RESUMEN
BACKGROUND: We wished to explore possible sexual dimorphism in mechanisms sensitizing or activating meningeal nociceptors that can promote the headache phase of migraine. METHODS: Male and female C57BL6J mice received either supradural orexin B and an inflammatory mediator cocktail (IM) with migraine-like pain behaviors and photophobia recorded. Expression of orexin 2 receptor (OX2R) in trigeminal ganglion (TG) and phosphorylated extracellular signal-regulated kinases (ERK) levels in trigeminal nucleus caudalis (TNC) were evaluated. Orexin B-induced excitability of TG cells was assessed with patch-clamp electrophysiology. Intranasal delivery of CRISPR/Cas9 plasmids was used to edit the expression of OX2R in the TG. RESULTS: Supradural orexin B induced migraine-like pain behaviors, photophobia and increased TNC ERK phosphorylation exclusively in males. Blockade of orexin signaling with supradural suvorexant, a dual orexin receptor antagonist, prevented, but did not reverse, migraine-like pain in males induced by supradural IM cocktail. OX2R expression was higher in male TG and orexin B increased TG neuron excitability in males. Intranasal OX2R CRISPR/Cas9 reduced TG receptor expression and orexin B-induced TNC ERK phosphorylation and prevented migraine-like pain induced by supradural orexin B in males. CONCLUSIONS: Our studies reveal a male-specific mechanism of TG nociceptor sensitization and migraine-like pain behavior mediated by orexin B/OX2R signaling. Sexually dimorphic mechanisms of trigeminal nociceptor sensitization and activation offer opportunities to improve patient outcomes by considering patient sex and may influence clinical trial design and interpretation.
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Ratones Endogámicos C57BL , Trastornos Migrañosos , Receptores de Orexina , Ganglio del Trigémino , Animales , Masculino , Femenino , Ratones , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/fisiopatología , Receptores de Orexina/metabolismo , Receptores de Orexina/genética , Ganglio del Trigémino/metabolismo , Ganglio del Trigémino/efectos de los fármacos , Meninges/efectos de los fármacos , Meninges/metabolismo , Caracteres Sexuales , Orexinas/metabolismoRESUMEN
BACKGROUND: Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) is a new avenue for treating migraine. The efficacy and safety of intravenous Lu AG09222, a humanized monoclonal antibody directed against the PACAP ligand, for migraine prevention are unclear. METHODS: In a phase 2, double-blind, randomized, placebo-controlled trial, we enrolled adult participants (18 to 65 years of age) with migraine for whom two to four previous preventive treatments had failed to provide a benefit. The trial included a 4-week treatment period and an 8-week follow-up period. Participants were randomly assigned in a 2:1:2 ratio to receive a single-dose baseline infusion of 750 mg of Lu AG09222, 100 mg of Lu AG09222, or placebo. The primary end point was the mean change from baseline in the number of migraine days per month, during weeks 1 through 4, in the Lu AG09222 750-mg group as compared with the placebo group. RESULTS: Of 237 participants enrolled, 97 received 750 mg of Lu AG09222, 46 received 100 mg of Lu AG09222, and 94 received placebo. The mean number of baseline migraine days per month was 16.7 in the overall population, and the mean change from baseline over weeks 1 through 4 was -6.2 days in the Lu AG09222 750-mg group, as compared with -4.2 days in the placebo group (difference, -2.0 days; 95% confidence interval, -3.8 to -0.3; P = 0.02). Adverse events with a higher incidence in the Lu AG09222 750-mg group than in the placebo group during the 12-week observation period included coronavirus disease 2019 (7% vs. 3%), nasopharyngitis (7% vs. 4%), and fatigue (5% vs. 1%). CONCLUSIONS: In a phase 2 trial, a single intravenous infusion of 750 mg of Lu AG09222 showed superiority over placebo in reducing migraine frequency over the subsequent 4 weeks. (Funded by H. Lundbeck; HOPE ClinicalTrials.gov number, NCT05133323.).
