Metabolic Aspects of Migraine: Association With Obesity and Diabetes Mellitus

Migraine is a disabling neurovascular disorder, characterized by moderate to severe unilateral headaches, nausea, photophobia, and/or phonophobia, with a higher prevalence in women than in men, which can drastically affect the quality of life of migraine patients. In addition, this chronic disorder is related with metabolic comorbidities associated with the patient's lifestyle, including obesity and diabetes mellitus (DM). Beyond the personal and socioeconomic impact caused by migraine, obesity and DM, it has been suggested that these metabolic disorders seem to be related to migraine since: (i) they are a risk factor for developing cardiovascular disorders or chronic diseases; (ii) they can be influenced by genetic and environmental risk factors; and (iii) while clinical and epidemiological studies suggest that obesity is a risk factor for migraine, DM (i.e., type 1 and type 2 DM) have been reported to be either a protective or a risk factor in migraine. On this basis, and given the high worldwide prevalence of migraine, obesity, and DM, this article provides a narrative review of the current literature related to the association between the etiology and pathophysiology of migraine and these metabolic disorders, considering lifestyle aspects, as well as the possible involvement of neurotransmitters, neuropeptides, and/or sex hormones. While a link between migraine and metabolic disorders has been suggested, many studies are contradictory and the mechanisms involved in this association are not yet sufficiently established. Therefore, further research should be focused on understanding the possible mechanisms involved

Functional Analysis of TRPA1, TRPM3, and TRPV1 Channels in Human Dermal Arteries and Their Role in Vascular Modulation

Transient receptor potential (TRP) channels are pivotal in modulating vascular functions. In fact, topical application of cinnamaldehyde or capsaicin (TRPA1 and TRPV1 channel agonists, respectively) induces “local” changes in blood flow by releasing vasodilator neuropeptides. We investigated TRP channels’ contributions and the pharmacological mechanisms driving vasodilation in human isolated dermal arteries. Ex vivo studies assessed the vascular function of artery segments and analyzed the effects of different compounds. Concentration–response curves to cinnamaldehyde, pregnenolone sulfate (PregS, TRPM3 agonist), and capsaicin were constructed to evaluate the effect of the antagonists HC030031 (TRPA1); isosakuranetin (TRPM3); and capsazepine (TRPV1). Additionally, the antagonists/inhibitors olcegepant (CGRP receptor); L-NAME (nitric oxide synthase); indomethacin (cyclooxygenase); TRAM-34 plus apamin (K+ channels); and MK-801 (NMDA receptors, only for PregS) were used. Moreover, CGRP release was assessed in the organ bath fluid post-agonist-exposure. In dermal arteries, cinnamaldehyde- and capsaicin-induced relaxation remained unchanged after the aforementioned antagonists, while PregS-induced relaxation was significantly inhibited by isosakuranetin, L-NAME and MK-801. Furthermore, there was a significant increase in CGRP levels post-agonist-exposure. In our experimental model, TRPA1 and TRPV1 channels seem not to be involved in cinnamaldehyde- or capsaicin-induced relaxation, respectively, whereas TRPM3 channels contribute to PregS-induced relaxation, possibly via CGRP-independent mechanisms.</p

Intracellular pathways of calcitonin gene‐related peptide‐induced relaxation of human coronary arteries:A key role for Gβγ subunit instead of cAMP

