensory neuropeptides, such as calcitonin gene-related peptide (CGRP). Objectives: We sought to investigate whether (1) a brief meningeal K+ stimulus leads to CGRP-dependent enhancement of meningeal afferent responses and (2) CSD-induced meningeal afferent activation and sensitization involve CGRP receptor signaling...
January 2018: Pain Reports (Baltimore, Md.)
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