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CGRP antagonists

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https://www.readbyqxmd.com/read/28446517/a-novel-%C3%AE-calcitonin-gene-related-peptide-analogue-protects-against-end-organ-damage-in-experimental-hypertension-cardiac-hypertrophy-and-heart-failure
#1
Aisah A Aubdool, Pratish Thakore, Fulye Argunhan, Sarah-Jane Smillie, Moritz Schnelle, Salil Srivastava, Khadija M Alawi, Elena Wilde, Jennifer Mitchell, Keith Farrell-Dillon, Daniel A Richards, Giuseppe Maltese, Richard C Siow, Manasi Nandi, James E Clark, Ajay M Shah, Anette Sams, Susan D Brain
Background -Research into the therapeutic potential of α-calcitonin gene-related peptide (α-CGRP) has been limited due to its peptide nature and short half-life. Here, we evaluate whether a novel potent and long lasting (t½ ≥ 7h) acylated α-CGRP analogue (αAnalogue) could alleviate and reverse cardiovascular disease in two distinct murine models of hypertension and heart failure in vivoMethods -The ability of the αAnalogue to act selectively via the CGRP pathway was shown in skin using a CGRP receptor antagonist...
April 26, 2017: Circulation
https://www.readbyqxmd.com/read/28413467/calcitonin-gene-related-peptide-protects-type-ii-alveolar-epithelial-cells-from-hyperoxia-induced-dna-damage-and-cell-death
#2
Hongmin Fu, Tiesong Zhang, Rongwei Huang, Zhen Yang, Chunming Liu, Ming Li, Fang Fang, Feng Xu
Hyperoxia therapy for acute lung injury (ALI) may unexpectedly lead to reactive oxygen species (ROS) production and cause additional ALI. Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide that regulates inflammasome activation. However, the role of CGRP in DNA damage during hyperoxia is unclear. Therefore, the aim of the present study was to investigate the effects of CGRP on DNA damage and the cell death of alveolar epithelial type II cells (AEC II) exposed to 60% oxygen. AEC II were isolated from 19-20 gestational day fetal rat lungs and were exposed to air or to 60% oxygen during treatment with CGRP or the specific CGRP receptor antagonist CGRP8-37...
April 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28376659/kappa-opioid-receptor-antagonists-a-possible-new-class-of-therapeutics-for-migraine-prevention
#3
Jennifer Y Xie, Milena De Felice, Caroline M Kopruszinski, Nathan Eyde, Justin LaVigne, Bethany Remeniuk, Pablo Hernandez, Xu Yue, Naomi Goshima, Michael Ossipov, Tamara King, John M Streicher, Edita Navratilova, David Dodick, Hugh Rosen, Ed Roberts, Frank Porreca
Background Stress is the most commonly reported migraine trigger. Dynorphin, an endogenous opioid peptide acting preferentially at kappa opioid receptors (KORs), is a key mediator of stress responses. The aim of this study was to use an injury-free rat model of functional cephalic pain with features of migraine and medication overuse headache (MOH) to test the possible preventive benefit of KOR blockade on stress-induced cephalic pain. Methods Following sumatriptan priming to model MOH, rats were hyper-responsive to environmental stress, demonstrating delayed cephalic and extracephalic allodynia and increased levels of CGRP in the jugular blood, consistent with commonly observed clinical outcomes during migraine...
January 1, 2017: Cephalalgia: An International Journal of Headache
https://www.readbyqxmd.com/read/28369749/olcegepant-blocks-neurogenic-and-non-neurogenic-cgrpergic-vasodepressor-responses-and-facilitates-noradrenergic-vasopressor-responses-in-pithed-rats
#4
V H Avilés-Rosas, E Rivera-Mancilla, B A Marichal-Cancino, G Manrique-Maldonado, A H Altamirano-Espinoza, A MaassenVanDenBrink, C M Villalón
BACKGROUND AND PURPOSE: Olcegepant (BIBN4096BS) is a selective non-peptide CGRP receptor antagonist with acute antimigraine properties. Since systemic vascular tone is modulated by perivascular (primary sensory CGRPergic and sympathetic) nerves, this randomized study investigated in pithed rats the effect of acute intravenous (i.v.) treatment with olcegepant on the neurogenic and non-neurogenic: (i) CGRPergic vasodepressor responses; and (ii) noradrenergic vasopressor responses. The pithed rat is an experimental model predictive of systemic (cardio) vascular side effects...
