RESUMO
The calcitonin gene-related peptide (CGRP) suppresses fear memory retention in mice. Although intracerebroventricular administration of CGRP alters the fear memory processes, making it a promising therapeutic strategy for post-traumatic stress disorder (PTSD), direct brain injection into patients is not practical. Therefore, we propose that intranasal application may be an effective way to deliver CGRP to the brain. This study tested whether CGRP nasal administration exerts the same effect as intracerebroventricular administration using C57BL6J mice. The amount of CGRP in the cerebrospinal fluid and hippocampus 30 min after nasal administration of CGRP was significantly higher when compared with saline. Intranasal CGRP also elicited photophobic behaviors similar to intracerebroventricular injection. Moreover, intranasal CGRP decreased fear memory retention but did not affect reactivation and extinction of fear memory. We found intranasal CGRP significantly increased the expression of protein kinase D (PKD), phosphorylated histone deacetylase 5 (p-HDAC5) and neuronal PAS domain protein 4 (Npas4) in the hippocampus. CGRP-mediated impairment of fear memory and Npas4 expression increases were attenuated significantly by the CGRP receptor antagonist BIBN4096. Together, our data demonstrate that intranasal CGRP delivery activates the PKD/p-HDAC5/Npas4 pathway, decreases fear memory retention.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Medo , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Retenção Psicológica/efeitos dos fármacos , Administração Intranasal , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hipocampo/metabolismo , Histona Desacetilases/metabolismo , Masculino , Camundongos , Modelos Animais , Proteína Quinase C/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
The calcitonin gene-related peptide (CGRP) has been demonstrated relating to vascular and inflammatory regulations not only the nerve systems. As the anti-inflammation factor and the most potent vasodilator, the CGRP holds therapeutic potentials for the treatment of cardiovascular diseases which was, however, limited by its peptide nature and short half-life. With advantages in improving the stability, circulation time and protection from degradation, the nanoparticles were promising as delivery carriers for the peptide. Nevertheless, few nanoparticulate systems were developed to deliver the CGRP peptide for the modulation of vascular or inflammatory functions instead of neural regulation. In this study, the CGRP was encapsulated into the poly (lactic-co-glycolic acid) (PLGA) nanoparticle for sustained release of CGRP in vivo. The nanoparticles recovered the systemic level of CGRP and the vascular inflammatory factors in the CGRP+/- rats comparing to the administration of (Dulbecco's Phosphate Buffered Saline) DPBS or peptide only. With the decrease of vascular wall thickness and the attenuation of the T cell infiltration in the lung, the polymer based CGRP delivery system showed potentials to facilitate the therapeutic effects of the CGRP which may help for the development of CGRP-based therapy in vascular and inflammatory disorder related diseases.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/deficiência , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Portadores de Fármacos/química , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Química Farmacêutica , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Inflamação/tratamento farmacológico , Masculino , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Doenças Vasculares/tratamento farmacológicoRESUMO
BACKGROUND: Calcitonin gene-related peptide (CGRP) is regarded as an important molecule in trigeminovascular sensitization (TVS). CGRP-induced headaches (CGRP-IH) are evoked by intravascular administration of CGRP in nonmigraine and migraine subjects. CGRP might be associated with vasodilatation of the middle cerebral artery (MCA). It is unclear whether CGRP-induced hemodynamic changes relate to CGRP-IH in nonmigraine subjects. METHODS: Twenty healthy subjects participated in our study. Polymodal recording of mean arterial velocity in MCA (vm MCA), end-tidal carbon dioxide partial pressure (Et-CO2), mean arterial pressure (MAP), and heart rate (HR) was employed using transcranial Doppler (TCD) sonography. During the experiment, we administered intravenous infusion of CGRP at a rate of 1.5 mcg/min. The vm MCA, Et-CO2, HR, and MAP were determined at time points T 0, T 1, T 2, and T 3. We calculated the responses at different time points and combined them into a single response vm MCAtot, Et-CO2tot, HRtot, and MAPtot. RESULTS: We found significant differences along the time points in vm MCA (p = <0.001), Et-CO2 (p = 0.003), MAP (p < 0.001), and HR (p < 0.001). The relationship between vm MCAtot and Et-CO2tot was significant and positive (p = 0.005). The t-test showed significant differences between CGRP-IH and non-CGRP-IH subjects in vm MCAtot (p = 0.021) but not in Et-CO2tot (p = 0.838), MAPtot (p = 0.839), and HRtot (p = 0.198). Only vm MCAtot showed a significant relationship with CGRP-IH (p = 0.028). CONCLUSIONS: Our study provides evidence for vasodilatation of MCA in relation to CGRP-IH due to intravascular CGRP detected by multimodal TCD. In the context of TVS induced by CGRP, MCA vasodilatation seems to represent an epiphenomenon of the underlying TVS.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Cefaleia , Transtornos de Enxaqueca , Administração Intravenosa , Adulto , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Dióxido de Carbono/sangue , Feminino , Cefaleia/induzido quimicamente , Cefaleia/diagnóstico por imagem , Cefaleia/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/efeitos dos fármacos , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/diagnóstico por imagem , Transtornos de Enxaqueca/fisiopatologia , Ultrassonografia Doppler Transcraniana , Vasodilatação/efeitos dos fármacosRESUMO
