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Migraine Disorders: HELP
Articles by Lars Edvinsson
Based on 39 articles published since 2008
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Between 2008 and 2019, L. Edvinsson wrote the following 39 articles about Migraine Disorders.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Is CGRP a marker for chronic migraine? 2013

Silberstein, Stephen D / Edvinsson, Lars. ·From the Jefferson Headache Center (S.D.S.), Jefferson Hospital for Neuroscience, Philadelphia, PA · and Internal Medicine (L.E.), Lund University, Sweden. ·Neurology · Pubmed #23975870.

ABSTRACT: -- No abstract --

2 Editorial Role of VIP/PACAP in primary headaches. 2013

Edvinsson, Lars. ·Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Sweden. ·Cephalalgia · Pubmed #23575820.

ABSTRACT: -- No abstract --

3 Review PACAP38 and PAC 2018

Rubio-Beltrán, Eloisa / Correnti, Edvige / Deen, Marie / Kamm, Katharina / Kelderman, Tim / Papetti, Laura / Vigneri, Simone / MaassenVanDenBrink, Antoinette / Edvinsson, Lars / Anonymous6340957. ·Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. a.rubiobeltran@erasmusmc.nl. · Department of Child Neuropsychiatry, University of Palermo, Palermo, Italy. · Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark. · Department of Neurology, University Hospital, LMU Munich, Munich, Germany. · Department of Neurology, Ghent University Hospital, Ghent, Belgium. · Headache Center, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. · Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo; Pain Medicine Unit, Santa Maria Maddalena Hospital, Occhiobello, Italy. · Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Internal Medicine, Institute of Clinical Sciences, Lund University, Lund, Sweden. ·J Headache Pain · Pubmed #30088106.

ABSTRACT: Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) is a widely distributed neuropeptide involved in neuroprotection, neurodevelopment, nociception and inflammation. Moreover, PACAP38 is a potent inducer of migraine-like attacks, but the mechanism behind this has not been fully elucidated.Migraine is a neurovascular disorder, recognized as the second most disabling disease. Nevertheless, the antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor are the only prophylactic treatment developed specifically for migraine. These antibodies have displayed positive results in clinical trials, but are not effective for all patients; therefore, new pharmacological targets need to be identified.Due to the ability of PACAP38 to induce migraine-like attacks, its location in structures previously associated with migraine pathophysiology and the 100-fold selectivity for the PAC

4 Review Blocking CGRP in migraine patients - a review of pros and cons. 2017

Deen, Marie / Correnti, Edvige / Kamm, Katharina / Kelderman, Tim / Papetti, Laura / Rubio-Beltrán, Eloisa / Vigneri, Simone / Edvinsson, Lars / Maassen Van Den Brink, Antoinette / Anonymous7800920. ·Danish Headache Center, Department of Neurology, Rigshospitalet, Copenhagen, Denmark. mariedeen85@gmail.com. · Department of Child Neuropsychiatry, University of Palermo, Palermo, Italy. · Department of Neurology, University Hospital, LMU, Munich, Germany. · Department of Neurology, Ghent University Hospital, Ghent, Belgium. · Headache Center, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. · Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo; Advanced Algology Research and Pain Medicine Unit, Santa Maria Maddalena Hospital, Occhiobello, Italy. · Department of Internal Medicine, Institute of Clinical Sciences, Lund University, Lund, Sweden. ·J Headache Pain · Pubmed #28948500.

ABSTRACT: Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than migraine such as hypertension, depression and epilepsy. During the last decade, however, blocking calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for prevention of migraine attacks. CGRP has been shown to be released during migraine attacks and it may play a causative role in induction of migraine attacks. Here, we review the pros and cons of blocking CGRP in migraine patients. To date, two different classes of drugs blocking CGRP have been developed: small molecule CGRP receptor antagonists (gepants), and monoclonal antibodies, targeting either CGRP or the CGRP receptor. Several trials have been conducted to test the efficacy and safety of these drugs. In general, a superior efficacy compared to placebo has been shown, especially with regards to the antibodies. In addition, the efficacy is in line with other currently used prophylactic treatments. The drugs have also been well tolerated, except for some of the gepants, which induced a transient increase in transaminases. Thus, blocking CGRP in migraine patients is seemingly both efficient and well tolerated. However, CGRP and its receptor are abundantly present in both the vasculature, and in the peripheral and central nervous system, and are involved in several physiological processes. Therefore, blocking CGRP may pose a risk in subjects with comorbidities such as cardiovascular diseases. In addition, long-term effects are still unknown. Evidence from animal studies suggests that blocking CGRP may induce constipation, affect the homeostatic functions of the pituitary hormones or attenuate wound healing. However, these effects have so far not been reported in human studies. In conclusion, this review suggests that, based on current knowledge, the pros of blocking CGRP in migraine patients exceeds the cons.

