Increasing the effect of triptans in migraine.
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Cross-Over Studies↗
Biomedical subjects
Jes Olesen
Publications and source records attributed to Jes Olesen.
Pharmacological and molecular comparison of K(ATP) channels in rat basilar and middle cerebral arteries.
ATP-sensitive potassium (K(ATP)) channels play an important role in the regulation of cerebral vascular tone. In vitro studies using synthetic K(ATP) channel openers suggest that the pharmacological profiles differ between rat basilar arteries and rat middle cerebral arteries. To address this issue, we studied the possible involvement of endothelial K(ATP) channels by pressurized arteriography after luminal administration of synthetic K(ATP) channel openers to rat basilar and middle cerebral arteries. Furthermore, we examined the mRNA and protein expression profile of K(ATP) channels to rat basilar and middle cerebral arteries using quantitative real-time PCR (Polymerase Chain Reaction) and Western blotting, respectively. In the perfusion system, we found no significant responses after luminal application of three K(ATP) channel openers to rat basilar and middle cerebral arteries. In contrast, abluminal application caused a concentration-dependent dilatation of both arteries, that was more potent in basilar than in middle cerebral arteries. Quantitative real-time PCR detected the presence of mRNA transcripts of the K(ATP) channel subunits Kir6.1, Kir6.2, SUR1 and SUR2B, while SUR2A mRNA was barely detected in both rat basilar and middle cerebral arteries. Of the five mRNAs, the expression levels of Kir6.1 and SUR2B transcripts were predominant in both rat basilar and middle cerebral arteries. Western blotting detected the presence of Kir6.1, Kir6.2, SUR1 and SUR2B proteins in both arteries. Densitometric measurements of the Western blot signals further showed higher expression levels of Kir6.1 and SUR2B proteins in rat middle cerebral arteries than was found in rat basilar arteries. In conclusion, our in vitro pharmacological studies showed no evidence for functional endothelial K(ATP) channels in either artery. Furthermore, the results indicate that Kir6.1/SUR2B is the major K(ATP) channel complex in rat basilar and middle cerebral arteries.
Angiography↗
European Brain Council: partnership to promote European and national brain research.
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Brain↗
Phosphodiesterase 3 and 5 and cyclic nucleotide-gated ion channel expression in rat trigeminovascular system.
Activation of the trigeminovascular pain signalling system appears involved in migraine pathophysiology. However, the molecular mechanisms are only partially known. Stimulation of cAMP and cGMP production as well as inhibition of their breakdown induce migraine-like headache. Additionally, migraine may be associated with mutations in ion channels. The aim of the present study was to describe the expression of phosphodiesterase 3 (PDE3) and 5 (PDE5) and cyclic nucleotide-gated ion channels (CNG) in cerebral arteries, meninges, and the trigeminal ganglion. mRNA for PDE and CNG was determined in the rat middle cerebral artery, basilar artery, trigeminal ganglion, and dura mater using real-time PCR. PDE and CNG proteins were identified using Western blot. For comparison, rat aorta and mesenteric artery were analysed. PDE3A, PDE3B, and PDE5A mRNA were detected in all tissues examined except for PDE3A mRNA in dura mater and the trigeminal ganglion. PDE5A and PDE3A protein expression was present in both cerebral and peripheral arteries, whereas PDE3B protein was present only in the cerebral arteries. The CNGA4 and B1 subunit mRNAs were detected in cerebral arteries and CNGA2 also in the mesenteric artery. CNGA2 and A3 proteins were found in cerebral arteries and dura and CNGA1, CNGA2 and CNGA3 in the trigeminal ganglion. In conclusion, PDE3A, PDE3B, PDE5A, and five CNG subunits were expressed in several components of the trigeminovascular system of the rat. This suggests that modulation of cAMP and cGMP levels by PDE and activation of CNG may play a role in trigeminovascular pain signalling leading to migraine headache.
3',5'-Cyclic-AMP Phosphodiesterases↗
Probable medication-overuse headache: the effect of a 2-month drug-free period.