OBJECTIVE: To evaluate the impact of two calcitonin gene-related peptide (CGRP)-targeted monoclonal antibodies (mAbs), erenumab and galcanezumab, on the pharmacokinetic (PK) profile, safety, and tolerability of ubrogepant. BACKGROUND: People taking CGRP-targeted mAbs for migraine prevention sometimes take ubrogepant, an oral small-molecule CGRP receptor antagonist, for acute treatment of breakthrough migraine attacks. DESIGN: In this two-arm, multicenter, open-label, phase 1b trial, adults with migraine were randomized to arm 1 (ubrogepant ± erenumab) or arm 2 (ubrogepant ± galcanezumab). The PK profile of ubrogepant was characterized for administration before and 4 days after CGRP-targeted mAb injection. Participants received single-dose ubrogepant 100 mg on day 1, subcutaneous erenumab 140 mg (arm 1) or galcanezumab 240 mg (arm 2) on day 8, and ubrogepant 100 mg once daily on days 12-15. In each study arm, serial blood samples were drawn on days 1 and 12 for measurement of plasma ubrogepant concentrations. The primary outcomes were area under the plasma ubrogepant concentration-time curve (AUC) from time 0 to t post-dose (AUC0- t ) and from time 0 to infinity (AUC0-inf ), and maximum plasma concentration (Cmax ) of ubrogepant when ubrogepant was administered before or after a single dose of erenumab or galcanezumab. Vital signs and laboratory parameters were monitored. RESULTS: Forty participants enrolled (20 per arm; mean [standard deviation] ages, 32.2 [8.9] and 38.4 [8.8] years; 50% [10/20] and 60% [12/20] female in arms 1 and 2, respectively). There were no significant differences in ubrogepant Cmax after versus before erenumab administration (geometric least-squares mean [LSM] ratio, 1.04 [90% CI, 0.93-1.16]), and no significant differences in AUC0- t (1.06 [0.96-1.16]) or AUC0-inf (1.05 [0.96-1.15]). Similarly, ubrogepant Cmax (1.00 [90% CI, 0.82-1.20]), AUC0- t (1.05 [0.90-1.23]), and AUC0-inf (1.05 [0.90-1.22]) geometric LSM ratios were statistically equivalent after galcanezumab versus ubrogepant alone. Treatment-emergent adverse events (TEAEs) were similar to those reported with each treatment alone. No serious TEAEs, TEAEs leading to discontinuation, or clinically relevant changes in laboratory parameters or vital signs were reported. CONCLUSIONS: The PK profile of ubrogepant was not significantly changed and no safety concerns were identified when ubrogepant was coadministered with erenumab or galcanezumab.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Transtornos de Enxaqueca/tratamento farmacológico , Piridinas/efeitos adversos , Piridinas/farmacocinética , Pirróis/efeitos adversos , Pirróis/farmacocinética , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Pirróis/administração & dosagemRESUMO
OBJECTIVE: To investigate if calcitonin gene-related peptide infusion induces migraine-like attacks in chronic migraine patients. METHODS: Fifty-eight patients with chronic migraine, either with or without headache on the experimental day, were assessed for the incidence of migraine-like attacks after an intravenous infusion with calcitonin gene-related peptide 1.5 µg/min over 20 min. The primary endpoint was the incidence of migraine-like attacks after calcitonin gene-related peptide. Exploratory endpoints were the association between the incidence of migraine-like attacks and presence of headache on the experimental day, and headache frequency in the past month. Migraine-like attack data was compared to a historic cohort of 91 episodic migraine patients without headache on the experimental day. Total tenderness score, pressure-pain threshold and supra-threshold pressure pain at baseline were investigated in relation to incidence of migraine-like attacks and presence of headache on the experimental day. RESULTS: In total, 83% of the 58 chronic migraine patients developed migraine-like attacks after calcitonin gene-related peptide infusion. Migraine-like attacks were found in 92% of chronic migraine patients with headache on the experimental day compared to 65% of chronic migraine patients without headache on the experimental day (p = 0.035). No differences were observed in total tenderness score and pressure-pain threshold between chronic migraine patients with and without headache on the experimental day. The incidence of migraine-like attacks following calcitonin gene-related peptide in chronic migraine patients without headache (65%) was equal to the historic cohort of 91 episodic migraine patients without headache (67%) on the experimental day. CONCLUSIONS: Chronic migraine patients are hypersensitive to calcitonin gene-related peptide. The potency of calcitonin gene-related peptide as a migraine inductor is increased in chronic migraine patients with ongoing headache. We suggest that calcitonin gene-related peptide, besides being a migraine trigger also acts as a modulator of nociceptive transmission in the trigeminal system.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Hipersensibilidade , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/genética , Adulto , Idoso , Peptídeo Relacionado com Gene de Calcitonina/efeitos adversos , Peptídeo Relacionado com Gene de Calcitonina/genética , Feminino , Cefaleia , Humanos , Incidência , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/metabolismoRESUMO
OBJECTIVE: A hallmark of migraine is photophobia. In mice, photophobia-like behavior is induced by calcitonin gene-related peptide (CGRP), a neuropeptide known to be a key player in migraine. In this study, we sought to identify sites within the brain from which CGRP could induce photophobia. DESIGN: We focused on the posterior thalamic region, which contains neurons responsive to both light and dural stimulation and has CGRP binding sites. We probed this area with both optogenetic stimulation and acute CGRP injections in wild-type mice. Since the light/dark assay has historically been used to investigate anxiety-like responses in animals, we measured anxiety in a light-independent open field assay and asked if stimulation of a brain region, the periaqueductal gray, that induces anxiety would yield similar results to posterior thalamic stimulation. The hippocampus was used as an anatomical control to ensure that light-aversive behaviors could not be induced by the stimulation of any brain region. RESULTS: Optogenetic activation of neuronal cell bodies in the posterior thalamic nuclei elicited light aversion in both bright and dim light without an anxiety-like response in an open field assay. Injection of CGRP into the posterior thalamic region triggered similar light-aversive behavior without anxiety. In contrast to the posterior thalamic nuclei, optogenetic stimulation of dorsal periaqueductal gray cell bodies caused both light aversion and an anxiety-like response, while CGRP injection had no effect. In the dorsal hippocampus, neither optical stimulation nor CGRP injection affected light aversion or open field behaviors. CONCLUSION: Stimulation of posterior thalamic nuclei is able to initiate light-aversive signals in mice that may be modulated by CGRP to cause photophobia in migraine.
