scholarly journals Hypofunctionality of Gi Proteins as Aetiopathogenic Mechanism for Migraine and Cluster Headache

Cephalalgia ◽  
2001 ◽  
Vol 21 (1) ◽  
pp. 38-45 ◽  
Author(s):  
N Galeotti ◽  
C Ghelardini ◽  
M Zoppi ◽  
E Del Bene ◽  
L Raimondi ◽  
...  
Keyword(s):  
Cluster Headache ◽  
Pain Perception ◽  
Primary Headache ◽  
Adenylyl Cyclase Activity ◽  
Protein Levels ◽  
Gi Protein ◽  
Camp Levels ◽  
Reduced Activity ◽  
Gi Proteins ◽  
Headache Patients

The involvement of Gi proteins in the modulation of pain perception has been widely established, and mutations in G-proteins have already been identified as the aetiopathological cause of human diseases. The aim of the present study was to determine whether a deficiency or a hypofunctionality of the Gi proteins occurred in primary headache. The functionality and the level of expression of Gi proteins were investigated in lymphocytes from migraine without aura, migraine with aura and cluster headache sufferers. A reduced capability to inhibit forskolin-stimulated adenylyl cyclase activity in headache patients was observed. Migraine patients also showed basal adenosine cAMP levels about four times higher than controls. The reduced activity of Gi proteins seems not to be related to a reduction of protein levels since no significant reduction of the Giα subunits was observed. These results indicate Gi protein hypofunctionality as an aetiopathogenic mechanism in migraine and cluster headache.

Abnormal tyrosine metabolism in chronic cluster headache

Cephalalgia ◽  
2016 ◽  
Vol 37 (2) ◽  
pp. 148-153 ◽  
Author(s):  
Giovanni D’Andrea ◽  
Massimo Leone ◽  
Gennaro Bussone ◽  
Paola Di Fiore ◽  
Andrea Bolner ◽  
...  
Keyword(s):  
Cluster Headache ◽  
Plasma Levels ◽  
Primary Headache ◽  
Chronic Cluster Headache ◽  
Predisposing Factor ◽  
Episodic Cluster Headache ◽  
Tyrosine Metabolism ◽  
Low Levels ◽  
And Control ◽  
Headache Patients

Objective Episodic cluster headache is characterized by abnormalities in tyrosine metabolism (i.e. elevated levels of dopamine, tyramine, octopamine and synephrine and low levels of noradrenalin in plasma and platelets.) It is unknown, however, if such biochemical anomalies are present and/or constitute a predisposing factor in chronic cluster headache. To test this hypothesis, we measured the levels of dopamine and noradrenaline together with those of elusive amines, such as tyramine, octopamine and synephrine, in plasma of chronic cluster patients and control individuals. Methods Plasma levels of dopamine, noradrenaline and trace amines, including tyramine, octopamine and synephrine, were measured in a group of 23 chronic cluster headache patients (10 chronic cluster ab initio and 13 transformed from episodic cluster), and 16 control participants. Results The plasma levels of dopamine, noradrenaline and tyramine were several times higher in chronic cluster headache patients compared with controls. The levels of octopamine and synephrine were significantly lower in plasma of these patients with respect to control individuals. Conclusions These results suggest that anomalies in tyrosine metabolism play a role in the pathogenesis of chronic cluster headache and constitute a predisposing factor for the transformation of the episodic into a chronic form of this primary headache.