OBJECTIVE: To describe the emerging profile of headache frequency following a 2-month drug-free period in patients with medication overuse. METHODS: All patients treated and discharged from Danish Headache Center in 2002 and 2003 had prospectively filled out a diagnostic headache diary on a daily basis. For patients with probable medication-overuse headache (MOH), the authors determined headache frequencies before and after medication withdrawal from these prospective recordings. RESULTS: Among 1,326 patients, 337 had probable MOH. Two hundred sixteen patients who stayed medication-free for 2 months were eligible. Overall, 45% of the patients improved, 48% had no change, and 7% had more headaches. Median age was 48 years, and male/female ratio 1:2.7. The relative reduction in headache frequency varied considerably with a 67% median reduction in migraine, 0% in tension-type headache (TTH), and 37% in patients with both migraine and TTH (MT). Comparing the diagnostic groups, the relative reduction in frequency differed between migraine and TTH (p < 0.001) and between MT and TTH (p < 0.01). Triptan/ergot overusers improved the most (p < 0.0001). The difference between MT and TTH remained significant when triptan/ergot overuse was controlled (p < 0.05). CONCLUSION: These data demonstrate the benefit of withdrawal in already established medication overuse and support the existence of medication-overuse headache as a clinical entity.
Adult↗
The CACNA1A and ATP1A2 genes are not involved in dominantly inherited migraine with aura.
Epidemiological studies indicate that migraine with typical aura (MA) has a major genetic component but the genes for MA have not been identified. However, the autosomal dominantly inherited familial hemiplegic migraine (FHM) is often caused by mutations in the CACNA1A or ATP1A2 genes. The aim of the study was to investigate if the CACNA1A or ATP1A2 genes are involved in MA with an apparently autosomal dominant mode of inheritance. From a clinic population diagnosed by a trained physician we recruited 34 extended families (comprising 174 MA patients) with an apparently autosomal dominant mode of inheritance of MA. We performed a linkage analysis of 161 of 174 MA patients and 79 unaffected relatives using a framework marker set of 44 markers for chromosome 1 and 22 markers for chromosome 19. Linkage analysis was made with a non-parametric or autosomal dominant parametric model, either allowing for heterogeneity or not, using an affected only analysis. We identified no linkage to CACNA1A and ATP1A2 loci on chromosome 19 or 1, respectively. Additionally, at least two patients from each family and 92 healthy, unrelated controls were selected for a sequence analysis. We sequenced the 48 exons of CACNA1A and the 23 exons of ATP1A2, including promoter and flanking intron sequences. No polymorphism was identified in the CACNA1A or ATP1A2 genes with a strong correlation to MA. Our study shows that the CACNA1A or ATP1A2 genes are probably not involved in MA. To identify the genes involved in the common forms of migraine, future genetic studies should focus on MA and migraine without aura (MO) and not FHM.
Calcium Channels↗
Basilar-type migraine: clinical, epidemiologic, and genetic features.
BACKGROUND: It remains uncertain whether basilar-type migraine (BM) is a subtype of migraine with typical aura (MTA) or a distinct phenotype or genotype. OBJECTIVE: To analyze the symptomatology, familial distribution, and genotype of BM. METHODS: The authors recruited 105 families comprising 362 patients with MTA or BM (International Classification of Headache Disorders-1 criteria). Among these patients, 38 patients from 29 families had BM. In 12 of the families with BM with an apparently dominant inheritance the authors sequenced all exons of the CACNA1A (chromosome 19) and ATP1A2 (chromosome 1) genes responsible for most cases of the autosomal dominantly inherited familial hemiplegic migraine and performed a linkage analysis of chromosome 1 and 19 with a nonparametric or autosomal dominant parametric model using an affected only analysis. RESULTS: BM occurred in 10% (38/362) of patients with MTA. The basilar-type aura had a median duration of 60 minutes and comprised vertigo 61%, dysarthria 53%, tinnitus 45%, diplopia 45%, bilateral visual symptoms 40%, bilateral paresthesias 24%, decreased level of consciousness 21%, hypacusia 21%, and ataxia 5%. The relative frequency of the individual basilar-type symptoms was not different from patients with hemiplegic migraine from a previous study. The patients with BM were equally distributed among the 105 families with MTA (p = 0.37). The attacks of MTA were identical in families with or without BM. No causative mutations and no linkage was identified. CONCLUSIONS: Basilar-type aura seemingly may occur at times in any patient with migraine with typical aura. There is no firm clinical, epidemiologic, or genetic evidence that BM is an independent disease entity different from MTA.