Assuntos
Comportamento Animal , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Optogenética , Fotofobia/etiologia , Núcleos Posteriores do Tálamo , Animais , Comportamento Animal/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fotofobia/induzido quimicamente , Núcleos Posteriores do Tálamo/efeitos dos fármacosRESUMO
OBJECTIVE: Neuronal-specific enolase (NSE) and protein S100B have gained considerable interest as the markers of CNS injury, glial cell activation, and/or blood-brain barrier (BBB) disruption. No studies have investigated NSE and S100B in cluster headache (CH), but these biomarkers could contribute to the understanding of CH. METHODS: Patients with episodic CH in bout (eCHa), in remission (eCHr), and chronic CH (cCH) were included in this randomized, double-blind, placebo-controlled, 2-way cross-over provocation study carried out at the Danish Headache Center. The primary endpoints included (1) differences of NSE and S100B in between groups (eCHa, eCHr, and cCH) at baseline; (2) differences over time in plasma concentrations of NSE and S100B between patient developing an attack and those who did not; (3) differences in plasma concentrations over time of NSE and S100B between active day and placebo day. Baseline findings were compared to the historical data on migraine patients and healthy controls and presented with means ± SD. RESULTS: Nine eCHa, 9 eCHr, and 13 cCH patients completed the study and blood samples from 11 CGRP-induced CH attacks were obtained. There were no differences in NSE levels between CH groups at baseline, but CH patients in active disease phase had higher levels compared with 32 migraine patients (9.1 ± 2.2 µg/L vs 6.0 ± 2.2 µg/L, P < .0001) and 6 healthy controls (9.1 ± 2.2 µg/L vs 7.3 ± 2.0 µg/L, P = .007). CGRP-infusion caused no NSE changes and, but a slight, non-significant, increase in NSE was seen in patients who reported a CGRP-induced CH attack (2.39 µg/L, 95% Cl [-0.26, 3.85], P = .061). At baseline S100B levels in eCHa patients were higher compared to cCH patients (0.06 ± 0.02 µg/L vs 0.04 ± 0.02 µg/L, P = .018). Infusion of CGRP and CGRP-induced attacks did not change S100B levels. Apart from induced CH-attacks no other adverse events were noted. CONCLUSIONS: At baseline eCHa patients had higher S100B plasma levels than cCH patients and there was a slight, however not significant, NSE increase in response to CGRP-induced CH attack. Our findings suggest a possible role of an ictal activation of glial cells in CH pathophysiology, but further studies are warranted.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Cefaleia Histamínica/sangue , Neuroglia/metabolismo , Fosfopiruvato Hidratase/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Adulto , Biomarcadores/sangue , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Doença Crônica , Cefaleia Histamínica/induzido quimicamente , Cefaleia Histamínica/tratamento farmacológico , Estudos Cross-Over , Método Duplo-Cego , Humanos , Pessoa de Meia-Idade , Indução de Remissão , Índice de Gravidade de Doença , Adulto JovemRESUMO
OBJECTIVE: The monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor are new antimigraine drugs from which many patients already benefit. Very few side effects have been reported from the antibody trials, including very few gastrointestinal (GI) side effects. The current data derive from a double-blind cross-over study of CGRP infusion for 2 hours. We present the GI side effects of the infusion and raise the question if underreporting of GI symptoms in CGRP antibody trials has occurred. We also discuss why constipation may be more likely with CGRP receptor blockade than with CGRP neutralizing antibodies. METHODS: Thirty healthy volunteers were recruited to receive a 2-hour infusion of CGRP 1.5 µg/minutes on 2 different days. The participants were pretreated with sumatriptan tablets (2 × 50 mg) 1 day and with placebo the other day. During the infusion, the participants were asked about side effects including a detailed description about their GI symptoms. Clinical observations like flatulence, rumbling, and use of bedpan were also noted. After the infusion, the participants filled out a questionnaire about side effects at home until 12-hour after the infusion start. The study was conducted at the Danish Headache Center at Rigshospitalet Glostrup in the period February 2018 to July 2018. RESULTS: On both study days 93% (27/29 participants) experienced symptoms from the GI system during the infusion. Rumbling, stomach pain, nausea, diarrhea, and an urge to defecate were the most commonly experienced GI side effects. There was no difference in symptoms between placebo and sumatriptan pretreatment. CONCLUSION: We conclude that a 2-hour infusion of CGRP causes frequent and sometimes severe symptoms from the GI system. The symptoms are not antagonized by sumatriptan. More attention should be paid to constipation as a possible side effect of CGRP receptor antagonists.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Diarreia/induzido quimicamente , Motilidade Gastrointestinal/efeitos dos fármacos , Náusea/induzido quimicamente , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Sumatriptana/farmacologia , Adulto , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Constipação Intestinal/induzido quimicamente , Estudos Cross-Over , Diarreia/prevenção & controle , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/prevenção & controle , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Sumatriptana/administração & dosagem , Adulto JovemRESUMO