Background and Purpose: Calcitonin gene‐related peptide (CGRP) is a potent vasodilator. While its signalling is assumed to be mediated via increases in cAMP, this study focused on elucidating the actual intracellular signalling pathways involved in CGRP‐induced relaxation of human isolated coronary arteries (HCA). Experimental Approach: HCA were obtained from heart valve donors (27 M, 25 F, age 54 ± 2 years). Concentration–response curves to human α‐CGRP or forskolin were constructed in HCA segments, incubated with different inhibitors of intracellular signalling pathways, and intracellular cAMP levels were measured with and without stimulation. Results: Adenylyl cyclase (AC) inhibitors SQ22536 + DDA and MDL‐12330A, and PKA inhibitors Rp‐8‐Br‐cAMPs and H89, did not inhibit CGRP‐induced relaxation of HCA, nor did the guanylyl cyclase inhibitor ODQ, PKG inhibitor KT5823, EPAC1/2 inhibitor ESI09, potassium channel blockers TRAM‐34 + apamin, iberiotoxin or glibenclamide, or the Gαq inhibitor YM‐254890. Phosphodiesterase inhibitors induced a concentration‐dependent decrease in the response to KCl but did not potentiate relaxation to CGRP. Relaxation to forskolin was not blocked by PKA or AC inhibitors, although AC inhibitors significantly inhibited the increase in cAMP. Inhibition of Gβγ subunits using gallein significantly inhibited the relaxation to CGRP in human coronary arteries. Conclusion: While CGRP signalling is generally assumed to act via cAMP, the CGRP‐induced vasodilation in HCA was not inhibited by targeting this intracellular signalling pathway at different levels. Instead, inhibition of Gβγ subunits did inhibit the relaxation to CGRP, suggesting a different mechanism of CGRP‐induced relaxation than generally believed

Headache onset after vaccination against SARS-CoV-2: A systematic literature review and meta-analysis

Background Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are used to reduce the risk of developing Coronavirus Disease 2019 (COVID-19). Despite the significant benefits in terms of reduced risk of hospitalization and death, different adverse events may present after vaccination: among them, headache is one of the most common, but nowadays there is no summary presentation of its incidence and no description of its main features. Methods We searched PubMed and EMBASE covering the period between January 1(st) 2020 and August 6(th), 2021, looking for record in English and with an abstract and using three main search terms (with specific variations): COVID-19/SARS-CoV-2; Vaccination; headache/adverse events. We selected manuscript including information on subjects developing headache after injection, and such information had to be derived from a structured form (i.e. no free reporting). Pooled estimates and 95% confidence intervals were calculated. Analyses were carried out by vaccine vs. placebo, by first vs. second dose, and by mRNA-based vs. "traditional" vaccines; finally, we addressed the impact of age and gender on post-vaccine headache onset. Results Out of 9338 records, 84 papers were included in the review, accounting for 1.57 million participants, 94% of whom received BNT162b2 or ChAdOx1. Headache was generally the third most common AE: it was detected in 22% (95% CI 18-27%) of subjects after the first dose of vaccine and in 29% (95% CI 23-35%) after the second, with an extreme heterogeneity. Those receiving placebo reported headache in 10-12% of cases. No differences were detected across different vaccines or by mRNA-based vs. "traditional" ones. None of the studies reported information on headache features. A lower prevalence of headache after the first injection of BNT162b2 among older participants was shown. Conclusions Our results show that vaccines are associated to a two-fold risk of developing headache within 7 days from injection, and the lack of difference between vaccine types enable to hypothesize that headache is secondary to systemic immunological reaction than to a vaccine-type specific reaction. Some descriptions report onset within the first 24 h and that in around one-third of the cases, headache has migraine-like features with pulsating quality, phono and photophobia; in 40-60% of the cases aggravation with activity is observed. The majority of patients used some medication to treat headache, the one perceived as the most effective being acetylsalicylic acid

Nuevos escenarios para la docencia universitaria : entornos híbridos y pedagogías emergentes.

Memorias del IX Simposio Internacional de Docencia Universitaria (SIDU)Los trabajos reunidos en esta Memoria representan una contribución importante al campo de la educación y de la docencia universitaria, en tanto muestran distintas maneras de responder a las problemáticas educativas cotidianas y presentan propuestas para afrontar los retos emergentes en el campo de la educación superior. Invitamos a los lectores a realizar una lectura atenta y crítica de los trabajos compilados en esta publicación. Estamos seguros de que este acercamiento propiciará la reflexión y el análisis riguroso de los objetos de estudio abordados por los autores, y estimulará la generación de nuevos proyectos de investigación, intervención e innovación educativa que incidan en el desarrollo de mejores prácticas de docencia en educación media superior y superior.Pimera edición digitaldoi.org/10.56019/EDU-CETYS.2024.182