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Anticuerpos Monoclonales Humanizados , Trastornos Migrañosos , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Método Doble Ciego , Infusiones Intravenosas , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/antagonistas & inhibidores , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Brote de los SíntomasAsunto(s)
Anticuerpos Monoclonales Humanizados , Trastornos Migrañosos , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Fase II como Asunto , Estudios Multicéntricos como Asunto , Infusiones Intravenosas , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/antagonistas & inhibidores , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Brote de los SíntomasRESUMEN
Sodium serves as one of the primary cations in the central nervous system, playing a crucial role in maintaining normal brain function. In this study, we investigated alterations in sodium concentrations in the brain and/or cerebrospinal fluid across multiple models, including an aging model, a stroke model, a nitroglycerin (NTG)-induced rat migraine model, a familial hemiplegic migraine type 2 (FHM2) mouse model, and a transgenic mouse model of Alzheimer's disease (AD). Our results reveal that older rats exhibited higher sodium concentrations in cerebrospinal fluid (CSF), plasma, and various brain regions compared to their younger counterparts. Additionally, findings from the stroke model demonstrated a significant increase in sodium in the ischemic/reperfused region, accompanied by a decrease in potassium and an elevated sodium/potassium ratio. However, we did not detect significant changes in sodium in the NTG-induced rat migraine model or the FHM2 mouse model. Furthermore, AD transgenic mice showed no significant differences in sodium levels compared to wild-type mice in CSF, plasma, or the hippocampus. These results underscore the nuanced regulation of sodium homeostasis in various neurological conditions and aging, providing valuable insights into potential mechanisms underlying these alterations.
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Envejecimiento , Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Ratones Transgénicos , Trastornos Migrañosos , Sodio , Accidente Cerebrovascular , Animales , Enfermedad de Alzheimer/metabolismo , Sodio/líquido cefalorraquídeo , Sodio/sangre , Sodio/metabolismo , Ratas , Ratones , Masculino , Accidente Cerebrovascular/metabolismo , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/sangre , Humanos , Nitroglicerina/farmacología , Daño por Reperfusión/metabolismo , Encéfalo/metabolismo , Ratas Sprague-Dawley , Migraña con AuraRESUMEN
Migraine is a debilitating neurological disorder impacting millions worldwide. Calcitonin Gene-Related Peptide (CGRP) has emerged as a key player in migraine pathophysiology, leading to the development of targeted therapies. This study reviews novel CGRP-targeted treatments, including monoclonal antibodies small molecule inhibitors/nutraceuticals and introduces Asarinin as a potential modulator of the pathway. Asarinin, a natural compound found in various plants, is examined for its pharmacological potential in migraine management. Pharmacokinetic assessments, toxicological modelling, molecular property analysis, and network pharmacology were conducted. Molecular docking and dynamics studies with CGRP reveal potential interactions, providing a foundation for understanding Asarinin's therapeutic effects. Asarinin's favourable pharmacokinetics, safety profile, and bioactivity, supporting its candidacy as a therapeutic agent. In-depth molecular docking studies with the CGRP receptor (PDB: 6ZHO) demonstrate strong binding affinity (- 10.3kcal/mol), while molecular dynamics simulations unveil the dynamic behavior of the Asarinin-CGRP complex, (- 10.53 kcal/mol) for Atogepant-CGRP complex. Network analysis highlights key proteins in migraine pathology, indicating Asarinin's potential efficacy. The groundwork for future investigations, suggests Asarinin as a promising candidate for migraine management by targeting OPRM1 pathway. The integration of diverse assessments provides a comprehensive understanding of Asarinin's potential and paves the way for further preclinical and clinical research.
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Trastornos Migrañosos , Simulación del Acoplamiento Molecular , Receptores Opioides mu , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/metabolismo , Humanos , Receptores Opioides mu/metabolismo , Transducción de Señal/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/metabolismo , Simulación de Dinámica Molecular , Farmacología en Red , AnimalesRESUMEN
Migraines are a common type of headache affecting around 15% of the population. The signalling pathways leading to migraines have not been fully understood, but neuronal voltage-gated ion channels, such as KCNG4, have been linked to this pathology. KCNG4 (Kv6.4) is a silent member of the superfamily of voltage-gated potassium (Kv) channels, which expresses in heterotetramers with members of the KCNB (Kv2) family. The genetic variant Kv6.4-L360P has previously been linked to migraines, but their mode of action remains unknown. Here, we characterized the molecular characteristics of Kv6.4-L360P when co-expressed with Kv2.1. We found that Kv6.4-L360P almost completely abolishes Kv2 currents, and we propose that this mechanism in the trigeminal system, linked to the initiation of migraine, leads to the pathology.