Adult↗
The in vivo effect of adrenomedullin on rat dural and pial arteries.
Adrenomedullin is related to the calcitonin gene-related peptide (CGRP) family and is present in cerebral blood vessels. It may be involved in migraine mechanisms. We measured the change in dural and pial artery diameter, mean arterial blood pressure and local cerebral blood flow flux (LCBF(Flux)) after intravenous (i.v.) infusion of adrenomedullin. The study was performed in the presence or absence of the CGRP1 (calcitonin-receptor-like-receptor (CALCRL)/receptor activity-modifying protein-1 (RAMP1)) receptor antagonists BIBN4096BS, CGRP-(8-37) and the adrenomedullin receptor antagonist adrenomedullin-(22-52). I.v. infusion of 15 mug kg(-1) adrenomedullin (n=8) induced dilatation of dural (32+/-7.5%) and pial (18+/-5.5%) arteries, a reduction in mean arterial blood pressure (19+/-3%) and an increase in LCBF(Flux) (16+/-8.4%). The duration of the responses was 25 min for the dural artery, while the response of the pial artery lasted for 15 min. The CGRP1-receptor antagonists BIBN4096BS and CGRP-(8-37) and the adrenomedullin receptor antagonist adrenomedullin-(22-52) significantly inhibited the effect of adrenomedullin (n=7, P<0.05 for both arteries) on dural and pial artery diameter and mean arterial blood pressure. No significant inhibition of LCBF(Flux) was found. The antagonist alone had no effect on mean arterial blood pressure or LCBF(Flux). In conclusion, we suggest that adrenomedullin in the rat cranial circulation dilates dural and pial arteries, reduces mean arterial blood pressure and increases LCBF(Flux), probably via a CGRP1-receptor.
Adrenomedullin↗
Classification of headache disorders.
Clinical diagnostic classifications are critical when clear biological markers are not available. Such is the case in many headache disorders and mental disorders. Also, it is crucial that the classification is widely accepted and utilized. A main goal of classification is to be a universal language for categorizing a disease or a set of disorders, establishing diagnostic criteria, and promoting unity in treatment. The International Headache Society published its first Classification of Headache Disorders in 1988 and its second edition in 2004. The first classification paved the way for a better understanding of the epidemiology, mechanisms, and treatment of headache disorders, and the second edition likely will magnify our knowledge. This article provides an overview of the classification system and outlines some of the major changes in the revised edition.
Diagnosis, Differential↗
Are headache disorders caused by neurobiological mechanisms?
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Calcitonin Gene-Related Peptide↗
Implications of clinical subtypes of migraine with aura.