5 Review Migraine, Neurogenic Inflammation, Drug Development - Pharmacochemical Aspects. 2017

Lukacs, Melinda / Tajti, Janos / Fulop, Ferenc / Toldi, Jozsef / Edvinsson, Lars / Vecsei, Laszlo. ·Department of Neurology, University of Szeged, Szeged. Hungary. · Institute of Pharmaceutical Chemistry and MTA-SZTE Research Group for Stereochemistry, University of Szeged. Hungary. · Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged. Hungary. · Department of Clinical Experimental Research, Copenhagen University, Glostrup Hospital, Copenhagen. Denmark. · Department of Neurology, University of Szeged, Hungary and MTA-SZTE Neuroscience Research Group, Szeged. Hungary. ·Curr Med Chem · Pubmed #28707585.

ABSTRACT: BACKGROUND: Migraine is a primary headache disorder. Despite numerous studies conducted with the aim to understand the pathophysiology of migraine, several aspects are still unclear. The trigeminovascular system plays a key role. Neurogenic inflammation is presumed to be an important factor in migraine pathophysiology, mediated by the activation of primary neurons, leading to the release of various pro-inflammatory neuropeptides and neurotransmitters such as Calcitonin Gene-Related Peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP). Nitric oxide (NO), Pituitary adenylate cyclase-activating polypeptide (PACAP) and Glutamate (Glu) also play an important role in the modulation of inflammatory mechanisms. OBJECTIVE: To review the literature focusing on novel therapeutic targets in migraine, related to neurogenic inflammation. METHOD: A systematic literature search in the database of PUBMED was conducted regarding therapeutic strategies in migraine, focusing on substances and cytokines released during neurogenic inflammation, published until January 2017. RESULTS: Ongoing phase III clinical studies with monoclonal antibodies against CGRP and CGRP receptors offer promising novel aspects for migraine treatment. Preclinical and clinical studies targeting SP and nitric oxide synthase (NOS) were all terminated with no significant results compared to placebo. New promising therapeutic goal could be PACAP and its receptor (PAC1), and kynurenic acid (KYNA) analogues. CONCLUSION: Current migraine treatment offers pain relief only for a small proportion of migraine patients and might not be adequate for patients with cardiovascular comorbidity due to side effects. Better understanding of migraine pathophysiology might, therefore, lead to novel therapeutic lines both in migraine attack treatment and prophylaxis.

6 Review The Trigeminovascular Pathway: Role of CGRP and CGRP Receptors in Migraine. 2017

Edvinsson, Lars. ·Department of Medicine, Lund University, Lund, Sweden. ·Headache · Pubmed #28485848.

ABSTRACT: The trigeminal ganglion plays a key role in primary headache pathophysiology. Calcitonin gene-related peptide (CGRP) and CGRP receptors are expressed in trigeminal neurons that form C-fibers and A-fibers, respectively. In acute migraine and cluster headache attacks, there is release of CGRP into the cranial venous outflow. In addition, intravenous CGRP can induce migraine-like symptoms in migraine patients. These findings led to the development of anti-migraine therapies that inhibit CGRP action. Currently, CGRP receptor antagonists, the gepants, and monoclonal antibodies towards CGRP and the CGRP receptor are all showing positive relief of acute and chronic migraine in clinical trials. However, there is still much to learn about the role of CGRP and CGRP receptors in headache pathophysiology, the critical anatomical sites, peripheral or central, of anti-CGRP agents, and the potential involvement of CGRP-related peptides and receptors. This review provides a brief history of the discovery of the role of CGRP in migraine and highlights current progress in understanding the complexity of the trigeminovascular pathway and its peptide transmitters.