OBJECTIVE: Previous attempts to develop a pragmatic human model for testing new anti-migraine drugs, have failed. Calcitonin gene-related peptide (CGRP) induces a mild headache in healthy volunteers and migraine-like headache in migraine patients. The induced headache must respond to already established migraine treatment for validation. Thus, the objective of the study was to test the effect of sumatriptan against CGRP-induced symptoms in an attempt to validate CGRP-induced headache as a model for drug testing. METHODS: Thirty healthy volunteers were recruited to receive a 2-hour infusion of CGRP on 2 separate days. The participants were pretreated with sumatriptan 1 day and with placebo the other day in a randomized double-blind cross-over fashion. During the infusion, a questionnaire about headache and side effects was administered. Electrocardiography, heart rate, blood pressure, dermal blood flow, and diameter of peripheral arteries were monitored during the infusion. Participants were carefully instructed to fill out a headache questionnaire at home until 12 hours after the infusion start. Primary endpoints are difference between the sumatriptan day and the placebo day in area under the headache score curve (AUC) 0-2 hours after infusion start and in headache intensity 2 hours after infusion start. The study was conducted at the Danish Headache Center in Glostrup, Denmark. RESULTS: CGRP-induced headache in 86% (25/29) of the participants on the sumatriptan day and in 96% (28/29) of the participants on the placebo day. There was no difference in AUCheadache, 0-2 hours between the days (P = .794). There was a statistically significant decrease in mean atrial pressure (MAP) over time on both days with a16.2% reduction on the sumatriptan day and a 14.8% reduction on the placebo day (P < .001) and a statistically significant increase in heart rate (HR) over time on both days (from mean 57.5 at baseline to mean 105.4 at 120 minutes on the sumatriptan day and from mean 60.2 at baseline to 105.8 at 120 minutes on the placebo day, P < .001). The diameter of peripheral arteries increased statistically significant on both days (P < .001). CONCLUSION: Sumatriptan does not influence headache score, accompanying symptoms or other symptoms induced by CGRP. Furthermore, a 2-hour CGRP infusion causes a wide range of side effects and does not induce more headache than the usual 20-minute infusion. Thus, the prolonged infusion of CGRP in healthy volunteers is not a valid and pragmatic model for testing new anti-migraine drugs.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/tratamento farmacológico , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Sumatriptana/farmacologia , Vasodilatadores/farmacologia , Adulto , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Estudos Cross-Over , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Sumatriptana/administração & dosagem , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Adulto JovemRESUMO
Alpha-calcitonin gene-related peptide (α-CGRP) is a 37-amino acid neuropeptide that plays an important protective role in modulating cardiovascular diseases. Deletion of the α-CGRP gene increases the vulnerability of the heart to pressure-induced heart failure and the administration of a modified α-CGRP agonist decreases this vulnerability. Systemic administration of α-CGRP decreases blood pressure in normotensive and hypertensive animals and humans. Here we examined the protective effect of long-term administration of native α-CGRP against pressure-overload heart failure and the likely mechanism(s) of its action. Transverse aortic constriction (TAC) was performed to induce pressure-overload heart failure in mice. We found that TAC significantly decreased left ventricular (LV) fractional shortening, ejection fraction, and α-CGRP content, and increased hypertrophy, dilation, and fibrosis compared to sham mice. Administration of α-CGRP-filled mini-osmotic pumps (4 mg/kg bwt/day) in TAC mice preserved cardiac function and LV α-CGRP levels, and reduced LV hypertrophy, dilation, and fibrosis to levels comparable to sham mice. Additionally, TAC pressure-overload significantly increased LV apoptosis and oxidative stress compared to the sham mice but these increases were prevented by α-CGRP administration. α-CGRP administration in TAC animals decreased LV AMPK phosphorylation levels and the expression of sirt1, both of which are regulatory markers of oxidative stress and energy metabolism. These results demonstrate that native α-CGRP is protective against pressure-overload induced heart failure. The mechanism of this cardio-protection is likely through the prevention of apoptosis and oxidative stress, possibly mediated by sirt1 and AMPK. Thus, α-CGRP is a potential therapeutic agent in preventing the progression to heart failure, and the cardio-protective action of α-CGRP is likely the result of a direct cellular effect; however, a partial vasodilatory blood pressure-dependent mechanism of α-CGRP cannot be excluded.
Assuntos
Apoptose/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Insuficiência Cardíaca/fisiopatologia , Coração/fisiologia , Estresse Oxidativo/fisiologia , Quinases Proteína-Quinases Ativadas por AMP , Animais , Apoptose/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases/metabolismo , Sirtuína 1/metabolismoRESUMO
Episodic migraine is a debilitating condition. Preventive therapy is used to reduce frequency, duration, or severity of attacks. This review discusses principles of preventive treatment with a focus on preventive treatment options for people with episodic migraine. Specifically discussed is evidence and use of new migraine-specific treatment options for episodic migraine, such as calcitonin gene-related peptide monoclonal antibodies, a noninvasive transcutaneous electrical nerve stimulation device, and a single-pulse transcranial magnetic stimulator device. Also discussed are evidence-based updates from the 2012 American Academy of Neurology and the American Headache Society guidelines regarding major medication classes recommended for preventive episodic migraine treatment.