OBJECTIVE: To compare the clinical characteristics of familial hemiplegic migraine (FHM), sporadic hemiplegic migraine (SHM), and nonhemiplegic migraine with aura (NHMA) and further, to compare subtypes of NHMA. BACKGROUND: To discover distinct underlying genetic and pathophysiological mechanisms it is crucial to drive clinical subdivision of migraine with aura as far as possible. The documentation of subtypes of migraine with aura depends on the clinical characteristics as the genetic mechanisms are unknown except for the dominantly inherited FHM. METHODS: Patients with FHM, SHM, or familial NHMA were recruited from specialist practice and diagnosed according to the International Classification of Headache Disorders (ICHD) in a validated interview by a physician. Patients with hemiplegic migraine had a physical and neurological examination. Patients with population-based NHMA from a previous Danish study were used for comparison. RESULTS: We recruited 147 patients with FHM, 105 with SHM, and 362 with familial NHMA. FHM and SHM had similar aura and headache characteristics. Patients with FHM and SHM were more likely to experience two or more aura symptoms (100% vs. 31%, P < .0001), they more often had prolonged aura symptoms, they almost always had a headache associated with the aura (93% vs. 58%, P < .0001), and they more frequently had basilar-type symptoms (69% vs. 10%, P < .0001) than patients with population-based NHMA. Patients with familial NHMA were more likely to experience two or more aura symptoms than patients with population-based NHMA (61% vs. 32%, P < .0001). Within the subtypes of NHMA, patients with typical aura with migraine headache had an earlier age at onset (20 +/- 10 vs. 23 +/- 13 years, P= .044) and a higher co-occurrence of migraine without aura (43% vs. 22%, P= .002) than patients with typical aura with nonmigraine headache. CONCLUSIONS: The present study proves that distinct subtypes of migraine with aura exist. It further underlines the phenotypic differences between the different subtypes of migraine with aura which likely are caused by different etiological mechanisms. In future studies FHM, SHM, and NHMA therefore should be analyzed as separate entities and patients with NHMA may be stratified by ICHD-2 subtype of NHMA.
Adolescent↗
Consensus document on European brain research.
Brain disease psychiatric and neurologic disease combined represents a considerable social and economic burden in Europe. Data collected by the World Health Organization (WHO) suggest that brain diseases are responsible for 35% of Europe's total disease burden. An analysis of all health economic studies of brain diseases in Europe, published by the European Brain Council (EBC) in June 2005, estimated the total cost of brain disease in Europe in 2004 to be Euro 386 billion. That burden is set to grow, mainly due to the fact that the European population is ageing. Investment in brain sciences does not match that burden now, let alone in the future. Brain research received only 8% of the life science budget in the European Commission's Fifth Framework Programme, which represents less than 0.01% of the annual cost of brain disorders for that period. Over the last decade, Europe has been losing ground to the USA and Japan in terms of both basic and clinical research. Many of Europe's young researchers are taking up posts in the USA and staying there. Big pharmaceutical companies are fleeing Europe for the USA, taking their drug development programmes with them. Research in the brain sciences now holds the promise of therapies that halt and even reverse neurodegeneration, of better diagnostic tools, neural prostheses for the paralysed and drugs for depression and anxiety that are tailored to the individual, thereby eliminating or reducing side effects. Our growing understanding of the normal brain could lead to better prevention of brain disease and to more effective teaching methods. The need for innovative treatments has never been greater, and Europe boasts clusters of excellent researchers in biotechnology who could collaborate with brain scientists and the pharmaceutical industry to realise this promise. But if Europe is to seize these opportunities and meet the challenge of brain disease, it needs to go forward on the basis of greater collaboration between countries, greater collaboration between industry, academia and patient organisations, and increased investment in the brain sciences. The EBC was formed in 2002 to bring together scientists, clinicians, the pharmaceutical industry, charities and patient organisations from all over Europe to campaign for these goals. It takes a novel, bottom-up approach to research policy, and in developing this consensus document, it aims to promote a greater and more focused effort in this area, to improve public understanding of the brain sciences and above all, to support brain research as a priority under the European Commission's Seventh Framework Programme (FP7, 2007-2013). The research programme outlined here was first conceived by the EBC board. An outline was sent to all member organisations and a number of individual experts for comments. Following that, a table of contents was developed. The 45 research themes were written by groups of experts from across Europe who represent a wide range of disciplines. Each one contains a proposal for future research on a specific brain-related theme which the EBC believes could form the basis of one or more integrated projects or strategic targeted research projects (STREP) funded under FP7. The EBC has deliberately focused on the major diseases and then described the basic research needed to understand and treat or perhaps even cure those diseases. The programme is therefore constructed "from man to molecule" and not the other way round, with equal importance attached to basic and clinical research. The EBC suggests that each of the proposed integrated projects or STREP should be awarded a budget in the order of Euro 10 to 15 million. In addition, brain research should be treated as an important element of many other parts of FP7, such as the European Research Council and research programmes on information technology and the causes of violence. Any research programme that concerns human behaviour should, by definition, take account of brain research. The EBC envisages that the priority for brain research it proposes at the European level will translate into higher priority for brain research at the national level, and this document may also serve as a starting point for the development of national consensus programmes. It seems likely that consensus conferences on brain research in Europe may further develop the themes and ideas discussed here. An EBC task force may also be established to further the consensus process. In general, increasing funding in the brain sciences would bring enormous economic returns by lightening the burden on healthcare systems and increasing the productivity of affected individuals-and might easily pay for itself. The human and social returns of such an investment are inestimable. And the time to act is now.