7 Review CGRP receptor antagonism and migraine therapy. 2013

Edvinsson, Lars / Warfvinge, Karin. ·Department of Medicine, Institute of Clinical Sciences, Lund University and Lund University Hospital, Lund, Sweden. lars.edvinsson@med.lu.se ·Curr Protein Pept Sci · Pubmed #23745702.

ABSTRACT: Migraine is the most prevalent of the neurological disorders and can affect the patient throughout the lifetime. Calcitonin gene-related peptide (CGRP) is a neuropeptide that is expressed in the central and peripheral nervous systems. It is now 2 decades since it was proposed to be involved in migraine pathophysiology. The cranial sensory system contains C-fibers storing CGRP and trigeminal nerve activation and acute migraine attacks result in release of CGRP. The CGRP receptor consists of a complex of calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1) and receptor component protein (RCP). At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via brainstem and midbrain to thalamus and higher cortical pain regions. CLR and RAMPs are widely expressed throughout the brain, in the trigeminal ganglion and in intracranial arteries. CGRP does not induce neurogenic inflammation or sensitization at peripheral meningeal sites but relays nociceptive information from trigeminal primary afferent neurons to the second-order neurons in the spinal trigeminal nucleus neurons. CGRP receptor antagonists have been developed as novel antimigraine drugs and found to be effective in the treatment of acute migraine attacks. Other ways to stop CGRP activity has been introduced recently through antibodies against CGRP and the CGRP receptor. While the CGRP receptors are expressed both in the CNS and at various places related to the trigeminal system the exact site of action for their therapy effect is still unresolved but the new approaches may resolve this.

8 Review Pearls and pitfalls in neural CGRP immunohistochemistry. 2013

Warfvinge, Karin / Edvinsson, Lars. ·Department of Clinical Experimental Research, Glostrup Research Institute, Glostrup University Hospital, Denmark. Karin.Warfvinge@sciencesupport.se ·Cephalalgia · Pubmed #23671255.

ABSTRACT: PEARLS: In 1985, CGRP was first described in cerebral arteries using immunohistochemistry. Since then, cerebral CGRP (and, using novel antibodies, its receptor components) has been widely scrutinized. Here, we describe the distribution of cerebral CGRP and pay special attention to the surprising reliability of results over time. PITFALLS: Pitfalls might include a fixation procedure, antibody clone and dilution, and interpretation of results. Standardization of staining protocols and true quantitative methods are lacking. The use of computerized image analysis has led us to believe that our examination is objective. However, in the steps of performing such an analysis, we make subjective choices. By pointing out these pitfalls, we aim to further improve immunohistochemical quality. RECOMMENDATIONS: Having a clear picture of the tissue/cell morphology is a necessity. A primary morphological evaluation with, for example, hematoxylin-eosin, helps to ensure that small changes are not missed and that background and artifactual changes, which may include vacuoles, pigments, and dark neurons, are not over-interpreted as compound-related changes. The antigen-antibody reaction appears simple and clear in theory, but many steps might go wrong. Remember that methods including the antigen-antibody complex rely on handling/fixation of tissues or cells, antibody shipping/storing issues, antibody titration, temperature/duration of antibody incubation, visualization of the antibody and interpretation of the results. Optimize staining protocols to the material you are using.

9 Review [Calcitonin gene-related peptide and migraine. Increases understanding of physiopathology can lead to new drug therapy]. 2010

Edvinsson, Lars. ·Avdelningen för medicin, institutionen för kliniska vetenskaper, Skånes universitetssjukhus, Lund. lars.edvinsson@med.lu.se ·Lakartidningen · Pubmed #21294334.

ABSTRACT: -- No abstract --

10 Review CGRP and its receptors provide new insights into migraine pathophysiology. 2010

Ho, Tony W / Edvinsson, Lars / Goadsby, Peter J. ·Clinical Neuroscience, Merck Research Laboratories, North Wales, PA 19454-1099, USA. ·Nat Rev Neurol · Pubmed #20820195.