March 29, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28364596/cardioprotective-effects-of-calcitonin-gene-related-peptide-in-isolated-rat-heart-and-in-h9c2-cells-via-redox-signaling
#5
Francesca Tullio, Claudia Penna, Karine Cabiale, Saveria Femminò, Marco Galloni, Pasquale Pagliaro
The calcitonin-gene-related-peptide (CGRP) release is coupled to the signaling of Angeli's salt in determining vasodilator effects. However, it is unknown whether CGRP is involved in Angeli's salt cardioprotective effects and which are the mechanisms of protection. We aimed to determine whether CGRP is involved in myocardial protection induced by Angeli's salt. We also analyzed the intracellular signaling pathway activated by CGRP. Isolated rat hearts were pre-treated with Angeli's salt or Angeli's salt plus CGRP8-37, a specific CGRP-receptor antagonist, and subjected to ischemia (30-min) and reperfusion (120-min)...
March 29, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28355142/effects-of-adrenomedullin-and-glucagon-like-peptide-on-distal-flap-necrosis-and-vascularity-the-role-of-receptor-systems-and-nitric-oxide
#6
Betul Cam, Deniz Bagdas, M Ozgur Ozyigit, Engin Sagdilek, Naciye Isbil Buyukcoskun, Kasım Ozluk
OBJECTIVE: Flap necrosis in the distal area due to the deficiency of blood circulation is a major complication in flap treatment. In many previous studies, some natural substances such as chlorogenic acid, adrenomedullin (ADM), and glucagon-like peptide-1 (GLP-1) have been used to improve flap viability via their vasodilator, angiogenic, and antioxidant effects. The aim of this study is to clarify the mechanism through the use of selective antagonists for calcitonin gene-related peptide (CGRP) receptors and GLP-1 receptors such as CGRP-(8-37), exendin-(9-39), respectively, in the flap healing effects of ADM and GLP-1...
March 24, 2017: Wounds: a Compendium of Clinical Research and Practice
https://www.readbyqxmd.com/read/28321564/an-update-on-migraine-current-understanding-and-future-directions
#7
Francesca Puledda, Roberta Messina, Peter J Goadsby
Migraine is a common brain disorder with high disability rates which involves a series of abnormal neuronal networks, interacting at different levels of the central and peripheral nervous system. An increase in the interest around migraine pathophysiology has allowed researchers to unravel certain neurophysiological mechanisms and neurotransmitter involvement culminating in the recent development of novel therapies, which might substantially change the clinical approach to migraine patients. The present review will highlight the current aspects of migraine pathophysiology, covering an understanding of the complex workings of the migraine state and the brain regions responsible for them...
March 20, 2017: Journal of Neurology
https://www.readbyqxmd.com/read/28317098/cgrp-receptor-activity-in-mice-with-global-expression-of-human-receptor-activity-modifying-protein-1
#8
Keegan J Bohn, Baolin Li, Xiaofang Huang, Bianca N Mason, Anne-Sophie Wattiez, Adisa Kuburas, Christopher S Walker, Peiyi Yang, Jianliang Yu, Beverly A Heinz, Kirk W Johnson, Andrew F Russo
BACKGROUND AND PURPOSE: CGRP is a potent vasodilator and nociceptive neuropeptide linked to migraine. CGRP receptors are heterodimers of receptor activity-modifying protein-1 (RAMP1) and either calcitonin receptor-like receptor (CLR), which forms the canonical CGRP receptor, or calcitonin receptor (CTR), which forms the amylin-1 (AMY1 ) receptor. The goal of this study was to test whether transgenic mice globally expressing human RAMP1 (hRAMP1) have increased CGRP receptor activity and whether the receptors are sensitive to the human selective antagonist telcagepant...
March 20, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28306261/asymmetric-synthesis-of-the-major-metabolite-of-a-calcitonin-gene-related-peptide-receptor-antagonist-and-mechanism-of-epoxide-hydrogenolysis
#9
Guanglin Luo, Ling Chen, Charles M Conway, Walter Kostich, Benjamin M Johnson, Alicia Ng, John E Macor, Gene M Dubowchik
An asymmetric synthesis of the major metabolite of the calcitonin gene-related peptide recepotor antagonist BMS-846372 is presented. The variously substituted cyclohepta[b]pyridine ring system represents an underexplored ring system and showed some unexpected chemistry. Reactivities of epoxide and ketone functional groups on the cycloheptane ring were extensively controlled by a remote bulky TIPS group. The rate difference of the hydrogenolysis between two diastereomeric epoxide intermediates shed some light on the mechanism of epoxide hydrogenolysis, and further, deuterium labeling studies revealed more mechanistic details on this well-known chemical transformation for the first time...