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Trastornos Migrañosos , Canales de Potasio con Entrada de Voltaje , Canales de Potasio Shab , Animales , Humanos , Variación Genética , Células HEK293 , Trastornos Migrañosos/genética , Trastornos Migrañosos/metabolismo , Canales de Potasio con Entrada de Voltaje/genética , Canales de Potasio con Entrada de Voltaje/metabolismo , Canales de Potasio Shab/genética , Canales de Potasio Shab/metabolismoRESUMEN
Migraine, a primary headache disorder whose mechanism remains incompletely understood, appears to involve the activation of the trigeminovascular system (TS) during attacks. Research suggests that inflammatory processes mediated by the immune system may play a role in migraine pathophysiology. Neuroinflammation is often associated with migraine attacks, with cytokines serving as crucial mediators in the process. Elevated levels of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), have been observed in the blood and cerebrospinal fluid of individuals experiencing migraine attacks. These cytokines have the capacity to sensitize pain pathways in the brain, thereby increasing sensitivity to pain stimuli. This phenomenon, known as central sensitization, is believed to contribute to the intensity and persistence of migraine pain. Kynurenines, endogenous mediators of glutamatergic mechanisms, can significantly influence the pathophysiology of primary headache disorders. The kynurenine system is collectively known as the kynurenine pathway (KP), which can act on multiple receptors, such as glutamate receptors, aryl hydrocarbon receptors (AhRs), G protein-coupled receptors 35 (GPR35), and α-7 nicotinic acetylcholine (α7 nACh) receptors. These receptors are also found on various cells of the immune system, so the role of the KP in the pathomechanism of primary headaches may also be mediated through them. In this review, our goal is to show a possible link between the receptors of the KP and immune system in the context of inflammation and migraine. Migraine research in recent years has focused on neuropeptides, such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as potential pathogenic factors and possible therapeutic approaches. These peptides share many similarities in their characteristics and roles. For instance, they exhibit potent vasodilation, occur in both the peripheral and central nervous systems, and play a role in transmitting nociception and neurogenic inflammation. The investigation of potential connections between the aforementioned neuropeptides and the kynurenine pathway could play a significant role in uncovering the pathomechanism of migraine and identifying new drug candidates.
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Quinurenina , Trastornos Migrañosos , Humanos , Trastornos Migrañosos/inmunología , Trastornos Migrañosos/fisiopatología , Trastornos Migrañosos/metabolismo , Quinurenina/metabolismo , Animales , Neuroinmunomodulación/fisiología , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/fisiopatologíaRESUMEN
BACKGROUND: Microglia is the primary source of inflammatory factors during migraine attacks. This study aims to investigate the role of microglia related genes (MRGs) in migraine attacks. METHODS: The RNA sequencing results of migraineurs and the panglaodb database were used to obtain differentially expressed genes (DEGs) in migraine related to microglia. A migraine rat model was established for validating and localizing of the MRGs, and subsequent screening for target genes was conducted. A shRNA was designed to interference the expression of target genes and administered into the trigeminal ganglion (TG) of rats. Pain sensitivity in rats was evaluated via the hot water tail-flick (HWTF) and formalin-induced pain (FIP) experiments. ELISA was used to quantify the levels of inflammatory cytokines and CGRP. WB and immunofluorescence assays were applied to detect the activation of microglia. RESULTS: A total of five DEGs in migraine related to microglia were obtained from RNA sequencing and panglaodb database. Animal experiments showed that these genes expression were heightened in the TG and medulla oblongata (MO) of migraine rats. The gene S100A8 co-localized with microglia in both TG and MO. The HWTF and FIP experiments demonstrated that interference with S100A8 alleviated the sense of pain in migraine rats. Moreover, the levels of TNFα, IL-1ß, IL-6, and CGRP in the TG and MO of rats in the model rats were increased, and the expression of microglia markers IBA-1, M1 polarization markers CD86 and iNOS was upregulated. Significantly, interference with S100A8 reversed these indicators. CONCLUSION: Interference with S100A8 in microglia increased the pain threshold during migraine attacks, and inhibited neuroinflammation and microglia activation.