ABSTRACT: Over the past 300 years, the migraine field has been dominated by two main theories-the vascular theory and the central neuronal theory. The success of vasoconstrictors such as ergotamine and the triptans in treating acute migraine bolstered the vascular theory, but evidence is now emerging that vasodilatation is neither necessary nor sufficient to induce a migraine attack. Attention is now turning to the core migraine circuits in the brain, which include the trigeminal ganglia, trigeminal nucleus, medullary modulatory regions, pons, periaqueductal gray matter, hypothalamus and thalamus. Migraine triggers are likely to reflect a disturbance in overall balance of the circuits involved in the modulation of sensory activity, particularly those with relevance to the head. In this Review, we consider the evidence pointing towards a neuronal mechanism in migraine development, highlighting the role of calcitonin gene-related peptide (CGRP), which is found in small to medium-sized neurons in the trigeminal ganglion. CGRP is released during migraine attacks and can trigger migraine in patients, and CGRP receptor antagonists can abort migraine. We also examine whether other drugs, such as triptans, might exert their antimigraine effects via their actions on the neuronal circuit as opposed to the intracranial vasculature.

11 Review CGRP receptor antagonism and migraine. 2010

Edvinsson, Lars / Ho, Tony W. ·Department of Medicine, Institute of Clinical Sciences, Lund University Hospital, Lund University, 22185 Lund, Sweden. lars.edvinsson@med.lu.se ·Neurotherapeutics · Pubmed #20430315.

ABSTRACT: Calcitonin gene-related peptide (CGRP) is expressed throughout the central and peripheral nervous systems, consistent with control of vasodilatation, nociception, motor function, secretion, and olfaction. alphaCGRP is prominently localized in primary spinal afferent C and ADelta fibers of sensory ganglia, and betaCGRP is the main isoform in the enteric nervous system. In the CNS there is a wide distribution of CGRP-containing neurons, with the highest levels occurring in striatum, amygdala, colliculi, and cerebellum. The peripheral projections are involved in neurogenic vasodilatation and inflammation, and central release induces hyperalgesia. CGRP is released from trigeminal nerves in migraine. Trigeminal nerve activation results in antidromic release of CGRP to cause non-endothelium-mediated vasodilatation. At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via the brainstem and midbrain to the thalamus and higher cortical pain regions. Recently developed CGRP receptor antagonists are effective at aborting acute migraine attacks. They may act both centrally and peripherally to attenuate signaling within the trigeminovascular pathway.

12 Review New drugs in migraine treatment and prophylaxis: telcagepant and topiramate. 2010

Edvinsson, Lars / Linde, Mattias. ·Department of Internal Medicine, University Hospital, Lund, Sweden. lars.edvinsson@med.lu.se ·Lancet · Pubmed #20416945.

ABSTRACT: Although the triptan drugs provide effective relief from migraine for many patients, a substantial number of affected individuals are unresponsive to these compounds, and such therapy can also lead to a range of adverse effects. Telcagepant represents a new class of antimigraine drug-the calcitonin gene-related peptide receptor blockers. This compound exerts its effects by blocking receptors for the calcitonin-gene-related peptide at several sites in the trigeminal and central nervous systems, resulting in pain relief. Telcagepant does not cause vasoconstriction, a major limitation in the use of triptans. Comparisons with triptans in clinical trials for acute treatment of migraine attacks revealed clinical effects similar to those of triptans but better than those of placebo. Telcagepant might provide hope for those who have a poor response to, or are unable to use, older drugs. In patients who need prophylaxis because of frequent attacks of migraine, topiramate is a first-line drug for migraine prevention in many countries; it is generally safe and reasonably well tolerated. Data suggest that topiramate could aid reversion of chronic migraine to episodic migraine.

13 Review The blood-brain barrier in migraine treatment. 2008

Edvinsson, L / Tfelt-Hansen, P. ·Department of Internal Medicine, University Hospital, Lund, Sweden. lars.edvinsson@med.lu.se ·Cephalalgia · Pubmed #18727638.

