Lars Edvinsson

Glostrup Hospital, Glostrup, Capital Region, Denmark

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Publications (491)1634.23 Total impact

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    ABSTRACT: Background Migraine is a paroxysmal, disabling primary headache that affects 16 % of the adult population. In spite of decades of intense research, the origin and the pathophysiology mechanisms involved are still not fully known. Although triptans and gepants provide effective relief from acute migraine for many patients, their site of action remains unidentified. It has been suggested that during migraine attacks the leakiness of the blood-brain barrier (BBB) is altered, increasing the passage of anti-migraine drugs. This study aimed to investigate the effect of experimental inflammation, following dural application of complete Freund’s adjuvant (CFA) or inflammatory soup (IS) on brain and trigeminal microvascular passage. Methods In order to address this issue, we induced local inflammation in male Sprague-Dawley-rats dura mater by the addition of CFA or IS directly on the dural surface. Following 2, 24 or 48 h of inflammation we calculated permeability-surface area product (PS) for [ 51 Cr]-EDTA in the trigeminal ganglion (TG), spinal trigeminal nucleus, cortex, periaqueductal grey and cerebellum. Results We observed that [ 51 Cr]-EDTA did not pass into the central nervous system (CNS) in a major way. However, [ 51 Cr]-EDTA readily passed the TG by >30 times compared to the CNS. Application of CFA or IS did not show altered transfer constants. Conclusions With these experiments we show that dural IS/CFA triggered TG inflammation, did not increase the BBB passage, and that the TG is readily exposed to circulating molecules. The TG could provide a site of anti-migraine drug interaction with effect on the trigeminal system.
    The Journal of Headache and Pain 12/2015; 16(1). DOI:10.1186/s10194-015-0575-8 · 2.80 Impact Factor
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    Jacob Edvinsson · Karin Warfvinge · Lars Edvinsson ·
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    ABSTRACT: Onabotulinumtoxin type A (BoNT-A) has been found to reduce pain in chronic migraine. The aim of the present study was to ask if BoNT-A can interact directly on sensory mechanisms in the trigeminal ganglion (TG) using an organ culture method. To induce inflammation, rat TGs were incubated for 24 hrs with either the mitogen MEK1/2 inhibitor U0126, BoNT-A or NaCl. After this the TGs were prepared for immunohistochemistry. Sections of the TG were then incubated with primary antibodies against CGRP (neuronal transmitter), iNOS (inflammatory marker), IL-1β (Interleukin 1β), SNAP-25 (synaptic vesicle docking protein) or SV2-A (Botulinum toxin receptor element). We report that CGRP, iNOS, IL-1β, SNAP-25 and SV2-A were observed in fresh TG with a differential distribution. Interestingly, NaCl organ culture of the TG resulted in enhanced expression of CGRP and SNAP-25 in neurons and iNOS in SGCs. Co-incubation with U0126 or BoNT-A retained the increased expression of SNAP-25, while it decreased the IL-1β immunoreactivity in neurons. The iNOS expression in SGCs returned to levels observed in fresh specimens. Moreover, we observed no alteration SV2-A expression in SGCs. Thus, the overall picture is that both U0126 and BoNT-A have the ability to modify the expression of certain molecules in the TG. We hypothesize that chronic migraine might be associated with some degree of inflammation in the TG that could involve both neurons and SGCs. It is clinically well recognized that treatment with corticosteroids will reduce the symptoms of chronic migraine; however this remedy is associated with long-term side effects. Understanding the mechanisms involved in the expressional alterations may suggest novel ways to modify the changes and indicate novel therapeutics. The results of the present work illustrate one way by which BoNT-A may modify these expressional alterations.