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Calgranulina A , Microglía , Trastornos Migrañosos , Enfermedades Neuroinflamatorias , Ratas Sprague-Dawley , Animales , Microglía/metabolismo , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/genética , Ratas , Masculino , Calgranulina A/metabolismo , Calgranulina A/genética , Enfermedades Neuroinflamatorias/metabolismo , Ganglio del Trigémino/metabolismo , Modelos Animales de EnfermedadRESUMEN
Migraine as a common neurological disorder still lacks effective therapies. Tetramethylpyrazine (TMP) is the main bioactive component from Ligusticum chuanxiong hort., a traditional edible-medicinal herb. This study aimed to investigate the action of TMP on migraine by metabolomics with mass spectrometry imaging (MSI) analysis and molecular exploring, including random forest model analysis, KEGG enrichment analysis and metabolite-metabolite interaction network analysis. The results indicated that 26 key representative metabolic biomarkers were identified, especially γ-glu-cys, which were highly related to glutathione (GSH) metabolism. MSI found the abundance of eleven endogenous metabolites were modulated by TMP, particularly glucose, the most important energy metabolism molecule, and GSH were increased that maintains intracellular redox balance, which was consistent with activation of Nrf2 signals by TMP. These findings provide insights into the effectiveness of metabolomics integrated with MSI in explaining the metabolic mechanisms of TMP, and afford valuable information for healthy development of TMP in migraine.
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Espectrometría de Masas , Metabolómica , Trastornos Migrañosos , Pirazinas , Pirazinas/metabolismo , Pirazinas/análisis , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/tratamiento farmacológico , Humanos , Animales , Ratas , Ligusticum/química , Ligusticum/metabolismo , Biomarcadores/metabolismo , Biomarcadores/análisis , Ratas Sprague-Dawley , Masculino , Glutatión/metabolismo , Medicamentos Herbarios Chinos/metabolismo , Medicamentos Herbarios Chinos/químicaRESUMEN
BACKGROUND: Stress is one of the most common precipitating factors in migraine and is identified as a trigger in nearly 70% of patients. Responses to stress include release of glucocorticoids as an adaptive mechanism, but this may also contribute to migraine attacks. Here, we investigated the role of glucocorticoids on stress-induced migraine-like behaviors. METHODS: We have shown previously that repeated stress in mice evokes migraine-like behavioral responses and priming to a nitric oxide donor. Metyrapone, mifepristone, and corticosterone (CORT) were used to investigate whether CORT contributes to the stress-induced effects. Facial mechanical hypersensitivity was evaluated by von Frey testing and grimace scoring assessed the presence of non-evoked pain. We also measured serum CORT levels in control, stress, and daily CORT injected groups of both male and female mice. RESULTS: Metyrapone blocked stress-induced responses and priming in male and female mice. However, repeated CORT injections in the absence of stress only led to migraine-like behaviors in females. Both female and male mice showed similar patterns of serum CORT in response to stress or exogenous administration. Finally, administration of mifepristone, the glucocorticoid receptor antagonist, prior to each stress session blocked stress-induced behavioral responses in male and female mice. CONCLUSIONS: These findings demonstrate that while CORT synthesis and receptor activation is necessary for the behavioral responses triggered by repeated stress, it is only sufficient in females. Better understanding of how glucocorticoids contribute to migraine may lead to new therapeutic opportunities.