ABSTRACT: Salient aspects of the anatomy and function of the blood-barrier barrier (BBB) are reviewed in relation to migraine pathophysiology and treatment. The main function of the BBB is to limit the access of circulating substances to the neuropile. Smaller lipophilic substances have some access to the central nervous system by diffusion, whereas other substances can cross the BBB by carrier-mediated influx transport, receptor-mediated transcytosis and absorptive-mediated transcytosis. Studies of drugs relevant to migraine pathophysiology and treatment have been examined with the pressurized arteriography method. The drugs, given both luminally and abluminally, provide important notions regarding antimigraine site of action, probably abluminal to the BBB. The problems with the BBB in animal models designed to study the pathophysiology, acute treatment models and preventive treatments are discussed with special emphasize on the triptans and calcitonin gene-related peptide (CGRP). The human experimental headache model, especially the use of glycerol trinitrate (the nitric oxide model), and experiences with CGRP administrations utilize the systemic administration of the agonists with effects on other vascular beds also. We discuss how this can be related to genuine migraine attacks. Our view is that there exists no clear proof of breakdown or leakage of the BBB during migraine attacks, and that antimigraine drugs need to pass the BBB for efficacy.

14 Review Treatment of migraine attacks based on the interaction with the trigemino-cerebrovascular system. 2008

Link, Andrea Stephanie / Kuris, Anikó / Edvinsson, Lars. ·Biomedical Center Lund, Lund, Sweden. ·J Headache Pain · Pubmed #18217201.

ABSTRACT: Primary headaches such as migraine are among the most prevalent neurological disorders, affecting up to one-fifth of the adult population. The scientific work in the last decade has unraveled much of the pathophysiological background of migraine, which is now considered to be a neurovascular disorder. It has been discovered that the trigemino-cerebrovascular system plays a key role in migraine headache pathophysiology by releasing the potent vasodilator calcitonin gene-related peptide (CGRP). This neuropeptide is released in parallel with the pain and its concentration correlates well with the intensity of the headache. The development of drugs of the triptan class has provided relief for the acute attacks but at the cost of, mainly cardiovascular, side effects. Thus, the intention to improve treatment led to the development of small CGRP receptor antagonists such as olcegepant (BIBN4096BS) and MK-0974 that alleviate the acute migraine attack without acute side events. The purpose of this review is to give a short overview of the pathological background of migraine headache and to illustrate the mechanisms behind the actions of triptans and the promising CGRP receptor blockers.

15 Clinical Trial Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. 2015

Bigal, Marcelo E / Edvinsson, Lars / Rapoport, Alan M / Lipton, Richard B / Spierings, Egilius L H / Diener, Hans-Christoph / Burstein, Rami / Loupe, Pippa S / Ma, Yuju / Yang, Ronghua / Silberstein, Stephen D. ·Research and Development Department, Teva Pharmaceuticals, Frazer, PA, USA. Electronic address: marcelo.bigal@tevapharm.com. · Department of Internal Medicine, Lund University Hospital, Lund, Sweden. · The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Department of Neurology, Albert Einstein College of Medicine, New York, NY, USA. · Clinical Research, MedVadis Research, Boston, MA, USA. · Department of Neurology, Essen Headache Center, Essen, Germany. · Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. · Research and Scientific Affairs Department, Teva Pharmaceuticals, Frazer, PA, USA. · Statistics Department, Teva Pharmaceuticals, Frazer, PA, USA. · Department of Neurology, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA. ·Lancet Neurol · Pubmed #26432181.