March 28, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28254863/bone-pain-induced-by-multiple-myeloma-is-reduced-by-targeting-v-atpase-and-asic3
#10
Masahiro Hiasa, Tatsuo Okui, Yohance M Allette, Matthew S Ripsch, Ge-Hong Sun-Wada, Hiroki Wakabayashi, G David Roodman, Fletcher A White, Toshiyuki Yoneda
Multiple myeloma patients experience severe bone pain (MMBP) that is undertreated and poorly understood. In this study, we studied MMBP in an intratibial mouse xenograft model that employs JJN3 human multiple myeloma cells. In this model, mice develop MMBP associated in bone with increased sprouting of calcitonin gene-related peptide-positive (CGRP(+)) sensory nerves and in dorsal root ganglia (DRG) with upregulation of phosphorylated ERK1/2 (pERK1/2) and pCREB, two molecular indicators of neuron excitation...
March 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28205139/the-potentiating-effect-of-calcitonin-gene-related-peptide-on-transient-receptor-potential-vanilloid-1-activity-and-the-electrophysiological-responses-of-rat-trigeminal-neurons-to-nociceptive-stimuli
#11
Duangthip Chatchaisak, Mark Connor, Anan Srikiatkhachorn, Banthit Chetsawang
Growing evidence suggests that calcitonin gene-related peptide (CGRP) participates in trigeminal nociceptive responses. However, the role of CGRP in sensitization or desensitization of nociceptive transduction remains poorly understood. In this study, we sought to further investigate the CGRP-induced up-regulation of transient receptor potential vanilloid-1 (TRPV1) and the responses of trigeminal neurons to nociceptive stimuli. Rat trigeminal ganglion (TG) organ cultures and isolated trigeminal neurons were incubated with CGRP...
February 15, 2017: Journal of Physiological Sciences: JPS
https://www.readbyqxmd.com/read/28192258/binding-and-functional-pharmacological-characteristics-of-gepant-type-antagonists-in-rat-brain-and-mesenteric-arteries
#12
Majid Sheykhzade, Nilofar Amandi, Monica Vidal Pla, Bahareh Abdolalizadeh, Anette Sams, Karin Warfvinge, Lars Edvinsson, Darryl S Pickering
AIM: The neuropeptide calcitonin gene-related peptide (CGRP) is found in afferent sensory nerve fibers innervating the resistance arteries and plays a pivotal role in a number of neurovascular diseases such as migraine and subarachnoid bleedings. The present study investigates the binding and antagonistic characteristics of small non-peptide CGRP receptor antagonists (i.e. gepants) in isolated rat brain and mesenteric resistance arteries. METHODS: The antagonistic behavior of gepants was investigated in isolated rat mesenteric arteries using a wire myograph setup while binding of gepants to CGRP receptors was investigated in rat brain membranes using a radioligand competitive binding assay...
March 2017: Vascular Pharmacology
https://www.readbyqxmd.com/read/28179394/pathophysiology-of-migraine-a-disorder-of-sensory-processing
#13
REVIEW
Peter J Goadsby, Philip R Holland, Margarida Martins-Oliveira, Jan Hoffmann, Christoph Schankin, Simon Akerman
Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs...
April 2017: Physiological Reviews
https://www.readbyqxmd.com/read/28179153/activation-of-npffr2-leads-to-hyperalgesia-through-the-spinal-inflammatory-mediator-cgrp-in-mice
#14
Ya-Tin Lin, Ho-Ling Liu, Yuan-Ji Day, Che-Chien Chang, Po-Hung Hsu, Jin-Chung Chen
Neuropeptide FF (NPFF) is recognized as an opioid modulating peptide that regulates morphine-induced analgesia. The aim of this study was to delineate the role of NPFFR2 in pain transmission. We found the expression levels of NPFF and NPFFR2 were increased in the lumbar dorsal horn of animals with CFA- and carrageenan-induced inflammation and both NPFFR2 over-expressing transgenic (NPFFR2-Tg) and NPFFR2 agonist-treated mice displayed hyperalgesia. BOLD signals from functional MRI showed that NPFFR2-Tg mice exhibited increased activation of pain-related brain regions after painful stimulation when compared to WT mice...
February 5, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28165287/cgrp-receptor-antagonist-activity-of-olcegepant-depends-on-the-signalling-pathway-measured
#15
Christopher S Walker, Ann C Raddant, Michael J Woolley, Andrew F Russo, Debbie L Hay
Background Calcitonin gene-related peptide (CGRP) is a neuropeptide that acts in the trigeminovascular system and is believed to play an important role in migraine. CGRP activates two receptors that are both present in the trigeminovascular system; the CGRP receptor and the amylin 1 (AMY1) receptor. CGRP receptor antagonists, including olcegepant (BIBN4096BS) and telcagepant (MK-0974), can treat migraine. This study aimed to determine the effectiveness of these antagonists at blocking CGRP receptor signalling in trigeminal ganglia (TG) neurons and transfected CGRP and AMY1 receptors in Cos7 cells, to better understand their mechanism of action...