    The Journal of Headache and Pain 12/2015; 16(1):555. DOI:10.1186/s10194-015-0555-z · 2.80 Impact Factor
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    ABSTRACT: Aim: Extracellular signal-regulated kinase (ERK) 1/2 is activated during acute phase of stroke and contributes to stroke pathology. We have found that acute treatment with MEK1/2 inhibitors decrease infarct size and neurological deficits two days after experimental stroke. However it is not known whether benefits of this inhibition persist long-term. Therefore, the aim of this study was to assess neurological function, infarct size and recovery processes 14 days after stroke in male rats to determine long-term outcome following acute treatment with the MEK1/2 inhibitor U0126. Methods: Transient middle cerebral artery occlusion was induced in male rats. U0126 or vehicle was given at 0 and 24 h of reperfusion. Neurological function was assessed by staircase, 6-point and 28-point neuroscore tests up to 14 days after induction of stroke. At day 14, infarct volumes were determined and recovery processes were evaluated by measuring protein expression of the tyrosine kinase receptor Tie-2 and nestin. Levels of p-ERK1/2 protein were determined. Results: Acute treatment with U0126 significantly improved long-term functional recovery, reduced infarct size, and enhanced Tie-2 and nestin protein expression at 14 days post-stroke. There was no residual blockade of p-ERK1/2 at this time point. Conclusion: It is demonstrated that benefits of early treatment with U0126 persist beyond subacute phase of ischemic stroke in male rats. Prevention of ERK1/2 activation in the acute phase results in improved long-term functional outcome and enhances later-stage recovery processes. These results expand our understanding of the benefits and promise of using MEK1/2 inhibitors in stroke recovery. This article is protected by copyright. All rights reserved.
    Acta Physiologica 11/2015; DOI:10.1111/apha.12632 · 4.38 Impact Factor
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    ABSTRACT: Introduction: Cigarette smoking is a well-known risk factor for developing cardiovascular diseases, but the underlying mechanisms are largely unknown. Recent data suggest that vasocontractile receptor modulation could be an important factor. Surfactant protein D (SP-D) is important in the particle clearance in the lungs and knock-out (KO) mice for this protein develop emphysema. SP-D is also weakly expressed in the vasculature. We aimed to investigate whether SP-D was important in the cardiovascular response to cigarette smoke exposure (CSE), by utilizing SP-D KO mice and a myograph setup. Methods: Wild type (WT) and SP-D KO mice were exposed to cigarette smoke (CS) or room air for 12 weeks. The pulmonary artery, left anterior descending coronary artery, and basilar artery were isolated and mounted in wire myographs. Contractile concentration response curves (CRC) to endothelin-1 and UDP were obtained. Results: CSE caused a leftward shift in the CRC for endothelin-1 in the basilar artery for both WT and SP-D KO. UDP, acting on the purinergic P2Y6 receptor, caused reduced contraction in the left descending artery and increased contraction in the basilar artery in the CSE WT mice. SP-D KO mice displayed no smoke induced changes, but were surprisingly similar to the CSE WT. Conclusion: The contractility to UDP was altered in the brain and heart vasculature of CSE mice. SP-D KO (both control and CSE) and CSE WT had similar changes in contractility compared to control WT.
    Nicotine & Tobacco Research 10/2015; DOI:10.1093/ntr/ntv243 · 3.30 Impact Factor
  • Lars Edvinsson ·
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    ABSTRACT: In this retrospective, Dr. Lars Edvinsson recounts early steps and milestones in our understanding of the neuropeptide calcitonin gene-related peptide (CGRP) in the trigeminovascular system and its role in migraine. The discovery of the presence and function of CGRP and other neuropeptides in the cerebral vasculature and its sensory innervation is described. He relates the seminal finding that CGRP is uniquely released during migraine and the journey to develop blockers of CGRP effects. Now, over 30 years since its discovery, CGRP has become the target for a number of promising novel treatments for migraine patients.