ABSTRACT: BACKGROUND: Benefits of calcitonin-gene related peptide (CGRP) inhibition have not been established in chronic migraine. Here we assess the safety, tolerability, and efficacy of two doses of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of chronic migraine. METHODS: In this multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel-group phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had chronic migraine. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1, stratified by sex and use of concomitant preventive drugs) to three 28-day treatment cycles of subcutaneous TEV-48125 675/225 mg (675 mg in the first treatment cycle and 225 mg in the second and third treatment cycles), TEV-48125 900 mg (900 mg in all three treatment cycles), or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Daily headache information was captured using an electronic diary. Primary endpoints were change from baseline in the number of headache-hours during the third treatment cycle (weeks 9-12) and safety and tolerability during the study. Secondary endpoint was change in the number of moderate or severe headache-days in weeks 9-12 relative to baseline. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered with ClinicalTrials.gov, number, NCT02021773. FINDINGS: Between Jan 8, 2014, and Aug 27, 2014, we enrolled 264 participants: 89 were randomly assigned to receive placebo, 88 to receive 675/225 mg TEV-48125, and 87 to receive 900 mg TEV-48125. The mean change from baseline in number of headache-hours during weeks 9-12 was -59.84 h (SD 80.38) in the 675/225 mg group and -67.51 h (79.37) in the 900 mg group, compared with -37.10 h (79.44) in the placebo group. The least square mean difference in the reduction of headache-hours between the placebo and 675/225 mg dose groups was -22.74 h (95% CI -44.28 to -1.21; p=0.0386), whereas the difference between placebo and 900 mg dose groups was -30.41 h (-51.88 to -8.95; p=0.0057). Adverse events were reported by 36 (40%) patients in the placebo group, 47 (53%) patients in the 675/225 mg dose group, and 41 (47%) patients in the 900 mg dose group, whereas treatment-related adverse events were recorded in 15 (17%) patients, 25 (29%) patients, and 28 (32%) patients, respectively. The most common adverse events were mild injection-site pain and pruritus. Four (1%) patients had serious non-treatment-related adverse events (one patient in the placebo group, one patient in the 675/225 mg group, and two patients in the 900 mg group); no treatment-related adverse events were serious and there were no relevant changes in blood pressure or other vital signs. INTERPRETATION: TEV-48125 given by subcutaneous injection every 28 days seems to be tolerable and effective, thus supporting the further development of TEV-48125 for the preventive treatment of chronic migraine in a phase 3 trial. FUNDING: Teva Pharmaceuticals.

16 Article Expression of Pituitary Adenylate Cyclase-activating Peptide, Calcitonin Gene-related Peptide and Headache Targets in the Trigeminal Ganglia of Rats and Humans. 2018

Frederiksen, Simona Denise / Warfvinge, Karin / Ohlsson, Lena / Edvinsson, Lars. ·Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet Glostrup, 2600 Glostrup, Denmark; Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, 221 84 Lund, Sweden. Electronic address: simona.frederiksen@hotmail.com. · Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet Glostrup, 2600 Glostrup, Denmark; Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, 221 84 Lund, Sweden. Electronic address: karin.warfvinge@med.lu.se. · Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, 221 84 Lund, Sweden. Electronic address: lena.ohlsson@med.lu.se. · Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet Glostrup, 2600 Glostrup, Denmark; Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, 221 84 Lund, Sweden. Electronic address: lars.edvinsson@med.lu.se. ·Neuroscience · Pubmed #30336190.

ABSTRACT: Neurotransmitter and headache target localization in the trigeminal ganglia (TG) might increase the understanding of sites of action, and mechanisms related to headache therapy. The overall aim of the study was to investigate the presence of migraine targets in the TG with particular emphasis on pituitary adenylate cyclase-activating peptide (PACAP) and calcitonin gene-related peptide (CGRP), known to be involved in cranial pain processing, and selected headache targets. Rat- and human TG were processed for immunohistochemistry. PACAP-38, CGRP and the headache targets were expressed in rat and human TG. PACAP receptors were confined to neurons and satellite glial cells (SGCs), however with variability between the receptor subtypes PACAP type I receptor (PAC

17 Article Migraine associated with altitude: results from a population-based study in Nepal. 2017

Linde, M / Edvinsson, L / Manandhar, K / Risal, A / Steiner, T J. ·Department of Neuromedicine and Movement Science, NTNU Norwegian University of Science and Technology, Trondheim, Norway. · Norwegian Advisory Unit on Headache, St Olavs University Hospital, Trondheim, Norway. · Institute of Clinical Sciences, Lund University, Lund, Sweden. · Dhulikhel Hospital, Kathmandu University Hospital, Dhulikhel, Nepal. · Division of Brain Sciences, Imperial College London, London, UK. ·Eur J Neurol · Pubmed #28556384.