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Corticosterona , Modelos Animales de Enfermedad , Glucocorticoides , Metirapona , Mifepristona , Trastornos Migrañosos , Estrés Psicológico , Animales , Trastornos Migrañosos/metabolismo , Ratones , Masculino , Femenino , Estrés Psicológico/metabolismo , Estrés Psicológico/complicaciones , Metirapona/farmacología , Corticosterona/sangre , Mifepristona/farmacología , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , Conducta Animal/efectos de los fármacosRESUMEN
BACKGROUND: Migraine is a neurological disorder characterized by complex, widespread, and sudden attacks with an unclear pathogenesis, particularly in chronic migraine (CM). Specific brain regions, including the insula, amygdala, thalamus, and cingulate, medial prefrontal, and anterior cingulate cortex, are commonly activated by pain stimuli in patients with CM and animal models. This study employs fluorescence microscopy optical sectioning tomography (fMOST) technology and AAV-PHP.eB whole-brain expression to map activation patterns of brain regions in CM mice, thus enhancing the understanding of CM pathogenesis and suggesting potential treatment targets. METHODS: By repeatedly administering nitroglycerin (NTG) to induce migraine-like pain in mice, a chronic migraine model (CMM) was established. Olcegepant (OLC) was then used as treatment and its effects on mechanical pain hypersensitivity and brain region activation were observed. All mice underwent mechanical withdrawal threshold, light-aversive, and elevated plus maze tests. Viral injections were administered to the mice one month prior to modelling, and brain samples were collected 2 h after the final NTG/vehicle control injection for whole-brain imaging using fMOST. RESULTS: In the NTG-induced CMM, mechanical pain threshold decreased, photophobia, and anxiety-like behavior were observed, and OLC was found to improve these manifestations. fMOST whole-brain imaging results suggest that the isocortex-cerebral cortex plate region, including somatomotor areas (MO), somatosensory areas (SS), and main olfactory bulb (MOB), appears to be the most sensitive area of activation in CM (P < 0.05). Other brain regions such as the inferior colliculus (IC) and intermediate reticular nucleus (IRN) were also exhibited significant activation (P < 0.05). The improvement in migraine-like symptoms observed with OLC treatment may be related to its effects on these brain regions, particularly SS, MO, ansiform lobule (AN), IC, spinal nucleus of the trigeminal, caudal part (Sp5c), IRN, and parvicellular reticular nucleus (PARN) (P < 0.05). CONCLUSIONS: fMOST whole-brain imaging reveals c-Fos + cells in numerous brain regions. OLC improves migraine-like symptoms by modulating brain activity in some brain regions. This study demonstrates the activation of the specific brain areas in NTG-induced CMM and suggests some regions as a potential treatment mechanism according to OLC.
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Encéfalo , Modelos Animales de Enfermedad , Trastornos Migrañosos , Nitroglicerina , Animales , Nitroglicerina/toxicidad , Nitroglicerina/farmacología , Nitroglicerina/administración & dosificación , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/diagnóstico por imagen , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/tratamiento farmacológico , Ratones , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Masculino , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratones Endogámicos C57BL , Mapeo Encefálico , Vasodilatadores/farmacología , Vasodilatadores/administración & dosificación , Umbral del Dolor/efectos de los fármacosRESUMEN
Migraines are a type of headache that occur with other neurological symptoms, but the pathophysiology remains unclear. In this issue of the JCI, Nelson-Maney and authors used constitutive and inducible knockouts of the CGRP receptor components, elegantly demonstrating an essential function of CGRP in modulating meningeal lymphatic vessels (MLVs) in migraine. CGRP was shown to induce rearrangement of membrane-bound gap junction proteins in MLVs, resulting in a reduced CSF flux into cervical lymph nodes. The authors also provided evidence of a primary role for CGRP in modulating neuro-immune function. Finally, by showing that blocking CGRP signaling in MLVs attenuated pain behavior associated with acute migraine in rodents, the authors provided a target for pharmacological blockade of CGRP in relation to primary headache disorders.
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Péptido Relacionado con Gen de Calcitonina , Vasos Linfáticos , Meninges , Trastornos Migrañosos , Transducción de Señal , Animales , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/fisiopatología , Trastornos Migrañosos/genética , Trastornos Migrañosos/patología , Ratones , Vasos Linfáticos/metabolismo , Vasos Linfáticos/fisiopatología , Vasos Linfáticos/patología , Péptido Relacionado con Gen de Calcitonina/metabolismo , Meninges/metabolismo , Meninges/fisiopatología , Ratones Noqueados , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Dolor/metabolismo , Dolor/fisiopatología , Dolor/patología , HumanosRESUMEN
BACKGROUND: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide pivotal in migraine pathophysiology and is considered a promising new migraine drug target. Although intravenous PACAP triggers migraine attacks and a recent phase II trial with a PACAP-inhibiting antibody showed efficacy in migraine prevention, targeting the PACAP receptor PAC1 alone has been unsuccessful. The present study investigated the role of three PACAP receptors (PAC1, VPAC1 and VPAC2) in inducing migraine-relevant hypersensitivity in mice. METHODS: Hindpaw hypersensitivity was induced by repeated PACAP38 injections. Tactile sensitivity responses were quantified using von Frey filaments in three knockout (KO) mouse strains, each lacking one of the PACAP-receptors (Ntotal = 160). Additionally, ex vivo wire myography was used to assess vasoactivity of the carotid artery, and gene expression of PACAP receptors was examined by qPCR. RESULTS: PACAP38 induced hypersensitivity in WT controls (p < 0.01) that was diminished in VPAC1 and VPAC2 KO mice (p < 0.05). In contrast, PAC1 KO mice showed similar responses to WT controls (p > 0.05). Myograph experiments supported these findings showing diminished vasoactivity in VPAC1 and VPAC2 KO mice. We found no upregulation of the non-modified PACAP receptors in KO mice. CONCLUSIONS: This study assessed all three PACAP receptors in a migraine mouse model and suggests a significant role of VPAC receptors in migraine pathophysiology. The lack of hypersensitivity reduction in PAC1 KO mice suggests the involvement of other PACAP receptors or compensatory mechanisms. The results indicate that targeting only individual PACAP receptors may not be an effective migraine treatment.