    Headache The Journal of Head and Face Pain 09/2015; 55(9). DOI:10.1111/head.12656 · 2.71 Impact Factor
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    ABSTRACT: Obesity is a strong risk factor for hypertension but the mechanism linking obesity to hypertension is not fully elucidated. In obesity, circulating concentrations of adiponectin are decreased and hypoadiponectinaemia has in some but not all studies been associated with increased risk of hypertension. Due to this inconsistency, we decided to study adiponectin from two aspects in a cross-sectional in vivo study and in an experimental in vitro study. In the cross-sectional study, 103 men with body mass index (BMI) ≥30.0 kg/m(2) were studied; 63 had 24-hr ambulatory blood pressure (ABP) ≥130/80 mmHg (ObeseHT) and 40 had 24-hr ABP <130/80 mmHg (ObeseNT). As controls, we studied 27 men with BMI between 20.0 and 24.9 kg/m(2) and 24-hr ABP <130/80 mmHg (LeanNT). Serum concentrations of adiponectin and body composition using dual energy X-ray absorptiometry scanning were determined. In vitro, the direct vasomotor response of adiponectin was tested on subcutaneous resistance arteries from human abdominal adipose tissue. The 2 obese groups had lower adiponectin concentrations compared with LeanNT (P<0.01) (median (interquartile range)): ObeseHT 6.5 (5.1-8.3) mg/L; ObeseNT 6.6 (5.2-7.8) mg/L; and LeanNT 9.4 (6.7-12.4) mg/L, with no significant difference in adiponectin concentrations (or body composition) between ObeseHT and ObeseNT (P=0.67). In vitro, recombinant human adiponectin neither had any direct vasodilatory effect nor did adiponectin affect angiotensin II-stimulated vasoconstriction. In conclusion, obese, hypertensive men have similar serum concentrations of adiponectin as obese, normotensive men. In combination with the in vitro data, these findings question a pathogenic role of adiponectin in human hypertension. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Basic & Clinical Pharmacology & Toxicology 08/2015; DOI:10.1111/bcpt.12452 · 2.38 Impact Factor
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    ABSTRACT: Functional imaging studies have revealed that certain brainstem areas are activated during migraine attacks. The neuropeptide calcitonin gene-related peptide (CGRP) is associated with activation of the trigeminovascular system, transmission of nociceptive information and plays a key role in migraine pathophysiology. Therefore, to elucidate the role of CGRP it is critical to identify the regions within the brainstem that processes CGRP signaling. In situ hybridization and immunofluorescence were performed to detect mRNA expression and define cellular localization of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), respectively. To define CGRP receptor binding sites, in vitro autoradiography was performed with [(3) H]MK-3207 (a CGRP receptor antagonist). CLR and RAMP1 mRNA and protein expression were detected in the pineal gland, medial mammillary nucleus, median eminence, infundibular stem, periaqueductal gray, area postrema, pontine raphe nucleus, gracile nucleus and spinal trigeminal nucleus and the spinal cord. RAMP1 mRNA expression was also detected in the posterior hypothalamic area, trochlear nucleus, dorsal raphe nucleus, medial lemniscus, pontine nuclei, vagus nerve, inferior olive, abducens nucleus, motor trigeminal nucleus; where protein co-expression of CLR and RAMP1 was observed via immunofluorescence. [(3) H]MK-3207 showed high binding densities concordant with mRNA and protein expression. The present study suggests that several regions in the brainstem may be involved in CGRP signaling. Interestingly, we found receptor expression and antagonist binding in some areas that are not protected by the blood-brain barrier, which suggests that CGRP receptor antagonists may not need to be CNS-penetrant to antagonize receptors in these brain regions. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 06/2015; 000(1). DOI:10.1002/cne.23828 · 3.23 Impact Factor
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    ABSTRACT: In the present study, we aimed to investigate whether changes in cerebrovascular voltage-dependent calcium channels and non-selective cation channels contribute to the enhanced endothelin-1-mediated vasoconstriction in the delayed hypoperfusion phase after experimental transient forebrain ischemia. Experimental forebrain ischemia was induced in Wistar male rats by a two-vessel occlusion model and the cerebral blood flow was measured by magnetic resonance imaging two days after reperfusion. In vitro vasoreactivity studies, immunofluorescence and quantitative PCR were performed on cerebral arteries from ischemic or sham-operated rats to evaluate changes in vascular voltage-dependent calcium channels, transient receptor potential canonical channels as well as endothelin-1 receptor function and expression. The expression of transient receptor potential canonical channels 1 and 6 in the vascular smooth muscle cells were enhanced and correlated with decreased cerebral blood flow two days after forebrain ischemia. Furthermore, under conditions when voltage-dependent calcium channels were inhibited, endothelin-1-induced cerebrovascular contraction was enhanced and this enhancement was presumably mediated by Ca(2+) influx via upregulated transient receptor potential canonical channels 1 and 6 channels. Our data demonstrates that endothelin-1-mediated influx of extracellular Ca(2+) activates transient receptor potential canonical channels 1 and 6 in cerebral vascular smooth muscle cells. This seems to have an important role in the enhanced cerebral vasoconstriction in the delayed post-ischemic hypoperfusion phase after experimental forebrain ischemia. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Acta Physiologica 05/2015; 214(3). DOI:10.1111/apha.12519 · 4.38 Impact Factor