Assuntos
Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/prevenção & controle , Medicina Preventiva/métodos , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Humanos , Transtornos de Enxaqueca/terapia , Estimulação Magnética Transcraniana/métodos , Estimulação Elétrica Nervosa Transcutânea/métodos , Resultado do TratamentoRESUMO
Cortical spreading depression (CSD) is a wave of neuronal depolarization thought to underlie migraine aura. Calcitonin gene-related peptide (CGRP) is a potent vasodilator involved in migraine pathophysiology. Evidence for functional connectivity between CSD and CGRP has triggered scientific interest in the possibility that CGRP antagonism may disrupt vascular responses to CSD and the ensuing plasma protein extravasation (PPE). Using imaging tools that allow us to generate continuous, live, high-resolution views of spatial and temporal changes that affect arteries and veins in the dura and pia, we determined the extent to which CGRP contributes to the induction of arterial dilatation or PPE by CSD in female rats, and how these events are affected by the anti-CGRP monoclonal antibody (anti-CGRP-mAb) fremanezumab. We found that the CSD-induced brief dilatation and prolonged constriction of pial arteries, prolonged dilatation of dural arteries and PPE are all unaffected by fremanezumab, whereas the brief constriction and prolonged dilatation of pial veins are affected. In comparison, although CGRP infusion gave rise to the expected dilatation of dural arteries, which was effectively blocked by fremanezumab, it did not induce dilatation in pial arteries, pial veins, or dural veins. It also failed to induce PPE. Regardless of whether the nociceptors become active before or after the induction of arterial dilatation or PPE by CSD, the inability of fremanezumab to prevent them suggests that these events are not mediated by CGRP, a conclusion with important implications for our understanding of the mechanism of action of anti-CGRP-mAbs in migraine prevention.SIGNIFICANCE STATEMENT The current study identifies fundamental differences between two commonly used models of migraine, CSD induction and systemic CGRP infusion. It raises the possibility that conclusions drawn from one model may not be true or relevant to the other. It sharpens the need to accept the view that there is more than one truth to migraine pathophysiology and that it is unlikely that one theory will explain all types of migraine headache or the mechanisms of action of drugs that prevent it. Regarding the latter, it is concluded that not all vascular responses in the meninges are born alike and, consequently, that drugs that prevent vascular dilatation through different molecular pathways may have different therapeutic outcomes in different types of migraine.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Artérias Cerebrais/fisiologia , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Enxaqueca com Aura/tratamento farmacológico , Vasodilatação/fisiologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Artérias Cerebrais/química , Artérias Cerebrais/efeitos dos fármacos , Depressão Alastrante da Atividade Elétrica Cortical/efeitos dos fármacos , Feminino , Infusões Intravenosas , Camundongos , Enxaqueca com Aura/induzido quimicamente , Enxaqueca com Aura/fisiopatologia , Imagem Óptica/métodos , Ratos , Ratos Sprague-Dawley , Vasodilatação/efeitos dos fármacosRESUMO
STUDY QUESTION: Is it possible to establish a mouse model of deep endometriosis (DE)? SUMMARY ANSWER: A mouse DE model that is macroscopically and microscopically similar to nodular lesions in humans can be constructed in as short as 3 weeks by intraperitoneal injection of uterine fragments along with the infusion of substance P (SP) and/or calcitonin gene-related peptide (CGRP). WHAT IS KNOWN ALREADY: Although a baboon DE model was reported 5 years ago, its prohibitive cost and demand for facilities and expertise associated with the use of non-human primates put its use out of reach for most laboratories. STUDY DESIGN, SIZE, DURATION: A total of 48 female Balb/C mice were used for this study. Among them, 16 were randomly selected as donors that contributed uterine fragments, and the remaining 32 were recipient mice. The mice with induced endometriosis were followed up for 3-4 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: One day before the induction of endometriosis by intraperitoneal injection of uterine fragments, osmotic pumps were inserted into equal groups of recipient mice to infuse either sterile saline, SP, CGRP, or both SP and CGRP. The hotplate test was administrated to all mice at the baseline and before and after induction of endometriosis. Four (3 for the SP+CGRP group) weeks after induction, all mice were sacrificed. Their endometriotic lesions were excised, weighed and processed for histopathologic examination, and histochemistry, immunohistochemistry and immunofluorescence analyses of markers of proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), smooth muscle metaplasia (SMM), mesothelial-mesenchymal transition (MMT) and endothelial-mesenchymal transition (EndoMT) were done. The extent of lesional fibrosis was evaluated by Masson trichrome staining. To further evaluate surrounding organ/tissue invasion, the peritoneal areas adhesive to the lesions were excised for immunohistochemical analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Endometriotic lesions in mice treated with SP and/or CGRP satisfied all requirements for DE, i.e. presence of endometrial epithelial and stromal cells, abundance of fibromuscular content, and encapsulation in surrounding tissues or organs. The lesion weight in the CGRP, SP and SP+CGRP groups was 1.62, 2.14 and 2.18-fold, respectively, heavier than that of control group. Concomitantly, the SP, CGRP and SP+CGRP groups had significantly shorter hotplate latency than that of control group. Lesions in mice treated with SP and/or CGRP, especially with SP+CGRP, exhibited characteristics consistent with EMT, FMT, SMM and extensive fibrosis, along with signs of MMT and EndoMT. Lesional invasion into surrounding tissues/organs was found to be 25.0, 75.0 and 87.5% in mice treated with CGRP, SP and SP+CGRP, but none in control mice. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This study is limited by the use of histologic and immunohistochemistry analyses only and lacks molecular data. WIDER IMPLICATIONS OF THE FINDINGS: The establishment of a mouse DE model supports the idea that endometriotic lesions are wounds undergoing repeated tissue injury and repair and underscores the importance of microenvironments in shaping the lesions' destiny. In addition, signs consistent with MMT and EndoMT indicate that there may be more culpable factors that still remain unidentified and should be pursued in the future. Moreover, the close correlation between the extent of lesional fibrosis and markers of EMT, MMT, EndoMT, FMT and SMM as shown here should facilitate our understanding of the molecular mechanisms underlying the DE pathophysiology. Since this DE model is based on a biologically plausible and evidence-backed theory, it should shed much needed insight into the molecular mechanisms underlying the pathophysiology of DE. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by Grants 81471434 (S.W.G.), 81530040 (S.W.G.), 81771553 (S.W.G.), 81671436 (X.S.L.) and 81871144 (X.S.L.) from the National Natural Science Foundation of China. None of the authors has any conflict of interest to disclose.
Assuntos
Modelos Animais de Doenças , Endometriose/patologia , Doenças Peritoneais/patologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Transdiferenciação Celular , Endométrio/citologia , Endométrio/patologia , Transição Epitelial-Mesenquimal , Feminino , Fibrose , Humanos , Injeções Intraperitoneais , Camundongos , Miofibroblastos , Peritônio/citologia , Peritônio/patologia , Substância P/administração & dosagemRESUMO
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide expressed both centrally and peripherally. CGRP has been shown to be involved in arteriolar dilation, cardiovascular regulation, pain transmission, migraine, and gastrointestinal physiology. Our current research is aimed at analyzing CGRP's impact on appetite/satiety, body metabolism, and energy homeostasis. Our study investigated the effects of a single-dose intraperitoneal (IP) treatment with CGRP on food and water consumption, energy expenditure, physical activity, respirometry, and a panel of plasma metabolic hormones in C57Bl/6 wild-type (WT) mice. After a CGRP IP injection at a dose of 2 nmol (10 µM CGRP in 200 µl of saline), a significant reduction in food intake and metabolic parameters as RQ, VCO2, and VO2 was observed. CGRP-injected mice had also significantly lower total energy expenditure (TEE) with no changes in activity levels compared to vehicle-injected controls. CGRP treatment in mice induced significantly lower plasma levels of glucagon and leptin but higher levels of amylin. Our data show that a single dose of CGRP peptide significantly decreased food consumption and altered calorimetric parameters and plasma metabolic hormone levels, thus confirming that CGRP plays a pivotal role in the regulation of appetite and metabolism. Future studies are necessary to analyze CGRP's long-term impact on body metabolism and its potential effects on appetite, obesity, and metabolic disorders.
Assuntos
Depressores do Apetite/farmacologia , Apetite , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Metabolismo Energético , Glucagon/sangue , Leptina/sangue , Animais , Depressores do Apetite/administração & dosagem , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Feminino , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND Intranasal calcitonin gene-related peptide (CGRP) delivery offers a noninvasive method of bypassing the blood-brain barrier for the delivery of CGRP to the brain. Here, we first reported the therapeutic benefits of intranasal CGRP delivery in rats following middle cerebral artery occlusion (MCAO). MATERIAL AND METHODS Real-time quantitative polymerase chain reaction (RT-qPCR) assay, enzyme-linked immunosorbent assay (ELISA), rat MCAO model, TTC (2, 3, 5-triphenyltetrazolium chloride) staining, hematoxylin and eosin (H & E) staining, Morris water maze test, TUNEL assay, immunofluorescence, and western blot assay were used to investigate the role of CGRP in rats. Cell Counting Kit-8 assay, colony formation assay, cell cycle assay, apoptosis assay, western blot assay, and TOP/FOP assay were used to investigate the role of CGRP in normal human astrocytes (NHA) cells. RESULTS The CGRP-MCAO-NDDS (nasal drug delivery system) group showed a significant reduction in the infarct volume and improvement in neurologic deficit tests of motor, sensory, reflex and vestibulo-motor functions compared to those rats in the CGRP-MCAO-IV group. CGRP markedly inhibited apoptosis and increased the expression of vascular endothelial growth factor (VEGF) and bFGF and decreased the expression of GAP43 in the cortex of MCAO rats. CGRP promoted cell proliferation and cell cycle process and inhibited cell apoptosis through the Wnt/ß-catenin pathway in NHA cells. CONCLUSIONS This noninvasive, simple, and cost-effective method is a potential treatment strategy for focal cerebral ischemic injury.