The role of α1- and α2-adrenoceptor subtypes in the vasopressor responses induced by dihydroergotamine in ritanserin-pretreated pithed rats

textabstractBackground: Dihydroergotamine (DHE) is an acute antimigraine agent that displays affinity for dopamine D2-like receptors, serotonin 5-HT1/2 receptors and α1/α2-adrenoceptors. Since activation of vascular α1/α2-adrenoceptors results in systemic vasopressor responses, the purpose of this study was to investigate the specific role of α1- and α2-adrenoceptors mediating DHE-induced vasopressor responses using several antagonists for these receptors. Methods: For this purpose, 135 male Wistar rats were pithed and divided into 35 control and 100 pretreated i.v. with ritanserin (100 μg/kg; to exclude the 5-HT2 receptor-mediated systemic vasoconstriction). Then, the vasopressor responses to i.v. DHE (1–3100 μg/kg, given cumulatively) were determined after i.v. administration of some α1/α2-adrenoceptor antagonists. Results: In control animals (without ritanserin pretreatment), the vasopressor responses to DHE were: (i) unaffected after prazosin (α1; 30 μg/kg); (ii) slightly, but significantly, blocked after rauwolscine (α2; 300 μg/kg); and (iii) markedly blocked after prazosin (30 μg/kg) plus rauwolscine (300 μg/kg). In contrast, after pretreatment with ritanserin, the vasopressor responses to DHE were: (i) attenuated after prazosin (α1; 10 and 30 μg/kg) or rauwolscine (α2; 100 and 300 μg/kg); (ii) markedly blocked after prazosin (30 μg/kg) plus rauwolscine (300 μg/kg); (iii) attenuated after 5-methylurapidil (α1A; 30–100 μg/kg), L-765,314 (α1B; 100 μg/kg), BMY 7378 (α1D; 30–100 μg/kg), BRL44408 (α2A; 100–300 μg/kg), imiloxan (α2B; 1000–3000 μg/kg) or JP-1302 (α2C; 1000 μg/kg); and (iv) unaffected after the corresponding vehicles (1 ml/kg). Conclusion: These results suggest that the DHE-induced vasopressor responses in ritanserin-pretreated pithed rats are mediated by α1- (probably α1A, α1B and α1D) and α2- (probably α2A, α2B and α2C) adrenoceptors. These findings could shed light on the pharmacological profile of the vascular side effects (i.e. systemic vasoconstriction) produced by DHE and may lead to the development of more selective antimigraine drugs devoid vascular side effects

The role of α1- and α2-adrenoceptor subtypes in the vasopressor responses induced by dihydroergotamine in ritanserin-pretreated pithed rats

Background: Dihydroergotamine (DHE) is an acute antimigraine agent that displays affinity for dopamine D2-like receptors, serotonin 5-HT1/2 receptors and α1/α2-adrenoceptors. Since activation of vascular α1/α2-adrenoceptors results in systemic vasopressor responses, the purpose of this study was to investigate the specific role of α1- and α2-adrenoceptors mediating DHE-induced vasopressor responses using several antagonists for these receptors. Methods: For this purpose, 135 male Wistar rats were pithed and divided into 35 control and 100 pretreated i.v. with ritanserin (100 μg/kg; to exclude the 5-HT2 receptor-mediated systemic vasoconstriction). Then, the vasopressor responses to i.v. DHE (1–3100 μg/kg, given cumulatively) were determined after i.v. administration of some α1/α2-adrenoceptor antagonists. Results: In control animals (without ritanserin pretreatment), the vasopressor responses to DHE were: (i) unaffected after prazosin (α1; 30 μg/kg); (ii) slightly, but significantly, blocked after rauwolscine (α2; 300 μg/kg); and (iii) markedly blocked after prazosin (30 μg/kg) plus rauwolscine (300 μg/kg). In contrast, after pretreatment with ritanserin, the vasopressor responses to DHE were: (i) attenuated after prazosin (α1; 10 and 30 μg/kg) or rauwolscine (α2; 100 and 300 μg/kg); (ii) markedly blocked after prazosin (30 μg/kg) plus rauwolscine (300 μg/kg); (iii) attenuated after 5-methylurapidil (α1A; 30–100 μg/kg), L-765,314 (α1B; 100 μg/kg), BMY 7378 (α1D; 30–100 μg/kg), BRL44408 (α2A; 100–300 μg/kg), imiloxan (α2B; 1000–3000 μg/kg) or JP-1302 (α2C; 1000 μg/kg); and (iv) unaffected after the corresponding vehicles (1 ml/kg). Conclusion: These results suggest that the DHE-induced vasopressor responses in ritanserin-pretreated pithed rats are mediated by α1- (probably α1A, α1B and α1D) and α2- (probably α2A, α2B and α2C) adrenoceptors. These findings could shed light on the pharmacological profile of the vascular side effects (i.e. systemic vasoconstriction) produced by DHE and may lead to the development of more selective antimigraine drugs devoid vascular side effects