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Modelos Animales de Enfermedad , Ratones Noqueados , Trastornos Migrañosos , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Receptores de Tipo II del Péptido Intestinal Vasoactivo , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo , Animales , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/farmacología , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/fisiopatología , Trastornos Migrañosos/metabolismo , Receptores de Tipo II del Péptido Intestinal Vasoactivo/metabolismo , Receptores de Tipo II del Péptido Intestinal Vasoactivo/genética , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/metabolismo , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/genética , Ratones , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/fisiopatología , Hiperalgesia/fisiopatología , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Masculino , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Ratones Endogámicos C57BL , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/metabolismo , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/genética , Miembro Posterior/fisiopatologíaRESUMEN
Motion-induced anxiety and agoraphobia are more frequent symptoms in patients with vestibular migraine (VM) than migraine without vertigo. The neuropeptide calcitonin gene-related peptide (CGRP) is a therapeutic target for migraine and VM, but the link between motion hypersensitivity, anxiety, and CGRP is relatively unexplored, especially in preclinical mouse models. To further examine this link, we tested the effects of systemic CGRP and off-vertical axis rotation (OVAR) on elevated plus maze (EPM) and rotarod performance in male and female C57BL/6J mice. Rotarod ability was assessed using two different dowel diameters: mouse dowel (r = 1.5â cm) versus rat dowel (r = 3.5â cm). EPM results indicate that CGRP alone or OVAR alone did not increase anxiety indices. However, the combination of CGRP and OVAR did elicit anxiety-like behavior. On the rotarod, CGRP reduced performance in both sexes on a mouse dowel but had no effect on a rat dowel, whereas OVAR had a significant effect on the rat dowel. These results suggest that only the combination of CGRP with vestibular stimulation induces anxiety-like behavior and that CGRP affects the dynamic balance function in mice depending on the type of challenge presented. These findings suggest that anxiety-like behaviors can be teased out from imbalance behaviors in a mouse model of "migraine." Future studies are aimed to determine if CGRP receptor antagonists that have been effective treating migraineurs and mouse "migraine" models may also reduce the anxiety observed in migraine.
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Ansiedad , Péptido Relacionado con Gen de Calcitonina , Ratones Endogámicos C57BL , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Masculino , Ansiedad/metabolismo , Femenino , Modelos Animales de Enfermedad , Ratones , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Prueba de Desempeño de Rotación con Aceleración Constante , Vestíbulo del Laberinto/efectos de los fármacos , Trastornos Migrañosos/metabolismoRESUMEN
INTRODUCTION: Calcitonin-gene related peptide (CGRP) is a vasoactive neuropeptide involved in the pathophysiology ofmigraine. CGRP has been targeted for both preventive and acute treatment of migraine. OBJECTIVE: Provide a summary of the most clinically relevant literature surrounding CGRP modulating therapies. METHODS: This update on CGRP modulating therapies includes articles selected as most clinically relevant by theauthors. CONCLUSION: CGRP modulating therapies are an exciting new addition to migraine treatment given their safety andtolerability. Additionally, compared to traditional migraine preventive medication these treatments are migrainespecific.Further real-world and clinical data is ongoing to better understand these treatments that continue to gainfavor in the management of migraine.
