CGRP antagonists

PURPOSE: This study aims to elucidate the calcitonin gene-related peptide (CGRP) mediation and primary mechanism of corneal sensory nerves on tear production of the lacrimal gland. METHODS: Mouse corneal denervation models were constructed through surgical axotomy, pharmacologic treatment with capsaicin or resiniferatoxin, and Trpv1-Cre/DTR mice with diphtheria toxin injection. The capsaicin-treated mice received subconjunctival injection of CGRP or substance P, while the normal C57BL/6J mice were administered with CGRP receptor antagonist BIBN-4096...

OBJECTIVE: To compare calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) versus nonspecific oral migraine preventives (NOEPs). BACKGROUND: Insurers mandate step therapy with NOEPs before approving CGRP mAbs. METHODS: Databases were searched for class I or II randomized controlled trials (RCTs) comparing CGRP mAbs or NOEPs versus placebo for migraine prevention in adults. The primary outcome measure was monthly migraine days (MMD) or moderate to severe headache days...

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of cerebral small vessel disease, caused by a mutation in the NOTCH3 gene on chromosome 19. The main clinical features include migraine (often with aura), early onset, recurrent subcortical ischemic strokes, mood disturbances, and cognitive impairment, frequently leading to dementia and disability with a reduction in life expectancy. Cerebral chronic global hypoperfusion, due to impaired cerebrovascular reactivity, seems to play a primary role in CADASIL...

BACKGROUND CONTEXT: Intervertebral disc degeneration is common and may play a role in low back pain, but it is not well-understood. Previous studies have shown that the outer layer of the annulus fibrosus of a healthy disc is innervated by nociceptive nerve fibers. In the process of disc degeneration, it can grow into the inner annulus fibrosus or nucleus pulposus and release neuropeptides. Disc degeneration is associated with inflammation that produces inflammatory factors and potentiates nociceptor sensitization...

Inhibition of calcitonin gene-related peptide (CGRP) or its cognate CGRP receptor (CGRPR) has arisen as a major breakthrough in the treatment of migraine. However, a second CGRP-responsive receptor exists, the amylin (Amy) 1 receptor (AMY1 R), yet its involvement in the pathology of migraine is poorly understood. AMY1 R and CGRPR are heterodimers consisting of receptor activity-modifying protein 1 (RAMP1) with the calcitonin receptor (CTR) and the calcitonin receptor-like receptor (CLR), respectively. Here, we present the structure of AMY1 R in complex with CGRP and Gs protein and compare it with the reported structures of the AMY1 R complex with rat amylin (rAmy) and the CGRPR in complex with CGRP...

OBJECTIVE: This article describes strategies for the preventive treatment of migraine including the emerging role of calcitonin gene-related peptide (CGRP)-targeted therapies and introduces novel paradigms for the preventive treatment of migraine. LATEST DEVELOPMENTS: Multiple migraine medications targeting CGRP have been introduced since 2018, including injectable monoclonal antibodies (ie, eptinezumab, erenumab, fremanezumab, and galcanezumab) and oral small-molecule CGRP receptor antagonists (ie, ubrogepant, rimegepant, atogepant, and zavegepant)...

BACKGROUND: Exercise training showed beneficial effects on brain. The purpose of the present study is to evaluate the effect of six weeks of high-intensity interval training (HIIT) and Endurance training (ET) with calcitonin gene-related peptide (CGRP) receptor antagonist on the expression of genes involved in mitochondrial dynamics and apoptosis in hippocampal tissue of male Wistar rats. METHODS: In this study, forty-two healthymale Wistar rats (8-week) were randomly divided into 6 groups (n = 7) as follow; 1) Control; 2) HIIT which performed 6 weeks of HIIT; 3) ET which performed 6 weeks of endurance training; 4) CGRPi received 10 mg/kg CGRP receptor antagonist every day at the last 2 weeks; 5) CGRPi-HIIT performed HIIT and received CGRP receptor antagonist; 6) CGRPi-ET performed ET and received CGRP receptor antagonist...

In the early 1990s, the neuropeptide calcitonin gene-related peptide (CGRP) was identified as a key messenger in the pathophysiology of migraine and emerged as a treatment target, fundamentally transforming our approach to migraine therapy. While previous prophylactic drugs were non-specific and often caused intolerable side effects, the discovery of CGRP marked the advent of a new era in migraine treatment. The two main classes of CGRP-specific migraine treatments are monoclonal antibodies that bind to CGRP or the CGRP receptor, and CGRP receptor antagonists, the so-called gepants...

During the progression of knee osteoarthritis (OA), the synovium and infrapatellar fat pad (IFP) can serve as source for Substance P (SP) and calcitonin gene-related peptide (CGRP), two important pain-transmitting, immune, and inflammation modulating neuropeptides. Our previous studies showed that infrapatellar fat pad-derived mesenchymal stem/stromal cells (MSC) acquire a potent immunomodulatory phenotype and actively degrade Substance P via CD10 both in vitro and in vivo. On this basis, our hypothesis is that CD10-bound IFP-MSC sEVs can be engineered to target CGRP while retaining their anti-inflammatory phenotype...

