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CGRP antagonists

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https://www.readbyqxmd.com/read/27909097/induction-of-migraine-like-photophobic-behavior-in-mice-by-both-peripheral-and-central-cgrp-mechanisms
#1
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. While 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 central nervous system, we used CGRP-induced light aversive behavior in mice as a measure of migraine-associated photophobia. Peripheral (intraperitoneal, IP) injection of CGRP resulted in light aversive behavior in wild-type CD1 mice similar to aversion previously seen following central (intracerebroventricular, ICV) injection...
December 1, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27884929/pro-nociceptive-migraine-mediator-cgrp-provides-neuroprotection-of-sensory-cortical-and-cerebellar-neurons-via-multi-kinase-signaling
#2
Polina A Abushik, Geneviève Bart, Paula Korhonen, Hanna Leinonen, Raisa Giniatullina, Dmitry A Sibarov, Anna-Liisa Levonen, Tarja Malm, Sergei M Antonov, Rashid Giniatullin
BACKGROUND: Blocking the pro-nociceptive action of CGRP is one of the most promising approaches for migraine prophylaxis. The aim of this study was to explore a role for CGRP as a neuroprotective agent for central and peripheral neurons. METHODS: The viability of isolated rat trigeminal, cortical and cerebellar neurons was tested by fluorescence vital assay. Engagement of Nrf2 target genes was analyzed by qPCR. The neuroprotective efficacy of CGRP in vivo was tested in mice using a permanent cerebral ischemia model...
November 24, 2016: Cephalalgia: An International Journal of Headache
https://www.readbyqxmd.com/read/27865545/anti-cgrp-antibodies-block-cgrp-induced-diarrhea-in-mice
#3
Eric A Kaiser, Brandon J Rea, Adisa Kuburas, Brian R Kovacevich, Leon F Garcia-Martinez, Ana Recober, Andrew F Russo
The multifunctional neuropeptide calcitonin gene-related peptide (CGRP) and its receptor are expressed throughout the gastrointestinal tract. Previous studies have shown that CGRP has roles in intestinal motility, water secretion, and inflammation. Furthermore, animal studies have demonstrated CGRP involvement in diarrhea secondary to C. difficile and food allergies. Diarrhea thus provides a convenient bioassay of CGRP activity in the GI system. In this proof of principle study, we report that prophylactic administration of an anti-CGRP antibody is able to block CGRP-induced diarrhea in mice...
November 14, 2016: Neuropeptides
https://www.readbyqxmd.com/read/27834685/antagonism-of-cannabinoid-receptor-1-attenuates-the-anti-inflammatory-effects-of-electroacupuncture-in-a-rodent-model-of-migraine
#4
Hui Zhang, Shengdong He, Youping Hu, Hui Zheng
BACKGROUND: The anti-nociceptive effects of electroacupuncture (EA) in migraine have been documented in multiple randomised controlled trials. Neurogenic inflammation plays a key role in migraine attacks, and the anti-inflammatory effects of acupuncture have been associated with the type 1 cannabinoid (CB1) receptor. OBJECTIVE: To investigate whether CB1 receptors mediate the anti-inflammatory effects of EA on migraine attacks. METHODS: A migraine model was produced in Sprague-Dawley rats by unilateral electrical stimulation of the trigeminal ganglion (TGES)...
December 2016: Acupuncture in Medicine: Journal of the British Medical Acupuncture Society
https://www.readbyqxmd.com/read/27791151/targeting-cyp2j-to-reduce-paclitaxel-induced-peripheral-neuropathic-pain
#5
Marco Sisignano, Carlo Angioni, Chul-Kyu Park, Sascha Meyer Dos Santos, Holger Jordan, Maria Kuzikov, Di Liu, Sebastian Zinn, Stephan W Hohman, Yannick Schreiber, Béla Zimmer, Mike Schmidt, Ruirui Lu, Jing Suo, Dong-Dong Zhang, Stephan M G Schäfer, Martine Hofmann, Ajay S Yekkirala, Natasja de Bruin, Michael J Parnham, Clifford J Woolf, Ru-Rong Ji, Klaus Scholich, Gerd Geisslinger
Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose- and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P450-epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxel-treated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity...