Dynamics of adenylate cyclase regulation via heterotrimeric G-proteins

2014 ◽  
Vol 42 (2) ◽  
pp. 239-243 ◽  
Author(s):  
Markus Milde ◽  
Ruth C. Werthmann ◽  
Kathrin von Hayn ◽  
Moritz Bünemann
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Umbilical Vein ◽  
Underlying Mechanism ◽  
Protein Activity ◽  
Gi Protein ◽  
Continuous Presence ◽  
Umbilical Vein Endothelial Cells ◽  
Camp Levels ◽  
Gi Proteins

A wide variety of G-protein-coupled receptors either activate or inhibit ACs (adenylate cyclases), thereby regulating cellular cAMP levels and consequently inducing proper physiological responses. Stimulatory and inhibitory G-proteins interact directly with ACs, whereas Gq-coupled receptors exert their effects primarily via Ca2+. Using the FRET-based cAMP sensor Epac1 (exchange protein directly activated by cAMP 1)–cAMPS (adenosine 3′,5′-cyclic monophosphorothioate), we studied cAMP levels in single living VSMCs (vascular smooth muscle cells) or HUVECs (human umbilical vein endothelial cells) with subsecond temporal resolution. Stimulation of purinergic (VSMCs) or thrombin (HUVECs) receptors rapidly decreased cAMP levels in the presence of the β-adrenergic agonist isoprenaline via a rise in Ca2+ and subsequent inhibition of AC5 and AC6. Specifically in HUVECs, we observed that, in the continuous presence of thrombin, cAMP levels climbed slowly after the initial decline with a delay of a little less than 1 min. The underlying mechanism includes phospholipase A2 activity and cyclo-oxygenase-mediated synthesis of prostaglandins. We studied further the dynamics of the inhibition of ACs via Gi-proteins utilizing FRET imaging to resolve interactions between fluorescently labelled Gi-proteins and AC5. FRET between Gαi1 and AC5 developed at much lower concentration of agonist compared with the overall Gi-protein activity. We found the dissociation of Gαi1 subunits and AC5 to occur slower than the Gi-protein deactivation. This led us to the conclusion that AC5, by binding active Gαi1, interferes with G-protein deactivation and reassembly and thereby might sensitize its own regulation.

scholarly journals Calcitonin Gene-Related Peptide (CGRP) and Cluster Headache

2020 ◽  
Vol 10 (1) ◽  
pp. 30 ◽  
Author(s):  
Andrea Carmine Belin ◽  
Caroline Ran ◽  
Lars Edvinsson
Keyword(s):  
Cluster Headache ◽  
Pain Perception ◽  
Primary Headache ◽  
Active Phase ◽  
Calcitonin Gene Related Peptide ◽  
Primary Headaches ◽  
Cgrp Receptor ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Autonomic Reflex

Cluster headache (CH) is a severe primary headache with a prevalence of 1/1000 individuals, and a predominance in men. Calcitonin gene-related peptide (CGRP) is a potent vasodilator, originating in trigeminal neurons and has a central role in CH pathophysiology. CGRP and the CGRP receptor complex have recently taken center stage as therapeutic targets for primary headaches, such as migraine. Multiple CGRP and CGRP receptor monoclonal antibodies, as well as small molecule antagonists (gepants) are on their way constituting a new frontier of migraine and possibly CH medication. During a CH attack, there is an activation of the trigeminal-autonomic reflex with the release of CGRP, and inversely if CGRP is administered to a CH patient in an active disease phase, it triggers an attack. Increased levels of CGRP have been found in ipsilateral jugular vein blood during the active phase of CH. This process is hypothesized to have a key role in the intense pain perception and in the associated distinctive vasodilation. So far, clinical tests of CGRP antibodies have been inconclusive in CH patients. This review summarizes the current state of knowledge on the role of CGRP in CH pathology, and as a target for future treatments.

The impact of sexual activity on idiopathic headaches: An observational study

Cephalalgia ◽  
2013 ◽  
Vol 33 (6) ◽  
pp. 384-389 ◽  
Author(s):  
Anke Hambach ◽  
Stefan Evers ◽  
Oliver Summ ◽  
Ingo W Husstedt ◽  
Achim Frese
Keyword(s):  
Observational Study ◽  
Cluster Headache ◽  
Sexual Activity ◽  
Case Reports ◽  
Primary Headache ◽  
Complete Relief ◽  
Headache Attack ◽  
Cluster Headache Attack ◽  
The Impact ◽  
Headache Patients