Assuntos
Isquemia Encefálica/terapia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/uso terapêutico , Administração Intranasal/métodos , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/metabolismo , Lesões Encefálicas/tratamento farmacológico , Calcitonina/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Artérias Cerebrais , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/tratamento farmacológico , Isquemia/tratamento farmacológico , Masculino , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/efeitos dos fármacosRESUMO
BACKGROUND: Although intra-arterial infusion of calcitonin gene-related peptide (CGRP) reportedly stimulates giant migrating contractions (GMCs) of the small intestine in conscious dogs, the effect of intravenous CGRP administration on colonic motility remains unclear. In the present study, we investigated the effects of intravenous CGRP on colonic motility and defecation and determined the underlying mechanism of action in conscious dogs. METHODS: Sixteen Beagle dogs weighing 11-13 kg were included. The effects of intravenous CGRP at doses of 3.33 (with various antagonists), 0.83, and 1.67 µg/kg on colonic motility and defecation were evaluated in neurally intact dogs (n = 6). For comparison, dogs with transection/re-anastomosis (T/R) between the proximal and middle segments of the colon (n = 5) and dogs with extrinsic denervation of the ileocolonic segments (n = 5) also received intravenous CGRP at 3.33 µg/kg. All dogs were equipped with strain gauge force transducers on the ileocolon for measurement of the colonic contractile activity. RESULTS: Intravenous CGRP evoked GMCs and defecation in the neurally intact group; these stimulatory effects were inhibited by atropine and hexamethonium. Compared with the neurally intact group, the T/R group exhibited similar proximal colonic motility and decreased distal colonic motility after intravenous CGRP administration, whereas the extrinsic denervation group exhibited increased colonic motility overall. CONCLUSIONS: Intravenous CGRP induces colonic motility and defecation through acetylcholine release in conscious dogs. The continuity of the enteric nerves plays an important role in CGRP-induced colonic contractions and defecation, while the extrinsic nerves suppress CGRP-induced colonic motility.
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Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Colo/efeitos dos fármacos , Defecação/efeitos dos fármacos , Fármacos Gastrointestinais/administração & dosagem , Motilidade Gastrointestinal/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Administração Intravenosa , Anastomose Cirúrgica , Animais , Atropina/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Colo/inervação , Denervação/efeitos adversos , Cães , Fármacos Gastrointestinais/antagonistas & inibidores , Fármacos Gastrointestinais/farmacologia , Motilidade Gastrointestinal/fisiologia , Hexametônio/farmacologia , Modelos AnimaisRESUMO
Importance: Signaling molecule calcitonin gene-related peptide (CGRP) induces migraine attacks and anti-CGRP medications abort and prevent migraine attacks. Whether CGRP provokes cluster headache attacks is unknown. Objective: To determine whether CGRP induces cluster headache attacks in episodic cluster headache in active phase, episodic cluster headache in remission phase, and chronic cluster headache. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, 2-way crossover study set at the Danish Headache Center, Rigshospitalet Glostrup, in Denmark. Analyses were intent to treat. Inclusion took place from December 2015 to April 2017. Inclusion criteria were diagnosis of episodic/chronic cluster headache, patients aged 18 to 65 years, and safe contraception in women. Exclusion criteria were a history of other primary headache (except episodic tension-type headache <5 days/mo), individuals who were pregnant or nursing; cardiovascular, cerebrovascular, or psychiatric disease; and drug misuse. Interventions: Thirty-seven patients with cluster headaches received intravenous infusion of 1.5 µg/min of CGRP or placebo over 20 minutes on 2 study days. Main Outcomes and Measures: Difference in incidence of cluster headache-like attacks, difference in area under the curve (AUC) for headache intensity scores (0 to 90 minutes), and difference in time to peak headache between CGRP and placebo in the 3 groups. Results: Of 91 patients assessed for eligibility, 32 patients (35.2%) were included in the analysis. The mean (SD) age was 36 (10.7) years (range, 19-60 years), and the mean weight was 78 kg (range, 53-100 kg). Twenty-seven men (84.4%) completed the study. Calcitonin gene-related peptide induced cluster headache attacks in 8 of 9 patients in the active phase (mean, 89%; 95% CI, 63-100) compared with 1 of 9 in the placebo group (mean, 11%; 95% CI, 0-37) (P = .05). In the remission phase, no patients with episodic cluster headaches reported attacks after CGRP or placebo. Calcitonin gene-related peptide-induced attacks occurred in 7 of 14 patients with chronic cluster headaches (mean, 50%; 95% CI, 20-80) compared with none after placebo (P = .02). In patients with episodic active phase, the mean AUC from 0 to 90 minutes for CGRP was 1.903 (95% CI, 0.842-2.965), and the mean AUC from 0 to 90 minutes for the placebo group was 0.343 (95% CI, 0-0.867) (P = .04). In patients with chronic cluster headache, the mean AUC from 0 to 90 minutes for CGRP was 1.214 (95% CI, 0.395-2.033), and the mean AUC from 0 to 90 minutes for the placebo group was 0.036 (95% CI, 0-0.114) (P = .01). In the remission phase, the mean AUC from 0 to 90 minutes for CGRP was 0.187 (95% CI, 0-0.571), and the mean AUC from 0 to 90 minutes for placebo was 0.019 (95% CI, 0-0.062) (P > .99). Conclusions and Relevance: Calcitonin gene-related peptide provokes cluster headache attacks in active-phase episodic cluster headache and chronic cluster headache but not in remission-phase episodic cluster headache. These results suggest anti-CGRP drugs may be effective in cluster headache management. Trial Registration: ClinicalTrials.gov (NCT02466334).