November 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27786243/new-strategies-for-the-treatment-and-prevention-of-primary-headache-disorders
#6
REVIEW
Nathaniel M Schuster, Alan M Rapoport
The primary headache disorders, which include migraine, cluster headache and tension-type headache, are among the most common diseases and leading causes of disability worldwide. The available treatment options for primary headache disorders have unsatisfactory rates of efficacy, tolerability and patient adherence. In this Review, we discuss promising new approaches for the prevention of primary headache disorders, such as monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor, and small-molecule CGRP receptor antagonists...
October 27, 2016: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/27756950/role-of-fosaprepitant-a-neurokinin-type-1-receptor-antagonist-in-morphine-induced-antinociception-in-rats
#7
Pranav Prasoon, Shivani Gupta, Rahul Kumar, Mayank Gautam, Saroj Kaler, Subrata Basu Ray
OBJECTIVES: Opioids such as morphine form the cornerstone in the treatment of moderate to severe pain. However, opioids also produce serious side effects such as tolerance. Fosaprepitant is a substance P (SP) receptor antagonist, which is used for treating chemotherapy-induced nausea and vomiting. SP is an important neuropeptide mediating transmission of pain at the spinal level. Thus, it was hypothesized that combining morphine with fosaprepitant would increase the antinociceptive effect of morphine...
July 2016: Indian Journal of Pharmacology
https://www.readbyqxmd.com/read/27754151/os-29-03-increased-neurokinin-release-from-afferent-renal-nerves-is-accompanied-by-decreased-afferent-electric-activity
#8
Tilmann Ditting, Kristina Rodionova, Sonja Heinlein, Karl Friedrich Hilgers, Christian Ott, Roland Schmieder, Kerstin Amann, Roland Veelken
OBJECTIVE: Afferent renal nerves exhibit a dual function. They influence intrarenal immunological processes by release of neurokinins like CGRP and control central sympathetic outflow via afferent electrical activity. The former seems to be important in renal inflammation whereas the sympathetic modulation by afferent electrical activity is not fully understood in cardiovascular disease and hypertension. Hence, we hypothesized that augmented effects of CGRP in renal inflammation occur with increased afferent renal nerve activity...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27746346/elevated-levels-of-calcitonin-gene-related-peptide-in-upper-spinal-cord-promotes-sensitization-of-primary-trigeminal-nociceptive-neurons
#9
Lauren E Cornelison, Jordan L Hawkins, Paul L Durham
Orofacial pain conditions including temporomandibular disorder (TMD) and migraine are characterized by peripheral and central sensitization of trigeminal nociceptive neurons. The goal of this study was to investigate the role of calcitonin gene-related peptide (CGRP) in promoting bidirectional signaling within the trigeminal system to mediate sensitization of primary nociceptive neurons. Adult male Sprague-Dawley rats were injected intercisternally with CGRP or co-injected with the receptor antagonist CGRP8-37 or KT 5720, a protein kinase A (PKA) inhibitor...
December 17, 2016: Neuroscience
https://www.readbyqxmd.com/read/27643081/os-29-03-increased-neurokinin-release-from-afferent-renal-nerves-is-accompanied-by-decreased-afferent-electric-activity
#10
Tilmann Ditting, Kristina Rodionova, Sonja Heinlein, Karl Friedrich Hilgers, Christian Ott, Roland Schmieder, Kerstin Amann, Roland Veelken
OBJECTIVE: Afferent renal nerves exhibit a dual function. They influence intrarenal immunological processes by release of neurokinins like CGRP and control central sympathetic outflow via afferent electrical activity. The former seems to be important in renal inflammation whereas the sympathetic modulation by afferent electrical activity is not fully understood in cardiovascular disease and hypertension. Hence, we hypothesized that augmented effects of CGRP in renal inflammation occur with increased afferent renal nerve activity...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27553188/targeting-of-calcitonin-gene-related-peptide-action-as-a-new-strategy-for-migraine-treatment
#11
Olga Kuzawińska, Krzysztof Lis, Grzegorz Cessak, Dagmara Mirowska-Guzel, Ewa Bałkowiec-Iskra
Migraine is a chronic, recurrent disorder, characterized by attacks of severe pain, affecting around 1% of adult population. Many studies suggest, that trigeminovascular system plays a key role in pathogenesis of migraine and other primary headaches. Calcitonin gene-related peptide (CGRP) is an endogenous substance, which is regarded a key mediator released from trigeminovascular system after stimulation of sensory nerve endings, responsible for dilatation of peripheral vessels and sensory transmission. CGRP is and extensively studied peptide as one of the most promising targets in migraine drug research...