ABSTRACT: BACKGROUND AND PURPOSE: A 1988 pilot study in Peru suggested an association between migraine and chronic exposure to high altitude. This study provides epidemiological evidence corroborating this. METHODS: In a cross-sectional nationwide population-based study, a representative sample of Nepali-speaking adults were recruited through stratified multistage cluster sampling. They were visited at home by trained interviewers using a culturally adapted questionnaire. The altitude of dwelling of each participant was recorded. RESULTS: Of 2100 participants, over half [1100 (52.4%)] were resident above 1000 m and almost one quarter [470 (22.4%)] at ≥2000 m. Age- and gender-standardized migraine prevalence increased from 27.9% to 45.5% with altitude between 0 and 2499 m and thereafter decreased to 37.9% at ≥2500 m. The likelihood of having migraine was greater (odds ratio, 1.5-2.2; P ≤ 0.007) at all higher altitudes compared with <500 m. In addition, all symptom indices increased with altitude across the range <500 m to 2000-2499 m, i.e. median attack frequency from 1.3 to 3.0 days/month (P < 0.001), median duration from 9 to 24 h (P < 0.001) and pain intensity [the proportion reporting 'bad pain' (highest intensity)] from 35.5% to 56.9% (P = 0.011). Each of these showed a downward trend above 2500 m. CONCLUSIONS: Dwelling at high altitudes increases not only migraine prevalence but also the severity of its symptoms.

18 Article Topical dura mater application of CFA induces enhanced expression of c-fos and glutamate in rat trigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72). 2017

Lukács, M / Warfvinge, K / Tajti, J / Fülöp, F / Toldi, J / Vécsei, L / Edvinsson, L. ·Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden. lukacs_melici@yahoo.com. · Department of Neurology, University of Szeged, 6725 Semmelweis street nr. 6, Szeged, Hungary. lukacs_melici@yahoo.com. · Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden. · Department of Clinical Experimental Research, Copenhagen University, Glostrup Hospital, Copenhagen, Denmark. · Department of Neurology, University of Szeged, 6725 Semmelweis street nr. 6, Szeged, Hungary. · Institute of Pharmaceutical Chemistry and MTA-SZTE Research Group for Stereochemistry, University of Szeged, Szeged, Hungary. · Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary. · MTA SZTE Neuroscience Research Group, Szeged, Hungary. ·J Headache Pain · Pubmed #28337634.

ABSTRACT: BACKGROUND: Migraine is a debilitating neurological disorder where trigeminovascular activation plays a key role. We have previously reported that local application of Complete Freund's Adjuvant (CFA) onto the dura mater caused activation in rat trigeminal ganglion (TG) which was abolished by a systemic administration of kynurenic acid (KYNA) derivate (SZR72). Here, we hypothesize that this activation may extend to the trigeminal complex in the brainstem and is attenuated by treatment with SZR72. METHODS: Activation in the trigeminal nucleus caudalis (TNC) and the trigeminal tract (Sp5) was achieved by application of CFA onto the dural parietal surface. SZR72 was given intraperitoneally (i.p.), one dose prior CFA deposition and repeatedly daily for 7 days. Immunohistochemical studies were performed for mapping glutamate, c-fos, PACAP, substance P, IL-6, IL-1β and TNFα in the TNC/Sp5 and other regions of the brainstem and at the C RESULTS: We found that CFA increased c-fos and glutamate immunoreactivity in TNC and C CONCLUSION: This is the first study demonstrating that dural application of CFA increases the expression of c-fos and glutamate in TNC neurons. Treatment with the KYNA analogue prevented this expression.

19 Article Expression of messenger molecules and receptors in rat and human sphenopalatine ganglion indicating therapeutic targets. 2016

Steinberg, Anna / Frederiksen, Simona D / Blixt, Frank W / Warfvinge, Karin / Edvinsson, Lars. ·Karolinska Institutet, Department of Clinical Neuroscience, Division of Neurology, Karolinska University Hospital Solna, 171 76, Stockholm, Sweden. anna.steinberg@karolinska.se. · Department of Neurology, Karolinska University Hospital Solna, S-171 76, Stockholm, Sweden. anna.steinberg@karolinska.se. · Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden. · Department of Clinical Experimental Research, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark. ·J Headache Pain · Pubmed #27587062.