Biomedical Research↗
Phosphodiesterase 5 and effects of sildenafil on cerebral arteries of man and guinea pig.
Sildenafil (Viagra), a selective inhibitor of phosphodiesterase 5 (PDE5), induces headache and migraine. Although previously supposed to be a "vascular" headache, no significant cerebral artery dilatation was found in vivo. Thus, we hypothesised that PDE5 may not be present or that sildenafil is less effective on the cGMP hydrolysis in cerebral arteries, and that sildenafil may not be an effective dilator of cerebral arteries under baseline conditions. We evaluated the presence of PDE5 mRNA and protein in human arteries. Furthermore, the effects of two selective PDE5 inhibitors, sildenafil and UK-114,542, and a PDE1 inhibitor UK-90,234 on cGMP hydrolysis were investigated in human and guinea pig cerebral arteries. The vasoactive responses of the compounds were evaluated in guinea pig basilar arteries in vitro, with concomitant measurements of cAMP and cGMP. PDE5 was found in human middle cerebral arteries. Sildenafil and UK-114,542 inhibited cGMP hydrolysis concentration-dependently in both species. In guinea pig arteries, sildenafil induced an endothelium-dependent vasodilatation only at concentrations above 10 nM, which was augmented by sodium nitroprusside and attenuated by reduction of cGMP, but was cGMP independent at high concentrations. UK-114,542 was more and UK-90,234 was less potent than sildenafil. In conclusion, PDE5 is present in human and guinea pig cerebral arteries, and is inhibited by sildenafil at micromolar levels. Sildenafil in vitro is a poor dilator of guinea pig cerebral arteries unless a nitric oxide donor is co-administered, corresponding to the previous findings in vivo.
3',5'-Cyclic-GMP Phosphodiesterases↗
No increase of calcitonin gene-related peptide in jugular blood during migraine.
Increased calcitonin gene-related peptide (CGRP) in external jugular venous blood during migraine attack is one of the most cited findings in the headache literature. The finding has not been convincingly reproduced and is based on comparison with historic control subjects. The validity of this finding is important for the understanding of migraine. We therefore investigated the issue using an intrapatient comparison design and two different CGRP assays. We sampled blood from the external jugular and cubital vein during, as well as outside of, an attack of migraine without aura. We succeeded in 17 patients, whereas only cubital fossa blood could be sampled in an additional 4 patients. CGRP was measured with the same assay as most previous studies (assay I) and furthermore with a more sensitive and validated assay (assay II). For assay I, mean CGRP concentration in external jugular venous blood during attack was 17.18 pmol/L compared with 15.88 pmol/L outside of attack. Mean difference was 1.81 pmol/L (95% confidence interval [CI]: -2.88, 6.41; p = 0.44). In peripheral blood during attack, CGRP was 16.86 pmol/L compared with 17.57 pmol/L outside of attack. Mean difference was -0.79 pmol/L (95% CI: -4.64, 3.06; p = 0.69). For assay II, external jugular venous blood concentration of CGRP during attack was 32.59 pmol/L compared with 30.59 pmol/L outside of attack; mean difference was 2.00 pmol/L (standard error, 2.39; 95% CI: -3.07, 7.07; p = 0.416). In peripheral blood during attack, CGRP was 33.37 pmol/L compared with 31.84 pmol/L outside of attack; mean difference was 1.53 pmol/L (standard error, 1.90; 95% CI: -2.46, 5.51; p = 0.431). Thus, no difference between CGRP level in external jugular or cubital fossa blood during and outside of attack was found. No difference was found between external jugular and peripheral venous blood. Thus, previous findings of increased CGRP level in external jugular or cubital fossa venous blood could not be confirmed. Our finding strongly suggests that CGRP is not increased in jugular venous blood during migraine without aura. CGRP cannot be used as a biomarker to validate human or animal models of migraine.