Background Headache associated with sexual activity is a well-known primary headache disorder. In contrast, some case reports in the literature suggest that sexual activity during a migraine or cluster headache attack might relieve the pain in at least some patients. We performed an observational study among patients of a tertiary headache clinic. Methods A questionnaire was sent to 800 unselected migraine patients and 200 unselected cluster headache patients. We asked for experience with sexual activity during a headache attack and its impact on headache intensity. The survey was strictly and completely anonymous. Results In total, 38% of the migraine patients and 48% of the patients with cluster headache responded. In migraine, 34% of the patients had experience with sexual activity during an attack; out of these patients, 60% reported an improvement of their migraine attack (70% of them reported moderate to complete relief) and 33% reported worsening. In cluster headache, 31% of the patients had experience with sexual activity during an attack; out of these patients, 37% reported an improvement of their cluster headache attack (91% of them reported moderate to complete relief) and 50% reported worsening. Some patients, in particular male migraine patients, even used sexual activity as a therapeutic tool. Conclusions The majority of patients with migraine or cluster headache do not have sexual activity during headache attacks. Our data suggest, however, that sexual activity can lead to partial or complete relief of headache in some migraine and a few cluster headache patients.

scholarly journals Cluster Headache and the Comprehension Paradox

2022 ◽  
Vol 4 (1) ◽  
Author(s):  
Heiko Pohl ◽  
Andreas R. Gantenbein ◽  
Peter S. Sandor ◽  
Jean Schoenen ◽  
Colette Andrée
Keyword(s):  
Sick Leave ◽  
Cluster Headache ◽  
Leisure Activities ◽  
Primary Headache ◽  
Headache Disorders ◽  
Online Questionnaire ◽  
Primary Headache Disorders ◽  
The Times ◽  
Headache Patients

AbstractPatients with primary headache disorders such as cluster headache cycle between being entirely healthy and almost completely incapacitated. Sick leave or reduced performance due to headache attacks demands flexibility by their social counterparts. The objective of this study is to test the hypothesis that headache patients cause frustration that grows with the times colleagues have to take over their work. In this study, we analysed cluster headache patients’ answers to an online questionnaire. Participants self-reported their number of sick days, the number of days on which leisure activities were missed and whether they felt understood by colleagues and family. We then investigated the correlation between the number of sick days and the proportion of patients feeling understood by colleagues and friends. We found that feeling understood by colleagues and friends decreases with a growing number of sick days. However, when sick days accrue further, this proportion increases again. The number of sick days correlates similarly with both colleagues’ and friends’ understanding. The number of cluster headache patients feeling understood by others decreases with an increasing number of sick days. Their social circles’ frustration with the patients’ failure to meet obligations and expectations are a likely reason. With a growing number of sick days, however, the portion of patients feeling understood rises again despite patients meeting others’ expectations even less. This ‘comprehension paradox’ implies the influence of other factors. We suspect that growing numbers of sick days foster understanding as the disability of the disease becomes increasingly apparent.

scholarly journals Osmophobia in primary headache patients: associated symptoms and response to preventive treatments

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Marianna Delussi ◽  
Anna Laporta ◽  
Ilaria Fraccalvieri ◽  
Marina de Tommaso
Keyword(s):  
Cluster Headache ◽  
Rating Scale ◽  
Preventive Treatment ◽  
Primary Headache ◽  
Tension Type Headache ◽  
Primary Headaches ◽  
Self Rating ◽  
Type Headache ◽  
Headache Center ◽  
Headache Patients