  • Lars Edvinsson ·
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    ABSTRACT: Recently developed calcitonin gene-related peptide (CGRP) receptor antagonistic molecules have shown promising results in clinical trials for acute treatment of migraine attacks. Drugs from the gepant class of CGRP receptor antagonists are effective and do not cause vasoconstriction, (one of the major limitations in the use of triptans); however their use had to be discontinued because of risk of liver toxicity after continuous exposure. As an alternative approach to block CGRP transmission, fully humanized monoclonal antibodies towards CGRP and the CGRP receptor have been developed for treatment of chronic migraine (attacks >15 days/month). Initial results from phase I and II clinical trials have revealed promising results with minimal side effects and significant relief from chronic migraine as compared to placebo. The effectiveness of these various molecules raises the question of where is the target site(s) for antimigraine action. The gepants are small molecules that can partially pass the blood-brain barrier (BBB) and therefore, might have effects in the CNS. However, antibodies are large molecules and have limited possibility to pass the BBB, thus effectively excluding them from having a major site of action within the CNS. It is suggested that the antimigraine site should reside in areas not limited by the BBB such as intra- and extracranial vessels, dural mast cells, and the trigeminal system. In order to clarify this topic and surrounding questions, it is important to understand the localization of CGRP and the CGRP receptor components in these possible sites of migraine-related regions and their relation to the BBB. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 03/2015; 80(2). DOI:10.1111/bcp.12618 · 3.88 Impact Factor
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    ABSTRACT: Objective The trigeminovascular system plays a central role in migraine, a condition in need of new treatments. The neuropeptide, calcitonin gene-related peptide (CGRP), is proposed as causative in migraine and is the subject of intensive drug discovery efforts. This study explores the expression and functionality of two CGRP receptor candidates in the sensory trigeminal system.Methods Receptor expression was determined using Taqman G protein-coupled receptor arrays and immunohistochemistry in trigeminal ganglia (TG) and the spinal trigeminal complex of the brainstem in rat and human. Receptor pharmacology was quantified using sensitive signaling assays in primary rat TG neurons.ResultsmRNA and histological expression analysis in rat and human samples revealed the presence of two CGRP-responsive receptors (AMY1: calcitonin receptor/receptor activity-modifying protein 1 [RAMP1]) and the CGRP receptor (calcitonin receptor-like receptor/RAMP1). In support of this finding, quantification of agonist and antagonist potencies revealed a dual population of functional CGRP-responsive receptors in primary rat TG neurons.InterpretationThe unexpected presence of a functional non-canonical CGRP receptor (AMY1) at neural sites important for craniofacial pain has important implications for targeting the CGRP axis in migraine.
    03/2015; 2(6). DOI:10.1002/acn3.197
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    ABSTRACT: microRNAs (miRNAs) are important regulators of translation and have been implicated in the pathogenesis of a number of cardiovascular diseases, including stroke, and suggested as possible prognostic biomarkers. Our aim was to identify miRNAs that are differentially regulated in cerebral arteries after subarachnoid hemorrhage (SAH), using a rat injection model of SAH and a qPCR-based screen of 728 rat miRNAs. Additionally, serum was analyzed for a possible spill-over to the circulation of regulated miRNAs from the vessel walls. We identified 482 different miRNAs expressed in cerebral arteries post-SAH. Two miRNAs, miR-30a and miR-143, were significantly upregulated in cerebral arteries after SAH when compared to sham-operated animals. However, none of these exhibited significantly altered serum levels after SAH versus post-sham surgery. The most robust upregulation was seen for miR-143, which has several predicted targets and is a strong regulator of vascular morphology. We hypothesize that miR-30a and miR-143 may play a role in the vascular wall changes seen after SAH. We report that miR-30a and miR-143 in the cerebral arteries show significant changes over time after SAH, but do not differ from sham-operated rats at 24 h post-SAH. Although this finding suggests interesting novel possible mechanisms involved in post-SAH cerebrovascular changes, the lack of regulation of these miRNAs in serum excludes their use as blood-borne biomarkers for cerebrovascular changes following SAH.