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Cefaleia Histamínica/induzido quimicamente , Cefaleia Histamínica/fisiopatologia , Adulto , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
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 (150-200â¯g) anesthetized with isoflurane were injected intraorally with CGRP (100⯵l; 8-33â¯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 (Tâ¯=â¯0) and up to 24â¯h following injection of CGRP. Pretreatment with antagonists (CGRP8-37, 10â¯nmol; pizotifen, 2â¯mg/kg) was given by intra-oral or subcutaneous injection, 10 or 30â¯min, respectively, before the inflammatory stimulus. CGRP and CGRP8-37 were also injected into the rat hind paw to induce oedema. Data are presented as the mean (±SEM) difference in thickness between the right and the left sides at each time. RESULTS: Following intra-oral injection, CGRP induced a rapidly developing (5-15â¯min) and long-lasting (6â¯h), dose-dependent oedema in the rat cheek, blocked by pre-treatment with CGRP8-37 or pizotifen. CGRP induced a smaller oedematogenic effect in the rat hind paw also blocked by the CGRP antagonist. CGRP (16â¯pmol) potentiated the oedema induced by co-injected substance P (3.7â¯nmol) and contributed to the oedema following intraoral injection of carrageenan (100⯵g). Injection of CGRP8-37 alone induced an early but short-lasting oedema. CONCLUSION: Local injection of CGRP potently induced oedema in the orofacial tissue of rats which was blocked by a CGRP receptor antagonist. The overall inhibition of carrageenan-induced oedema by CGRP8-37 suggests that endogenous CGRP contributes to an oedematogenic response in orofacial tissues.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Bochecha/patologia , Edema/induzido quimicamente , Lábio/efeitos dos fármacos , Lábio/patologia , Animais , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Carragenina/administração & dosagem , Inflamação/induzido quimicamente , Masculino , Fragmentos de Peptídeos/administração & dosagem , Ratos Wistar , Substância P/administração & dosagemRESUMO
Migraine is a debilitating disorder characterized by recurrent headache arising from neurovascular dysfunction. Despite recent progress in migraine research, the exact mechanisms underpinning migraine are poorly understood. Furthermore, it is difficult to develop an animal model of migraine that resembles all symptoms of patients. In this study, we established a novel animal model of migraine induced by epidural injection of calcitonin gene-related peptide (CGRP), and examined climbing hutch behavior, facial-grooming behavior, body-grooming behavior, freezing behavior, resting behavior, and ipsilateral hindpaw facial grooming behavior of rats following CGRP injection. CGRP significantly reduced climbing hutch behavior, and face-grooming behavior, and increased immobile behavior. We also found that the P15 and P85 percentile range of behavioral data exhibited a high positive rate (83.3%) for establishing the model with less false positive rate. Our results verified that the rat model of migraine induced by CGRP featured many behaviors of migraine patients demonstrated during migraine attacks. Our findings suggest that this new model can be a useful tool for understanding the pathophysiology of migraine and studying novel therapeutic strategies for the treatment of migraine.
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Comportamento Animal/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Modelos Animais de Doenças , Transtornos de Enxaqueca/psicologia , Animais , Asseio Animal/efeitos dos fármacos , Masculino , Transtornos de Enxaqueca/induzido quimicamente , Ratos Sprague-DawleyRESUMO
Migraine has a strong genetic component and is characterized by multiphasic events including an initial premonitory phase with premonitory symptoms (PS). Calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide-38 (PACAP38) are endogenous neuropeptides that can trigger migraine attacks and have in recent years gained considerable interest in the migraine field. Yet, the exact pathophysiological mechanisms underlying CGRP- and PACAP38-induced attacks are not fully clarified. Human provocation models have shown that these peptides induce attacks in only two- thirds of migraine patients. Whether this diverse migraine response after CGRP or PACAP38 may be explained by genetic factors is unknown. The present thesis includes four studies that explore different factors that may be associated with the CGRP- and PACAP38-induced migraine response. In study I and II we investigated the role of familial predisposition (family load) and number of risk conferring gene variants on migraine attacks induced by CGRP or PA-CAP38. In study III, we investigated biochemical changes of CGRP, vasoactive intestinal peptide (VIP), S100B and TNF-alpha in the blood after PACAP38. Finally in study IV, we studied whether CGRP or PACAP38 may induce PS. Study I and II demonstrated that PACAP38 and CGRP induce migraine attacks in 63% and 72% of the patients, respectively. Moreover, we showed that patients with high family load or a high number of migraine associated gene variants did not report more migraine attacks after CGRP or PACAP38 than those with no familial predisposition or few gene variants. Study III showed that PACAP38 infusion caused changes in plasma concentrations for VIP and S100B, but not CGRP and TNF-alpha, suggesting activation of parasympathetic nerve endings. Study IV showed absence of PS after CGRP and lack of statistical difference in PS between patients who reported and not reported attacks after PACAP38 suggesting peripheral mechanisms of induction. In conclusion, the present thesis suggests that genetics factors such as family load and genetic variants do not contribute to susceptibility of migraine attacks induced by CGRP or PACAP38. Additionally, our data indicate that CGRP and PACAP38 primarily have a peripheral site of action. We believe that the acquired knowledge from this thesis on how CGRP and PACAP38 might be involved in migraine pathophysiology would contribute to the development of novel and better migraine treatments in the future.