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Péptido Relacionado con Gen de Calcitonina , Trastornos Migrañosos , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacologíaRESUMEN
Although the introduction of drugs targeting calcitonin gene-related peptide (CGRP) revolutionized migraine treatment, still a substantial proportion of migraine patients do not respond satisfactorily to such a treatment, and new therapeutic targets are needed. Therefore, molecular studies on migraine pathogenesis are justified. Oxidative stress is implicated in migraine pathogenesis, as many migraine triggers are related to the production of reactive oxygen and nitrogen species (RONS). Migraine has been proposed as a superior mechanism of the brain to face oxidative stress resulting from energetic imbalance. However, the precise mechanism behind the link between migraine and oxidative stress is not known. Nociceptive primary afferent nerve fiber endings express ion channel receptors that change harmful stimuli into electric pain signals. Transient receptor potential cation channel subfamily A member 1 (TRPA1) is an ion channel that can be activated by oxidative stress products and stimulate the release of CGRP from nerve endings. It is a transmembrane protein with ankyrin repeats and conserved cysteines in its N-terminus embedded in the cytosol. TRPA1 may be a central element of the signaling pathway from oxidative stress and NO production to CGRP release, which may play a critical role in headache induction. In this narrative review, we present information on the role of oxidative stress in migraine pathogenesis and provide arguments that TRPA1 may be "a missing link" between oxidative stress and migraine and therefore a druggable target in this disease.
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Trastornos Migrañosos , Estrés Oxidativo , Canal Catiónico TRPA1 , Humanos , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/etiología , Canal Catiónico TRPA1/metabolismo , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Transducción de Señal , Especies Reactivas de Oxígeno/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Alpha 7 nicotinic acetylcholine receptor (α7nAChR)-mediated astrocytic activation is closely related to central sensitization of chronic migraine (CM). Xiongzhi Dilong decoction (XZDL), originated from Xiongzhi Shigao decoction of Yi-zong-jin-jian, has been confirmed to relieve CM in experiment and clinic. However, its underlying mechanism for treating CM has not been elucidated. AIM OF THE STUDY: To reveal the underlying mechanisms of XZDL to alleviate CM in vivo focusing mainly on α7nAChR-mediated astrocytic activation and central sensitization in TNC. MATERIALS AND METHODS: CM rat model was established by subcutaneous injection of nitroglycerin (NTG) recurrently, and treated with XZDL simultaneously. Migraine-like behaviors of rats (ear redness, head scratching, and cage climbing) and pain-related reactions (mechanical hind-paw withdrawal threshold) of rats were evaluated before and after NTG injection and XZDL administration at different points in time for nine days. The immunofluorescence single and double staining were applied to detect the levels of CGRP, c-Fos, GFAP and α7nAChR in NTG-induced CM rats. ELISA kits were employed to quantify levels of TNF-α, IL-1ß, and IL-6 in medulla oblongata of CM rats. The expression levels of target proteins were examined using western blotting. Finally, methyllycaconitine citrate (MLA, a specific antagonist of α7nAChR) was applied to further validate the mechanisms of XZDL in vivo. RESULTS: XZDL significantly attenuated the pain-related behaviors of the NTG-induced CM rats, manifesting as constraints of aberrant migraine-like behaviors including elongated latency of ear redness and decreased numbers of head scratching and cage climbing, and increment of mechanical withdrawal threshold. Moreover, XZDL markedly lowered levels of CGRP and c-Fos, as well as inflammatory cytokines (IL-1ß, IL-6 and TNF-α) in CM rats. Furthermore, XZDL significantly enhanced α7nAChR expression and its co-localization with GFAP, while markedly inhibited the expression of GFAP and the activation of JAK2/STAT3/NF-κB pathway in the TNC of CM rats. Finally, blocking α7nAChR with MLA reversed the effects of XZDL on astrocytic activation, central sensitization, and the pain-related behaviors in vivo. CONCLUSION: XZDL inhibited astrocytic activation and central sensitization in NTG-induced CM rats by facilitating α7nAChR expression and suppressing JAK2/STAT3/NF-κB pathway, implying that the regulation of α7nAChR-mediated astrocytic activation represents a novel mechanism of XZDL for relieving CM.