Ubrogepant is the first oral calcitonin gene-related peptide (CGRP) receptor antagonist which is used for the acute treatment of migraine in adults. The present study employs liquid chromatography-high resolution mass spectrometry (LC-HRMS) and nuclear magnetic resonance spectroscopy (NMR) techniques for the identification and characterization of degradation impurities of ubrogepant. The forced degradation study of ubrogepant was performed as per the International Council for Harmonisation (ICH) Q1A and Q1B guidelines...

OBJECTIVE/BACKGROUND: sleep alterations strongly influence migraine severity. Prophylactic therapies have a major impact on migraine frequency and associated symptoms. The study purpose was to compare the impact of oral drug therapies or gene-related anti-calcitonin monoclonal antibodies (anti-CGRP mAbs) on sleep alterations. We also evaluated which drug therapies are more effective on sleep quality and the different impact on migraine frequency and life quality. PATIENTS/METHODS: this is a multicenter, prospective study conducted in three specialized headache centers (Marche Polytechnic University, Ancona; University of Palermo, Palermo; Fondazione Policlinico Campus Bio-Medico, Rome)...

The monosynaptic connection from the lateral parabrachial nucleus (LPB) to the central amygdala (CeA) serves as a fundamental pathway for transmitting nociceptive signals to the brain. The LPB receives nociceptive information from the dorsal horn and spinal trigeminal nucleus and sends it to the "nociceptive" CeA, which modulates pain-associated emotions and nociceptive sensitivity. To elucidate the role of densely expressed mu-opioid receptors (MORs) within this pathway, we investigated the effects of exogenously applied opioids on LPB-CeA synaptic transmission, employing optogenetics in mice expressing channelrhodopsin-2 in LPB neurons with calcitonin gene-related peptide (CGRP)...

BACKGROUND: Women show increased prevalence and severity of migraine compared to men. Whether small molecule calcitonin gene-related peptide receptor (CGRP-R) antagonists (i.e., gepants) and monoclonal antibodies targeting either the CGRP-R or the CGRP peptide might show sexually dimorphic outcomes for acute and preventive therapy has not been established. METHODS: We conducted a subpopulation analysis of available published data from FDA reviews to evaluate potential sex differences in the response rates of ubrogepant, rimegepant and zavegepant for acute migraine therapy...

OBJECTIVES: This study aimed to investigate the effect of calcitonin gene-related peptide (CGRP) on the temporal alteration of macrophage phenotypes and macrophage-regulated angiogenesis duringearlybonehealing and preliminarily elucidate the mechanism. METHODS: In vivo, the rat mandibular defect models were established with inferior alveolar nerve transection (IANT) or CGRP receptor antagonist injection. Radiographicandhistologic assessments for osteogenesis, angiogenesis, and macrophage phenotypic alteration within bone defects were performed...

Oxytocinergic transmission blocks nociception at the peripheral, spinal, and supraspinal levels through the oxytocin receptor (OTR). Indeed, a neuronal pathway from the hypothalamic paraventricular nucleus (PVN) to the spinal cord and trigeminal nucleus caudalis (Sp5c) has been described. Hence, although the trigeminocervical complex (TCC), an anatomical area spanning the Sp5c, C1, and C2 regions, plays a role in some pain disorders associated with craniofacial structures ( e.g. , migraine), the role of oxytocinergic transmission in modulating nociception at this level has been poorly explored...

Recently, we showed that while atogepant - a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist - does not fully prevent activation of nociceptors, it significantly reduces a cortical spreading depression (CSD)-induced early response probability in C-fibers and late response probability in A™-fibers. The current study investigates atogepant effect on CSD-induced activation and sensitization of high-threshold (HT) and wide dynamic range (WDR) dura-sensitive neurons. In anesthetized male rats, single-unit recordings were used to assess effects of atogepant (5mg/kg) vs vehicle on CSD-induced activation and sensitization of HT and WDR dura-sensitive neurons...

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No abstract text is available yet for this article.

BACKGROUND: Migraine is often associated with depression and anxiety, leading to a diminished quality of life. Calcitonin gene-related peptide (CGRP) antagonists have shown promise in treating migraines, but their effects on concurrent depression and anxiety have not been clarified. METHODS: A literature review was conducted on ClinicalTrials.gov, PubMed, Ovid Medline, and EMBASE focusing on phase 3 clinical trials, post-hoc analysis studies, and real-world evidence (RWE) published in the past 5 years...

Transient receptor potential (TRP) channels are pivotal in modulating vascular functions. In fact, topical application of cinnamaldehyde or capsaicin (TRPA1 and TRPV1 channel agonists, respectively) induces "local" changes in blood flow by releasing vasodilator neuropeptides. We investigated TRP channels' contributions and the pharmacological mechanisms driving vasodilation in human isolated dermal arteries. Ex vivo studies assessed the vascular function of artery segments and analyzed the effects of different compounds...