Abstract Background Osmophobia, is common among primary headaches, with prevalence of migraine. The study aimed to evaluate prevalence and clinical characteristics of patients with osmophobia in a cohort of primary headache patients selected at a tertiary headache center. The second aim was to verify the possible predicting role of osmophobia in preventive treatment response in a sub cohort of migraine patients. Methods This was an observational retrospective cohort study based on data collected in a tertiary headache center. We selected patients aged 18–65 years, diagnosed as migraine without aura (MO), migraine with aura (MA) or Chronic Migraine (CM), Tension-Type Headache (TTH); and Cluster Headache (CH). We also selected a sub-cohort of migraine patients who were prescribed preventive treatment, according to Italian Guidelines, visited after 3 months follow up. Patients were considered osmophobic, if reported this symptom in at least the 20% of headache episodes. Other considered variables were: headache frequeny, the migraine disability assessment (MIDAS), Allodynia Symptom Checklist, Self-rating Depression scale, Self-rating Anxiety scale, Pain intensity evaluated by Numerical Rating Scale-NRS- form 0 to 10. Results The 37,9% of patients reported osmophobia (444 patients with osmophobia, 726 without osmophobia). Osmophobia prevailed in patients with the different migraine subtypes, and was absent in patients with episodic tension type headache and cluster headache (chi square 68.7 DF 7 p < 0.0001). Headache patients with osmophobia, presented with longer hedache duration (F 4.91 p 0.027; more severe anxiety (F 7.56 0.007), depression (F 5.3 p 0.019), allodynia (F 6 p 0.014), headache intensity (F 8.67 p 0.003). Tension type headache patients with osmophobia (n° 21), presented with more frequent headache and anxiety. A total of 711 migraine patients was visited after 3 months treatment. The change of main migraine features was similar between patients with and without osmophobia. Conclusions While the present study confirmed prevalence of osmophobia in migraine patients, it also indicated its presence among chronic tension type headache cases, marking those with chronic headache and anxiety. Osmophobia was associated to symptoms of central sensitization, as allodynia. It was not relevant to predict migraine evolution after first line preventive approach.

scholarly journals ‘A cry in the dark’: a qualitative exploration of living with cluster headache

2020 ◽  
pp. 204946372097669
Author(s):  
Laura Andre ◽  
Debbie Cavers
Keyword(s):  
Primary Care ◽  
Cluster Headache ◽  
Lived Experience ◽  
Social Contact ◽  
Primary Headache ◽  
Headache Disorder ◽  
Psychosocial Needs ◽  
Structured Interviews ◽  
The Impact ◽  
Headache Patients

Context: Cluster headache is a rare primary headache disorder said to be one of the most painful conditions in existence. Limited evidence demonstrates cluster headache patients have difficulties securing a diagnosis and poor access to services. There is a gap in research around psychosocial needs, meaning there are no evidence-based guidelines to inform optimal management of this patient group in primary care. Objectives: The aim of this study is to explore the perspectives of cluster headache patients in the United Kingdom in order to suggest ways their care can be improved. Methods: It is an in-depth qualitative study involving telephone interviews with 15 participants with either chronic or episodic cluster headache. Semi-structured interviews (43–58 minutes) were conducted, recorded and transcribed verbatim. Two researchers conducted thematic analysis to identify themes. Results: Participants described the impact cluster headache has on their quality of life. They also felt the legitimacy of their disorder was questioned. This situation was often exacerbated by a reported lack of awareness among General Practitioners (GPs), which negatively impacted their care in terms of diagnosis and access to treatments and specialists. They attempted to control the pain through treatments and avoiding triggers, often with detrimental consequences for their social contact and mental health. Conclusion: Findings indicate the need to improve the lived experience of cluster headache patients in two key areas: (1) raising awareness of the disorder and its impact among GPs, and (2) extending care beyond clinical treatment provision, supporting patients in self-management and addressing its psychosocial impact, with implications for the management of this group in primary care.

scholarly journals The molecular clock gene cryptochrome 1 (CRY1) and its role in cluster headache

Cephalalgia ◽  
2021 ◽  
pp. 033310242110241
Author(s):  
Carmen Fourier ◽  
Caroline Ran ◽  
Christina Sjöstrand ◽  
Elisabet Waldenlind ◽  
Anna Steinberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cluster Headache ◽  
Molecular Clock ◽  
Seasonal Affective Disorder ◽  
Primary Headache ◽  
Headache Disorder ◽  
Primary Fibroblast ◽  
Significant Difference ◽  
Cry1 Gene ◽  
Headache Patients