    BMC Genomics 02/2015; 16(1):119. DOI:10.1186/s12864-015-1341-7 · 3.99 Impact Factor
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    ABSTRACT: Sex differences are well known in cerebral ischemia and may impact the effect of stroke treatments. In male rats, the MEK1/2 inhibitor U0126 reduces ischemia-induced endothelin type B (ETB) receptor upregulation, infarct size and improves acute neurologic function after experimental stroke. However, responses to this treatment in females and long-term effects on outcome are not known. Initial experiments used in vitro organ culture of cerebral arteries, confirming ERK1/2 activation and increased ETB receptor-mediated vasoconstriction in female cerebral arteries. Transient middle cerebral artery occlusion (tMCAO, 120 minutes) was induced in female Wistar rats, with U0126 (30 mg/kg intraperitoneally) or vehicle administered at 0 and 24 hours of reperfusion, or with no treatment. Infarct volumes were determined and neurologic function was assessed by 6-point and 28-point neuroscores. ETB receptor-mediated contraction was studied with myograph and protein expression with immunohistochemistry. In vitro organ culture and tMCAO resulted in vascular ETB receptor upregulation and activation of ERK1/2 that was prevented by U0126. Although no effect on infarct size, U0126 improved the long-term neurologic function after experimental stroke in female rats. In conclusion, early prevention of the ERK1/2 activation and ETB receptor-mediated vasoconstriction in the cerebral vasculature after ischemic stroke in female rats improves the long-term neurologic outcome.Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 December 2014; doi:10.1038/jcbfm.2014.217.
    Journal of Cerebral Blood Flow & Metabolism 12/2014; 35(3). DOI:10.1038/jcbfm.2014.217 · 5.41 Impact Factor
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    ABSTRACT: Background It has been suggested that transcriptional upregulation of cerebral artery contractile endothelin (ETB) and 5-hydroxytryptamine (5-HT1B) receptors play an important role in the development of late cerebral ischemia and increased vasoconstriction after subarachnoid hemorrhage (SAH). We tested the hypothesis that inhibition of calcium calmodulin-dependent protein kinase II (CaMKII) may reduce cerebral vasoconstriction mediated by endothelin and serotonin receptors and improve neurological outcome after experimental SAH.MethodsSAH was induced in adult rats by injection of 250 ¿L autologous blood into the basal cisterns. The CaMKII activity in cerebral vessels was studied by Western blot and immunohistochemistry. The vasomotor responses of middle cerebral and basilar arteries were measured in a sensitive myograph system. The functional outcome was examined by the rotating pole test 2 and 3 days after SAH.ResultsSAH induced a rapid early increase in phosphorylated CaMKII protein at 1 h that was attenuated by cisternal administration of the CaMKII inhibitor KN93 (0.501 ¿g/kg) 45 min prior and immediately after SAH as evaluated by Western blot. Application of KN93 at 1 h and every 12 h post-SAH significantly reduced vascular CaMKII immunoreactivity at 72 h. In addition, contractile responses of cerebral arteries to endothelin-1 (ET-1) and 5-hydroxycarboxamide (5-CT) were increased at this time-point. KN93 treatment significantly attenuated the contraction induced by ET-1 and 5-CT. Importantly, treatment with the CaMKII inhibitor prevented SAH-induced deficits in neurological function, as evaluated by the rotating pole test, and similar sensorimotor scores were seen in sham-operated animals.Conclusions The present study has shown that SAH is associated with increased contractile responses to ET-1 and 5-CT in cerebral arteries and enhanced early activation of CaMKII. Treatment with the CaMKII inhibitor KN93 attenuated the contractile responses and prevented impaired sensorimotor function after SAH.
    Journal of Neuroinflammation 12/2014; 11(1):207. DOI:10.1186/s12974-014-0207-2 · 5.41 Impact Factor
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    ABSTRACT: Increased expression of endothelin receptor type B (ETBR), a vasoactive receptor, has recently been implied in the reduced cerebral blood flow and exacerbated neuronal damage after ischemia-reperfusion (I/R). The study explores the regulatory mechanisms of ETBR to identify drug targets to restore normal cerebral artery contractile function as part of successful neuroprotective therapy. We have employed in vitro methods on human and rat cerebral arteries to study the regulatory mechanisms and the efficacy of target selective inhibitor, Mithramycin A (MitA), to block the ETBR mediated contractile properties. Later, middle cerebral artery occluded (MCAO) rats were used to substantiate the observations. Quantative PCR, immunohistochemistry, western blot and wire myograph methods were employed to study the expression and contractile properties of cerebral arteries. Increased expression of specificity protein (Sp1) was observed in human and rat cerebral arteries after organ culture, strongly correlating with the ETBR upregulation. Similar observations were made in MCAO rats. Treatment with MitA, a Sp1 specific inhibitor, significantly downregulated the ETBR mRNA and protein levels. It also significantly reduced the ETBR mediated cerebrovascular contractility. Detailed analysis indicated that ERK1/2 mediated phosphorylation of Sp1 might be essential for ETBR transcription. Transcription factor Sp1 regulates the ETBR mediated vasoconstriction in focal cerebral ischemia via MEK-ERK signaling, which is also conserved in humans. The results show that MitA can effectively be used to block ETBR mediated vasoconstriction as a supplement to an existing ischemic stroke therapy.