August 10, 2016: Neurologia i Neurochirurgia Polska
https://www.readbyqxmd.com/read/27525636/capsaicin-sensitive-sensory-nerves-mediate-the-cellular-and-microvascular-effects-of-h2s-via-trpa1-receptor-activation-and-neuropeptide-release
#12
Zsófia Hajna, Éva Sághy, Maja Payrits, Aisah A Aubdool, Éva Szőke, Gábor Pozsgai, István Z Bátai, Lívia Nagy, Dániel Filotás, Zsuzsanna Helyes, Susan D Brain, Erika Pintér
It is supposed that TRPA1 receptor can be activated by hydrogen sulphide (H2S). Here, we have investigated the role of TRPA1 receptor in H2S-induced [Ca(2+)]i increase in trigeminal ganglia (TRG) neurons, and the involvement of capsaicin-sensitive sensory nerves in H2S-evoked cutaneous vasodilatation. [Ca(2+)]i was measured with ratiometric technique on TRG neurons of TRPA1(+/+) and TRPA1(-/-) mice after NaHS, Na2S, allylisothiocyanate (AITC) or KCl treatment. Microcirculatory changes in the ear were detected by laser Doppler imaging in response to topical NaHS, AITC, NaOH, NaSO3 or NaCl...
October 2016: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/27513455/ramp1-suppresses-mucosal-injury-from-dextran-sodium-sulfate-induced-colitis-in-mice
#13
Noriko Kawashima-Takeda, Yoshiya Ito, Nobuyuki Nishizawa, Rei Kawashima, Kiyoshi Tanaka, Kazutake Tsujikawa, Masahiko Watanabe, Masataka Majima
BACKGROUND AND AIMS: Calcitonin gene-related peptide (CGRP) is thought be involved in the modulation of intestinal motility. CGRP receptor is composed of receptor activity-modifying protein (RAMP) 1 combined with calcitonin receptor-like receptor (CRLR) for CGRP. We investigated the role of CGRP in mice with experimentally induced colitis. METHODS: We used dextran sodium sulfate (DSS) to induce colitis in mice. We compared the severity of colitis in wild-type (WT) mice, mice treated with a CGRP receptor antagonist (CGRP8-37 ), and RAMP1 knockout ((-/-) ) mice...
August 11, 2016: Journal of Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/27484028/decompensated-liver-cirrhosis-and-neural-regulation-of-mesenteric-vascular-tone-in-rats-role-of-sympathetic-nitrergic-and-sensory-innervations
#14
Esther Sastre, Laura Caracuel, Isabel Prieto, Pablo Llévenes, M Ángeles Aller, Jaime Arias, Gloria Balfagón, Javier Blanco-Rivero
We evaluated the possible alterations produced by liver cholestasis (LC), a model of decompensated liver cirrhosis in sympathetic, sensory and nitrergic nerve function in rat superior mesenteric arteries (SMA). The vasoconstrictor response to electrical field stimulation (EFS) was greater in LC animals. Alpha-adrenoceptor antagonist phentolamine and P2 purinoceptor antagonist suramin decreased this response in LC animals more than in control animals. Both non-specific nitric oxide synthase (NOS) L-NAME and calcitonin gene related peptide (CGRP) (8-37) increased the vasoconstrictor response to EFS more strongly in LC than in control segments...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27465216/the-role-of-5-hydroxytryptamine-in-the-pathophysiology-of-migraine-and-its-relevance-to-the-design-of-novel-treatments
#15
Carlos M Villalón, Antoinette Maassen VanDenBrink
Migraine is a highly prevalent neurovascular disorder. Of the many factors that have been implicated over the years, 5-hydroxytryptamine (5-HT; serotonin) has long been involved in the pathophysiology of migraine. Certainly, some lines of evidence suggest: (i) a 5-HT depletion from blood platelets resulting in cranial extracerebral vasodilatation; and (ii) the effectiveness of an intravenous (i.v.) infusion of 5 HT to abort migraine in some patients. More direct evidence comes from some drugs that influence 5-HT release and/or interact (as agonists or antagonists) with 5-HT receptors to treat this disorder...