Asunto(s)
Astrocitos , Medicamentos Herbarios Chinos , Trastornos Migrañosos , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Masculino , Ratas , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Enfermedad Crónica , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/metabolismo , Nitroglicerina/farmacología , Ratas Sprague-DawleyRESUMEN
Migraine is a neurological disorder characterized by episodes of severe headache. Cortical spreading depression (CSD), the electrophysiological equivalent of migraine aura, results in opening of pannexin 1 megachannels that release ATP and triggers parenchymal neuroinflammatory signaling cascade in the cortex. Migraine symptoms suggesting subcortical dysfunction bring subcortical spread of CSD under the light. Here, we investigated the role of purinergic P2X7 receptors on the subcortical spread of CSD and its consequent neuroinflammation using a potent and selective P2X7R antagonist, JNJ-47965567. P2X7R antagonism had no effect on the CSD threshold and characteristics but increased the latency to hypothalamic voltage deflection following CSD suggesting that ATP acts as a mediator in the subcortical spread. P2X7R antagonism also prevented cortical and subcortical neuronal activation following CSD, revealed by bilateral decrease in c-fos positive neuron count, and halted CSD-induced neuroinflammation revealed by decreased neuronal HMGB1 release and decreased nuclear translocation of NF-kappa B-p65 in astrocytes. In conclusion, our data suggest that P2X7R plays a role in CSD-induced neuroinflammation, subcortical spread of CSD and CSD-induced neuronal activation hence can be a potential target.
Asunto(s)
Depresión de Propagación Cortical , Enfermedades Neuroinflamatorias , Antagonistas del Receptor Purinérgico P2X , Receptores Purinérgicos P2X7 , Depresión de Propagación Cortical/efectos de los fármacos , Depresión de Propagación Cortical/fisiología , Animales , Antagonistas del Receptor Purinérgico P2X/farmacología , Masculino , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/efectos de los fármacos , Optogenética , Ratones , Trastornos Migrañosos/fisiopatología , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/tratamiento farmacológico , Neuronas/efectos de los fármacos , Ratones Endogámicos C57BL , Niacinamida/análogos & derivados , PiperazinasRESUMEN
Classical migraine patients experience aura, which is transient neurological deficits associated with cortical spreading depression (CSD), preceding headache attacks. It is not currently understood how a pathological event in cortex can affect peripheral sensory neurons. In this study, we show that cerebrospinal fluid (CSF) flows into the trigeminal ganglion, establishing nonsynaptic signaling between brain and trigeminal cells. After CSD, ~11% of the CSF proteome is altered, with up-regulation of proteins that directly activate receptors in the trigeminal ganglion. CSF collected from animals exposed to CSD activates trigeminal neurons in naïve mice in part by CSF-borne calcitonin gene-related peptide (CGRP). We identify a communication pathway between the central and peripheral nervous system that might explain the relationship between migrainous aura and headache.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina , Depresión de Propagación Cortical , Trastornos Migrañosos , Ganglio del Trigémino , Animales , Ratones , Péptido Relacionado con Gen de Calcitonina/líquido cefalorraquídeo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Líquido Cefalorraquídeo/metabolismo , Modelos Animales de Enfermedad , Trastornos Migrañosos/líquido cefalorraquídeo , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/fisiopatología , Proteoma/metabolismo , Transducción de Señal , Ganglio del Trigémino/metabolismo , Ganglio del Trigémino/fisiopatologíaRESUMEN
BACKGROUND: Migraine prevalence and levels of calcitonin gene-related peptide (CGRP), a peptide involved in migraine pathophysiology, differ between men and women, and appear to be affected by changes in sex hormones. The present study investigated the sex-specific responses to CGRP in human isolated arteries. METHODS: CGRP-induced relaxation of 62 (28 men and 34 women) human isolated middle meningeal arteries (HMMA) and 139 (69 men and 70 women) human isolated coronary arteries (HCA) was compared between men and women in groups <50 years and ≥50 years of age as a proxy for pre- and postmenopausal status in women, as well as matched-age groups for men. RESULTS: In HCA, no differences were observed between male and female tissue, or between the different age groups. However, in HMMA, the maximum response was significantly smaller and CGRP was less potent in females <50 compared with males <50 years of age. No differences were observed between the older age groups. CONCLUSIONS: Sex differences were observed for CGRP-induced relaxation of HMMA, but not HCA. These differences could arise from differential receptor expression in the vascular beds combined with the effect of sex hormones on CGRP and subsequent receptor desensitization.