Adolescent↗
BIBN4096BS antagonizes human alpha-calcitonin gene related peptide-induced headache and extracerebral artery dilatation.
BACKGROUND AND OBJECTIVE: Calcitonin gene-related peptide (CGRP) plays a pivotal role in migraine pathogenesis. BIBN4096BS is the first CGRP receptor antagonist available for human studies, and its efficacy in the acute treatment of migraine has been demonstrated. We investigated the ability of BIBN4096BS to inhibit human alphaCGRP (h-alphaCGRP)-induced headache and cerebral hemodynamic changes in healthy volunteers. METHODS: Ten healthy volunteers completed this double-blind, placebo-controlled crossover study with 2.5 mg BIBN4096BS and placebo as pretreatments before a 20-minute intravenous infusion of h-alphaCGRP (1.5 microg/min). Transcranial Doppler ultrasonography was used to measure blood flow velocity in the middle cerebral artery (MCA); regional and global cerebral blood flow (CBF) was measured by xenon 133 inhalation single-photon emission computed tomography. The temporal and radial artery diameter was measured by high-frequency ultrasound. Systemic hemodynamics, end-tidal partial pressure of carbon dioxide (PETCO(2)), and headache were monitored. RESULTS: Of the 10 volunteers, 6 had a CGRP-induced headache during the in-hospital phase after placebo pretreatment but none after BIBN4096BS (P = .031). BIBN4096BS did not affect changes in the diameter of the MCA or changes in CBF induced by h-alphaCGRP. Vasodilatation of the extracranial arteries was, however, significantly inhibited (P < .001 for temporal artery and P = .001 for radial artery). CONCLUSIONS: These results show that BIBN4096BS effectively prevents CGRP-induced headache and extracerebral vasodilatation but does not significantly affect the induced cerebral hemodynamic changes.
Adult↗
No release of interstitial glutamate in experimental human model of muscle pain.
Glutamate may be released from muscle nociceptors and thereby contribute to mechanisms underlying acute and chronic muscle pain. In vivo concentration of glutamate during muscle pain has not previously been studied in either animals or humans. In the present study, we aimed to study the in vivo concentration of glutamate before, during and after acute pain of trapezius muscle in humans using the microdialysis technique. In addition, we examined the nutritive skeletal muscle blood flow and the interstitial concentrations of lactate, glucose, glycerol, pyruvate and urea. Experimental pain and tenderness were induced by intramuscular infusion of a chemical mixture consisting of bradykinin, prostaglandin E(2), histamine and serotonin. One EMG-needle and one microdialysis catheter were inserted into non-dominant and dominant trapezius muscles on a standard anatomical point in 19 healthy subjects. Dialysates were collected at rest, during infusion and 60 and 120 min after stop of infusion. Local tenderness was recorded at baseline and at the end of experiment. Local pain was recorded during infusion. The infusion of chemical mixture was more painful than infusion of placebo (p < 0.05) and resulted in significantly higher local tenderness score than placebo (p = 0.007). There was no difference in change in interstitial concentrations of glutamate, lactate, glucose, glycerol, pyruvate and urea from baseline to infusion and post-infusion periods between chemical mixture and placebo (p > 0.05). Muscle blood flow increased significantly over time in response to infusion of chemical mixture and placebo (p = 0.001). However, we found no difference in changes in muscle blood flow between chemical mixture and placebo (p > 0.05). In conclusion, the present study demonstrates no signs of increased release of glutamate from myofascial nociceptors during and after acute experimentally induced muscle pain and tenderness.
Acute Disease↗
Towards a better understanding of the size and burden and cost of brain disorders in Europe.
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Comprehension↗