    PLoS ONE 12/2014; 9(12):e113624. DOI:10.1371/journal.pone.0113624 · 3.23 Impact Factor
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    Alessandro S. Zagami · Lars Edvinsson · Peter J. Goadsby ·
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    ABSTRACT: Pituitary adenylate cyclase activating peptide (PACAP) is found in human trigeminocervical complex and can trigger migraine. PACAP levels were measured using a sensitive radioimmunoassay. Stimulation of the superior sagittal sinus (SSS) in cat elevated PACAP levels in cranial blood. Patients with moderate or severe migraine headache had elevated PACAP in the external jugular vein during headache (n = 15), that was reduced 1 h after treatment with sumatriptan 6 mg (n = 11), and further reduced interictally (n = 9). The data suggest PACAP, or its receptors, are a promising target for migraine therapeutics.
    12/2014; 1(12). DOI:10.1002/acn3.113
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    ABSTRACT: Calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated anti-migraine efficacy. One remaining question is where do these blockers act? We hypothesized that the trigeminal ganglion could be one possible site. We examined the binding sites of a CGRP receptor antagonist (MK-3207) and related this to the expression of CGRP and its receptor in rhesus trigeminal ganglion. Pituitary adenylate cyclase-activating polypeptide (PACAP) and glutamate were examined and related to the CGRP system. Furthermore, we examined if the trigeminal ganglion is protected by the blood-brain barrier (BBB). Autoradiography was performed with [(3)H]MK-3207 to demonstrate receptor binding sites in rhesus trigeminal ganglion (TG). Immunofluorescence was used to correlate binding and the presence of CGRP and its receptor components, calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), and the distribution of PACAP and glutamate in rhesus and rat TG. Evans blue was used to examine large molecule penetration into the rat TG. High receptor binding densities were found in rhesus TG. Immunofluorescence revealed expression of CGRP, CLR and RAMP1 in trigeminal cells. CGRP positive neurons expressed PACAP but not glutamate. Some neurons expressing CLR and RAMP1 co-localized with glutamate. Evans blue revealed that the TG is not protected by BBB. This study demonstrates CGRP receptor binding sites and expression of the CGRP receptor in rhesus and rat TG. The expression pattern of PACAP and glutamate suggests a possible interaction between the glutamatergic and CGRP system. In rat the TG is outside the BBB, suggesting that molecules do not need to be CNS-penetrant to block these receptors. Copyright © 2014. Published by Elsevier B.V.
    Brain Research 11/2014; 1600. DOI:10.1016/j.brainres.2014.11.031 · 2.84 Impact Factor
  • Gro K Povlsen · Lars Edvinsson ·
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    ABSTRACT: Cerebral vasospasm and late cerebral ischemia (LCI) remain leading causes of mortality in patients experiencing a subarachnoid hemorrhage (SAH). This occurs typically 3 to 4 days after the initial bleeding and peaks at 5 to 7 days. The underlying pathophysiology is still poorly understood. Because SAH is associated with elevated levels of endothelin-1 (ET-1), focus has been on counteracting endothelin receptor activation with receptor antagonists like clazosentan, however, with poor outcome in clinical trials. We hypothesize that inhibition of intracellular transcription signaling will be an effective approach to prevent LCI. Here, we compare the effects of clazosentan versus the MEK1/2 blocker U0126 in a rat model of SAH. Although clazosentan directly inhibits the contractile responses in vivo to ET-1, it did not prevent SAH-induced upregulation of ET receptors in cerebral arteries and did not show a beneficial effect on neurologic outcome. U0126 had no vasomotor effect by itself but counteracts SAH-induced receptor upregulation in cerebral arteries and improved outcome after SAH. We suggest that because SAH induces elevated expression of several contractile receptor subtypes, it is not sufficient to block only one of these (ET receptors) but inhibition of transcriptional MEK1/2-mediated upregulation of several contractile receptors may be a viable way towards alleviating LCI.Journal of Cerebral Blood Flow & Metabolism advance online publication, 19 November 2014; doi:10.1038/jcbfm.2014.205.