Functional Analysis of TRPA1, TRPM3, and TRPV1 Channels in Human Dermal Arteries and Their Role in Vascular Modulation

Transient receptor potential (TRP) channels are pivotal in modulating vascular functions. In fact, topical application of cinnamaldehyde or capsaicin (TRPA1 and TRPV1 channel agonists, respectively) induces “local” changes in blood flow by releasing vasodilator neuropeptides. We investigated TRP channels’ contributions and the pharmacological mechanisms driving vasodilation in human isolated dermal arteries. Ex vivo studies assessed the vascular function of artery segments and analyzed the effects of different compounds. Concentration–response curves to cinnamaldehyde, pregnenolone sulfate (PregS, TRPM3 agonist), and capsaicin were constructed to evaluate the effect of the antagonists HC030031 (TRPA1); isosakuranetin (TRPM3); and capsazepine (TRPV1). Additionally, the antagonists/inhibitors olcegepant (CGRP receptor); L-NAME (nitric oxide synthase); indomethacin (cyclooxygenase); TRAM-34 plus apamin (K+ channels); and MK-801 (NMDA receptors, only for PregS) were used. Moreover, CGRP release was assessed in the organ bath fluid post-agonist-exposure. In dermal arteries, cinnamaldehyde- and capsaicin-induced relaxation remained unchanged after the aforementioned antagonists, while PregS-induced relaxation was significantly inhibited by isosakuranetin, L-NAME and MK-801. Furthermore, there was a significant increase in CGRP levels post-agonist-exposure. In our experimental model, TRPA1 and TRPV1 channels seem not to be involved in cinnamaldehyde- or capsaicin-induced relaxation, respectively, whereas TRPM3 channels contribute to PregS-induced relaxation, possibly via CGRP-independent mechanisms

Intracellular pathways of calcitonin gene-related peptide-induced relaxation of human coronary arteries: A key role for Gβγ subunit instead of cAMP.

Publication status: PublishedBACKGROUND AND PURPOSE: Calcitonin gene-related peptide (CGRP) is a potent vasodilator. While its signalling is assumed to be mediated via increases in cAMP, this study focused on elucidating the actual intracellular signalling pathways involved in CGRP-induced relaxation of human isolated coronary arteries (HCA). EXPERIMENTAL APPROACH: HCA were obtained from heart valve donors (27 M, 25 F, age 54 ± 2 years). Concentration-response curves to human α-CGRP or forskolin were constructed in HCA segments, incubated with different inhibitors of intracellular signalling pathways, and intracellular cAMP levels were measured with and without stimulation. RESULTS: Adenylyl cyclase (AC) inhibitors SQ22536 + DDA and MDL-12330A, and PKA inhibitors Rp-8-Br-cAMPs and H89, did not inhibit CGRP-induced relaxation of HCA, nor did the guanylyl cyclase inhibitor ODQ, PKG inhibitor KT5823, EPAC1/2 inhibitor ESI09, potassium channel blockers TRAM-34 + apamin, iberiotoxin or glibenclamide, or the Gαq inhibitor YM-254890. Phosphodiesterase inhibitors induced a concentration-dependent decrease in the response to KCl but did not potentiate relaxation to CGRP. Relaxation to forskolin was not blocked by PKA or AC inhibitors, although AC inhibitors significantly inhibited the increase in cAMP. Inhibition of Gβγ subunits using gallein significantly inhibited the relaxation to CGRP in human coronary arteries. CONCLUSION: While CGRP signalling is generally assumed to act via cAMP, the CGRP-induced vasodilation in HCA was not inhibited by targeting this intracellular signalling pathway at different levels. Instead, inhibition of Gβγ subunits did inhibit the relaxation to CGRP, suggesting a different mechanism of CGRP-induced relaxation than generally believed