July 28, 2016: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/27397078/calcitonin-gene-related-peptide-contributes-to-peripheral-nerve-injury-induced-mechanical-hypersensitivity-through-ccl5-and-p38-pathways
#16
Jennifer T Malon, Ling Cao
The role of calcitonin gene related peptide (CGRP) in neuropathic pain was investigated in a mouse model of neuropathic pain, spinal nerve L5 transection (L5Tx). Intrathecal injection (i.t.) of CGRP8-37, a CGRP antagonist, significantly reduced L5Tx-induced mechanical hypersensitivity and lumbar spinal cord CCL5 expression. i.t. injection of a CCL5 neutralizing antibody significantly inhibited L5Tx-induced mechanical hypersensitivity. Further, pre-treatment with a p38-inhibitor, SB203580, was able to reduce CGRP-induced mechanical hypersensitivity, but not CGRP-induced CCL5 production...
August 15, 2016: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/27362770/involvement-of-cgrp-receptors-in-retinal-spreading-depression
#17
Yan Wang, Yanli Li, Minyan Wang
BACKGROUND: Cortical spreading depression (CSD) is a transient propagating excitation of synaptic activity followed by depression, which is implicated in migraine with aura and is regarded as the underlying cause of migraine. Calcitonin-gene related peptide (CGRP) receptors play a crucial role in mediating the magnitude of CSD in rat cortical slice. This study aimed to examine whether CGRP receptors are involved in retinal spreading depression (RSD) in chicks. METHODS: Western blot was used for detection of calcitonin-receptor like receptor (CALCRL) and intrinsic optical imaging was used for pharmacological investigation...
October 2016: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/27342083/accelerated-onset-of-the-vesicovesical-reflex-in-postnatal-ngf-oe-mice-and-the-role-of-neuropeptides
#18
Beatrice Girard, Abbey Peterson, Susan Malley, Margaret A Vizzard
The mechanisms underlying the postnatal maturation of micturition from a somatovesical to a vesicovesical reflex are not known but may involve neuropeptides in the lower urinary tract. A transgenic mouse model with chronic urothelial overexpression (OE) of NGF exhibited increased voiding frequency, increased number of non-voiding contractions, altered morphology and hyperinnervation of the urinary bladder by peptidergic (e.g., Sub P and CGRP) nerve fibers in the adult. In early postnatal and adult NGF-OE mice we have now examined: (1) micturition onset using filter paper void assays and open-outlet, continuous fill, conscious cystometry; (2) innervation and neurochemical coding of the suburothelial plexus of the urinary bladder using immunohistochemistry and semi-quantitative image analyses; (3) neuropeptide protein and transcript expression in urinary bladder of postnatal and adult NGF-OE mice using Q-PCR and ELISAs and (4) the effects of intravesical instillation of a neurokinin (NK)-1 receptor antagonist on bladder function in postnatal and adult NGF-OE mice using conscious cystometry...
November 2016: Experimental Neurology
https://www.readbyqxmd.com/read/27339365/anti-cgrp-monoclonal-antibodies-in-migraine-current-perspectives
#19
REVIEW
Maria Adele Giamberardino, Giannapia Affaitati, Martina Curto, Andrea Negro, Raffaele Costantini, Paolo Martelletti
Migraine is a highly disabling neurological pain disorder in which management is frequently problematic. Most abortive and preventative treatments employed are classically non-specific, and their efficacy and safety and tolerability are often unsatisfactory. Mechanism-based therapies are, therefore, needed. Calcitonin gene-related peptide (CGRP) is recognized as crucial in the pathophysiology of migraine, and new compounds that target the peptide have been increasingly explored in recent years. First tested were CGRP receptor antagonists; they proved effective in acute migraine treatment in several trials, but were discontinued due to liver toxicity in long-term administration...
December 2016: Internal and Emergency Medicine
https://www.readbyqxmd.com/read/27296555/calcitonin-gene-related-peptide-is-a-key-factor-in-the-homing-of-transplanted-human-mscs-to-sites-of-spinal-cord-injury
#20
Yu Zhang, Jinhua Yang, Peng Zhang, Tao Liu, Jianwei Xu, Zhihai Fan, Yixin Shen, Wenjie Li, Huanxiang Zhang
Mesenchymal stem cells (MSCs) can be used to treat many diseases, including spinal cord injury (SCI). Treatment relies mostly on the precise navigation of cells to the injury site for rebuilding the damaged spinal cord. However, the key factors guiding MSCs to the epicenter of SCI remain unknown. Here, we demonstrated that calcitonin gene-related peptide (CGRP), a neural peptide synthesized in spinal cord, can dramatically aid the homing of human umbilical cord mesenchymal stem cells (HUMSCs) in spinal cord-transected SCI rats...
2016: Scientific Reports
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