    Journal of Cerebral Blood Flow & Metabolism 11/2014; 35(2). DOI:10.1038/jcbfm.2014.205 · 5.41 Impact Factor
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    Kristian Agmund Haanes · Lars Edvinsson ·
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    ABSTRACT: The dura mater and its vasculature have for decades been central in the hypothesis of migraine and headache pathophysiology. Although recent studies have questioned the role of the vasculature as the primary cause, dural vessel physiology is still relevant in understanding the complex pathophysiology of migraine. The aim of the present study was to isolate the middle meningeal artery (MMA) from rodents and characterize their purinergic receptors using a sensitive wire myograph method and RT-PCR. The data presented herein suggest that blood flow through the MMA is, at least in part, regulated by purinergic receptors. P2X1 and P2Y6 receptors are the strongest contractile receptors and, surprisingly, ADPβS caused contraction most likely via P2Y1 or P2Y13 receptors, which is not observed in other arteries. Adenosine addition, however, caused relaxation of the MMA. The adenosine relaxation could be inhibited by SCH58261 (A2A receptor antagonist) and caffeine (adenosine receptor antagonist). This gives one putative molecular mechanism for the effect of caffeine, often used as an adjuvant remedy of cranial pain. Semi-quantitative RT-PCR expression data for the receptors correlate well with the functional findings. Together these observations could be used as targets for future understanding of the in vivo role of purinergic receptors in the MMA.
    PLoS ONE 09/2014; 9(9):e108782. DOI:10.1371/journal.pone.0108782 · 3.23 Impact Factor
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    ABSTRACT: To evaluate whether the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant might be effective for migraine prevention.
    Neurology 08/2014; 83(11). DOI:10.1212/WNL.0000000000000771 · 8.29 Impact Factor
  • Kristian Agmund Haanes · Lars Edvinsson ·
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    ABSTRACT: Extracellular UDP-glucose can activate the purinergic P2Y14 receptor. The aim of the present study was to examine the physiological importance of P2Y14 receptors in the vasculature. The data presented herein show that UDP-glucose causes contraction in mouse coronary and basilar arteries. The EC50 values and immunohistochemistry illustrated strongest P2Y14 receptor expression in the basilar artery. In the presence of pertussis toxin, UDP-glucose inhibited contraction in coronary arteries and in the basilar artery it surprisingly caused relaxation. After organ culture of the coronary artery, the EC50 value decreased and an increased staining for the P2Y14 receptor was observed, showing receptor plasticity.
    FEBS Letters 06/2014; 588(17). DOI:10.1016/j.febslet.2014.05.044 · 3.17 Impact Factor

Publication Stats

13k Citations
1,634.23 Total Impact Points


  • 2000-2015
    • Glostrup Hospital
      • Department of Clinical Experimental Research
      Glostrup, Capital Region, Denmark
    • IT University of Copenhagen
      København, Capital Region, Denmark
    • Erasmus Universiteit Rotterdam
      • Department of Pharmacology
      Rotterdam, South Holland, Netherlands
    • University of California, Irvine
      • Department of Pharmacology
      Irvine, California, United States
  • 1975-2015
    • Lund University
      • • Department of Clinical Sciences, Lund
      • • Department of Clinical Sciences, Malmö
      • • Department of Surgery
      • • Department of Clinical Pharmacology
      • • Division of Neurology
      Lund, Skåne, Sweden
  • 2007-2014
    • Copenhagen University Hospital
      København, Capital Region, Denmark
  • 2006
    • Xi'an Jiaotong University
      • Department of Pharmacology
      Ch’ang-an, Shaanxi, China
  • 2001
    • Baylor College of Medicine
      • Department of Anesthesiology
      Houston, Texas, United States
    • New York State
      New York City, New York, United States
  • 1994
    • Sahlgrenska University Hospital
      • Department of Cardiology
      Goeteborg, Västra Götaland, Sweden
    • Prince Henry's Institute
      Melbourne, Victoria, Australia
  • 1992
    • University of Gothenburg
      • Department of Pharmacology
      Göteborg, Vaestra Goetaland, Sweden
  • 1977-1990
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
  • 1989
    • Shinshu University
      • Department of Neurosurgery
      Shonai, Nagano, Japan
  • 1987
    • The John F. Kennedy Institute, Denmark
      Glostrup, Capital Region, Denmark
  • 1984
    • Karolinska Institutet
      Solna, Stockholm, Sweden