January 1, 2017: Cephalalgia: An International Journal of Headache
https://www.readbyqxmd.com/read/28053042/induction-of-migraine-like-photophobic-behavior-in-mice-by-both-peripheral-and-central-cgrp-mechanisms
#16
Bianca N Mason, Eric A Kaiser, Adisa Kuburas, Maria-Cristina M Loomis, John A Latham, Leon F Garcia-Martinez, Andrew F Russo
The neuropeptide calcitonin gene-related peptide (CGRP) is a key player in migraine. Although migraine can be treated using CGRP antagonists that act peripherally, the relevant sites of CGRP action remain unknown. To address the role of CGRP both within and outside the CNS, we used CGRP-induced light-aversive behavior in mice as a measure of migraine-associated photophobia. Peripheral (intraperitoneal) injection of CGRP resulted in light-aversive behavior in wild-type CD1 mice similar to aversion seen previously after central (intracerebroventricular) injection...
January 4, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28025094/serotonergic-mechanisms-of-trigeminal-meningeal-nociception-implications-for-migraine-pain
#17
Erkan Kilinc, Cindy Guerrero-Toro, Andrey Zakharov, Carmela Vitale, Max Gubert-Olive, Ksenia Koroleva, Arina Timonina, Liliana L Luz, Irina Shelukhina, Raisa Giniatullina, Fatma Tore, Boris V Safronov, Rashid Giniatullin
Serotonergic mechanisms play a central role in migraine pathology. However, the region-specific effects of serotonin (5-HT) mediated via multiple types of receptors in the nociceptive system are poorly understood. Using extracellular and patch-clamp recordings, we studied the action of 5-HT on the excitability of peripheral and central terminals of trigeminal afferents. 5-HT evoked long-lasting TTX-sensitive firing in the peripheral terminals of meningeal afferents, the origin site of migraine pain. Cluster analysis revealed that in majority of nociceptive fibers 5-HT induced either transient or persistent spiking activity with prevailing delta and theta rhythms...
December 23, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/28001346/analgesic-microneedle-patch-for-neuropathic-pain-therapy
#18
Xi Xie, Conrado Pascual, Christopher Lieu, Seajin Oh, Ji Wang, Bende Zou, Julian Xie, Zhaohui Li, James Xie, David C Yeomans, Mei X Wu, Xinmin Simon Xie
Neuropathic pain caused by nerve injury is debilitating and difficult to treat. Current systemic pharmacological therapeutics for neuropathic pain produce limited pain relief and have undesirable side effects, while current local anesthetics tend to nonspecifically block both sensory and motor functions. Calcitonin gene related peptide (CGRP), a neuropeptide released from sensory nerve endings, appears to play a significant role in chronic neuropathic pain. In this study, an analgesic microneedle (AMN) patch was developed using dissolvable microneedles to transdermally deliver selective CGRP antagonist peptide in a painless manner for the treatment of localized neuropathic pain...
January 24, 2017: ACS Nano
https://www.readbyqxmd.com/read/27940880/cgrp-in-human-models-of-primary-headaches
#19
Håkan Ashina, Henrik Winther Schytz, Messoud Ashina
OBJECTIVE: To review the role of CGRP in human models of primary headaches and to discuss methodological aspects and future directions. DISCUSSION: Provocation experiments demonstrated a heterogeneous CGRP migraine response in migraine patients. Conflicting CGRP plasma results in the provocation experiments are likely due to assay variation; therefore, proper validation and standardization of an assay is needed. To what extent CGRP is involved in tension-type headache and cluster headache is unknown...
December 9, 2016: Cephalalgia: An International Journal of Headache
https://www.readbyqxmd.com/read/27917413/efficacy-of-s-lacosamide-in-preclinical-models-of-cephalic-pain
#20
Aubin Moutal, Nathan Eyde, Edwin Telemi, Ki Duk Park, Jennifer Y Xie, David W Dodick, Frank Porreca, Rajesh Khanna
Migraine is one of the world's most common neurological disorders. Current acute migraine treatments have sub-optimal efficacy and new therapeutic options are needed. Approaches targeting calcitonin gene related peptide (CGRP) signaling are clinically effective but small molecule antagonists have not been advanced due to toxicity. In this study, we explored the axonal growth/specification collapsin response mediator protein 2 (CRMP2) as a novel "druggable" target for inhibiting CGRP release and for potential relevance for treatment of migraine pain...
June 2016: Pain Reports (Baltimore, Md.)
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