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CGRP antagonists

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https://www.readbyqxmd.com/read/29653090/vascular-and-molecular-pharmacology-of-the-metabolically-stable-cgrp-analogue-sax
#1
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 analog, 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...
April 10, 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
#2
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...
March 28, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29616830/cgrp-a-target-for-acute-therapy-in-migraine-clinical-data
#3
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
#4
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-signalling-in-the-nervous-system-xcl1-acts-via-its-receptor-xcr1-to-increase-trigeminal-neuronal-excitability
#5
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 11days post-CCI and sham controls...
March 24, 2018: Neuroscience
https://www.readbyqxmd.com/read/29572067/independent-roles-of-cgrp-in-cardioprotection-and-hemodynamic-regulation-in-ischemic-postconditioning
#6
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...
March 20, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29556965/targeted-cgrp-small-molecule-antagonists-for-acute-migraine-therapy
#7
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...
March 19, 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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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.)
https://www.readbyqxmd.com/read/29416550/the-wnt7b-%C3%AE-catenin-signaling-pathway-is-involved-in-the-protective-action-of-calcitonin-gene-related-peptide-on-hyperoxia-induced-lung-injury-in-premature-rats
#14
Shaohua Wang, Hongxing Dang, Feng Xu, Jian Deng, Xuemei Zheng
Background: Calcitonin gene-related peptide (CGRP) can protect against hyperoxia-induced lung injury, making the upregulation of CGRP a potential therapeutic approach for this type of injury. However, the effects of CGRP on the Wnt7b/β-catenin signaling pathway are unclear. In this study, we investigated the roles of CGRP and the Wnt7b/β-catenin signaling pathway in hyperoxia-induced lung injury. Methods: Premature Sprague Dawley (SD) rats were exposed to 21, 40, 60 and 95% oxygen for 3, 7 and 14 days...
2018: Cellular & Molecular Biology Letters
https://www.readbyqxmd.com/read/29396376/calcitonin-gene-related-peptide-is-a-potent-inducer-of-oedema-in-rat-orofacial-tissue
#15
Bárbara F G de Queiroz, Marcella P A de Almeida, Y S Bakhle, Janetti N Francischi
BACKGROUND AND AIMS: This study aimed to assess the potential of calcitonin-gene related peptide (CGRP), a neuropeptide released from sensory nerves, to induce oedema in orofacial tissue. EXPERIMENTAL APPROACH: Wistar rats (150-200 g) anesthetized with isoflurane were injected intraorally with CGRP (100 μl; 8-33 pmol) in the right side of the mouth. The contralateral side was injected with the same volume of physiological saline. Increased cheek thickness (in mm), as a measure of oedema formation, was assayed bilaterally with a digital caliper before (T = 0) and up to 24 h following injection of CGRP...
January 30, 2018: Neuropeptides
https://www.readbyqxmd.com/read/29393417/involvement-of-trpv1-in-the-expression-and-release-of-calcitonin-gene-related-peptide-induced-by-rutaecarpine
#16
Yongmei Yang, Qingquan Chen, Sujie Jia, Limei He, Aiping Wang, Dai Li, Yuanjian Li, Xiaohui Li
The traditional Chinese herb Wu-Chu-Yu has been used to treat hypertension for hundreds of years. A previous study indicated that rutaecarpine was the effective component of Wu‑Chu‑Yu, which lowered blood pressure by elevating the expression level of calcitonin gene‑related peptide (CGRP). The present study was performed to investigate the role of transient receptor potential cation channel subfamily V member 1 (TRPV1) in CGRP expression and release induced by rutaecarpine. Dorsal root ganglia (DRG) obtained from Sprague‑Dawley rats were cultured to analyze the mRNA expression and release of CGRP...
January 25, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29382888/a-unique-inbred-rat-strain-with-sustained-cephalic-hypersensitivity-as-a-model-of-chronic-migraine-like-pain
#17
Gordon Munro, Steffen Petersen, Inger Jansen-Olesen, Jes Olesen
Animal models of migraine-like pain enabling ongoing study of behaviour typically involve the systemic administration of chemical vasodilators or dural administration of inflammatory algogens. However, neither method mediates prolonged effects on behavior indicative of enduring pathophysiological changes occurring within dural or trigeminal pain circuits. We generated successive generations of a unique inbred rat strain, spontaneous trigeminal allodynia (STA) rats, previously reported to exhibit an episodic migraine-like behavioural phenotype...
January 30, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29363552/probing-the-mechanism-of-receptor-activity-modifying-protein-modulation-of-gpcr-ligand-selectivity-through-rational-design-of-potent-adrenomedullin-and-calcitonin-gene-related-peptide-antagonists
#18
Jason M Booe, Margaret L Warner, Amanda M Roehrkasse, Debbie L Hay, Augen A Pioszak
Binding of the vasodilator peptides adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) to the class B GPCR calcitonin receptor-like receptor (CLR) is modulated by receptor activity-modifying proteins (RAMP). RAMP1 favors CGRP, whereas RAMP2 and RAMP3 favor AM. Crystal structures of peptide-bound RAMP1/2-CLR extracellular domain (ECD) heterodimers suggested RAMPs alter ligand preference through direct peptide contacts and allosteric modulation of CLR. Here, we probed this dual mechanism through rational structure-guided design of AM and CGRP antagonist variants...
January 23, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29353067/antinociception-of-the-spirocyclopiperazinium-salt-compound-lxm-15-via-activating-%C3%AE-7-nachr-and-m4-machr-and-inhibiting-camkii%C3%AE-camp-creb-cgrp-signalling-pathway-in-mice
#19
Hua Yang, Qi Sun, Yingying Liang, Yimin Jiang, Runtao Li, Jia Ye
The aim of this study was to investigate the analgesic effect of the spirocyclopiperazinium salt compound LXM-15 by intragastric administration in thermal and chemical pain models and further to elucidate the possible molecular mechanisms. The results showed that LXM-15 exerted significant antinociception in hot-plate test, formalin test and acetic acid writhing test. Western blot analysis showed that LXM-15 significantly reduced the upregulation of phosphorylation of calcium/calmodulin -dependent protein kinase IIα (CaMKIIα) and cAMP response element-binding protein (CREB), and further decreased the elevation of calcitonin gene related peptide (CGRP) in the dorsal root ganglion (DRG) and spinal cord in mice...
April 2018: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29350125/current-management-migraine-headache
#20
Stephen D Silberstein
Migraine varies in its frequency, severity, and impact; treatment should consider these variations and the patient's needs and goals. Migraine pharmacologic treatment may be acute (abortive) or preventive (prophylactic), and patients often require both. New medication devices are available or in development, including an intracutaneous, microneedle system of zolmitriptan and sumatriptan, and breath-powered powder sumatriptan intranasal treatment. Lasmiditan, a 5-HT1F receptor agonist, is in development for acute treatment, as are small molecule calcitonin gene-related peptide (CGRP) receptor antagonists (Gepants) for acute and preventive treatment...
December 2017: CNS Spectrums
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