Background Cluster headache is a severe primary headache disorder commonly featuring a strikingly distinct circadian attack pattern. Therefore, the circadian system has been suggested to play a crucial role in the pathophysiology of cluster headache. Cryptochromes are key components of the molecular clock generating circadian rhythms and have previously been shown to be associated with several psychiatric disorders, including seasonal affective disorder, bipolar disorder, and depression. Methods In this case-control study, we investigated the role of cryptochrome ( CRY) genes in cluster headache by screening 628 cluster headache patients and 681 controls from Sweden for four known genetic variants in the CRY1 (rs2287161 and rs8192440) and CRY2 (rs10838524 and rs1554338) genes. In addition, we analyzed CRY1 gene expression in primary fibroblast cell lines from eleven patients and ten controls. Results The exonic CRY1 variant rs8192440 was associated with cluster headache on allelic level ( p=0.02) and this association was even more pronounced in a subgroup of patients with reported diurnal rhythmicity of attacks ( p=0.002). We found a small significant difference in CRY1 gene expression between cluster headache patients and control individuals ( p=0.04), but we could not identify an effect of the associated variant rs8192440 on CRY1 expression. Conclusions We discovered a disease-associated variant in the CRY1 gene and slightly increased CRY1 gene expression in tissue from cluster headache patients, strengthening the hypothesis of circadian dysregulation in cluster headache. How this gene variant may contribute to the pathophysiology of the disease remains subject to further studies.

Old Age of Onset in Cluster‐Headache Patients

2005 ◽  
Vol 45 (5) ◽  
pp. 615-616 ◽  
Author(s):  
Marthe Fischera ◽  
Kerstin Anneken ◽  
Stefan Evers
Keyword(s):  
Cluster Headache ◽  
Old Age ◽  
Age Of Onset ◽  
Headache Patients

Abstract 123: SUMO1 Modification Regulates SR Calcium ATPase Pump, SERCA2a in Heart Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Changwon Kho ◽  
Ahyoung Lee ◽  
Dongtak Jeong ◽  
Jae Gyun Oh ◽  
Antoine Chaanine ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Calcium Atpase ◽  
Post Translational Modifications ◽  
Beneficial Effects ◽  
Protein Levels ◽  
In Trans ◽  
Underlying Mechanisms ◽  
Hemodynamic Performance ◽  
Reduced Activity

Background: The cardiac calcium ATPase, SERCA2a, is a critical pump responsible for Ca2+ re-uptake during excitation-contraction coupling. Impaired Ca2+ uptake resulting from decreased expression and reduced activity of SERCA2a is a hallmark of heart failure. Accordingly, restoration of SERCA2a expression by gene transfer has proved to be effective in improving cardiac function in heart-failure patients, as well as in animal models. However, the underlying mechanisms of SERCA2a’s dysfunction remain incompletely understood. Methods and Results: In this study, we show that SERCA2a is modified by SUMO1 at lysine sites 480 and 585 and that this SUMOylation is essential for preserving SERCA2a ATPase activity and stability in mouse and human cells. SUMO1 and SERCA2a SUMOylation levels were both decreased in mouse and pig models of heart failure and failing human left ventricles. To determine whether reduced SUMO1 levels are responsible for reduced SERCA2a protein levels and reduced cardiac function, we used an adenovirus associated virus-mediated gene delivery approach to up-regulate SUMO1 in trans aortic constriction-induced mouse model of heart failure. We found that increasing SUMO1 levels led to a restoration of SERCA2a levels, improved hemodynamic performance, and reduced mouse mortality. By contrast, down-regulation of SUMO1 using small hairpin RNA accelerated cardiac functional deterioration and was accompanied by decreased SERCA2a function. Conclusion: In this study, we study a new mechanism for modulation of SERCA2a activity and beneficial effects of SUMO1 in the setting of heart failure. It suggests that changes in post-translational modifications of SERCA2a could negatively affect cardiac function in heart failure. Our data may provide a new platform for the design of therapeutic strategies for heart failure.

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