ABSTRACT: BACKGROUND: Migraine and Cluster Headache (CH) are two primary headaches with severe disease burden. The disease expression and the mechanisms involved are poorly known. In some attacks of migraine and in most attacks of CH, there is a release of vasoactive intestinal peptide (VIP) originating from parasympathetic cranial ganglia such as the sphenopalatine ganglion (SPG). Patients suffering from these diseases are often deprived of effective drugs. The aim of the study was to examine the localization of the botulinum toxin receptor element synaptic vesicle glycoprotein 2A (SV-2A) and the vesicular docking protein synaptosomal-associated protein 25 (SNAP25) in human and rat SPG. Additionally the expression of the neurotransmitters pituitary adenylate cyclase activating polypeptide (PACAP-38), nitric oxide synthase (nNOS), VIP and 5-hydroxttryptamine subtype receptors (5-HT1B,1D,1F) were examined. METHODS: SPG from adult male rats and from humans, the later removed at autopsy, were prepared for immunohistochemistry using specific antibodies against neurotransmitters, 5-HT1B,1D,1F receptors, and botulinum toxin receptor elements. RESULTS: We found that the selected neurotransmitters and 5-HT receptors were expressed in rat and human SPG. In addition, we found SV2-A and SNAP25 expression in both rat and human SPG. We report that all three 5-HT receptors studied occur in neurons and satellite glial cells (SGCs) of the SPG. 5-HT1B receptors were in addition found in the walls of intraganglionic blood vessels. CONCLUSIONS: Recent focus on the SPG has emphasized the role of parasympathetic mechanisms in the pathophysiology of mainly CH. The development of next generation's drugs and treatment of cranial parasympathetic symptoms, mediated through the SPG, can be modulated by treatment with BoNT-A and 5-HT receptor agonists.

20 Article Peripheral Sensory Neurons Expressing Melanopsin Respond to Light. 2016

Matynia, Anna / Nguyen, Eileen / Sun, Xiaoping / Blixt, Frank W / Parikh, Sachin / Kessler, Jason / Pérez de Sevilla Müller, Luis / Habib, Samer / Kim, Paul / Wang, Zhe Z / Rodriguez, Allen / Charles, Andrew / Nusinowitz, Steven / Edvinsson, Lars / Barnes, Steven / Brecha, Nicholas C / Gorin, Michael B. ·Department of Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine, UCLALos Angeles, CA, USA; Brain Research Institute, UCLALos Angeles, CA, USA. · Department of Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine, UCLA Los Angeles, CA, USA. · Department of Neurobiology and Medicine, David Geffen School of Medicine, UCLA Los Angeles, CA, USA. · Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University Lund, Sweden. · Brain Research Institute, UCLALos Angeles, CA, USA; Department of Neurology, David Geffen School of Medicine, UCLALos Angeles, CA, USA. · Department of Neurobiology and Medicine, David Geffen School of Medicine, UCLALos Angeles, CA, USA; Departments of Physiology & Biophysics and Ophthalmology and Visual Sciences, Dalhousie UniversityHalifax, NS, Canada. · Brain Research Institute, UCLALos Angeles, CA, USA; Department of Neurobiology and Medicine, David Geffen School of Medicine, UCLALos Angeles, CA, USA; Veterans Administration Greater Los Angeles Health SystemLos Angeles, CA, USA. ·Front Neural Circuits · Pubmed #27559310.

ABSTRACT: The ability of light to cause pain is paradoxical. The retina detects light but is devoid of nociceptors while the trigeminal sensory ganglia (TG) contain nociceptors but not photoreceptors. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to mediate light-induced pain but recent evidence raises the possibility of an alternative light responsive pathway independent of the retina and optic nerve. Here, we show that melanopsin is expressed in both human and mouse TG neurons. In mice, they represent 3% of small TG neurons that are preferentially localized in the ophthalmic branch of the trigeminal nerve and are likely nociceptive C fibers and high-threshold mechanoreceptor Aδ fibers based on a strong size-function association. These isolated neurons respond to blue light stimuli with a delayed onset and sustained firing, similar to the melanopsin-dependent intrinsic photosensitivity observed in ipRGCs. Mice with severe bilateral optic nerve crush exhibit no light-induced responses including behavioral light aversion until treated with nitroglycerin, an inducer of migraine in people and migraine-like symptoms in mice. With nitroglycerin, these same mice with optic nerve crush exhibit significant light aversion. Furthermore, this retained light aversion remains dependent on melanopsin-expressing neurons. Our results demonstrate a novel light-responsive neural function independent of the optic nerve that may originate in the peripheral nervous system to provide the first direct mechanism for an alternative light detection pathway that influences motivated behavior.

21 Article Immunohistochemical localization of the calcitonin gene-related peptide binding site in the primate trigeminovascular system using functional antagonist antibodies. 2016

Miller, Silke / Liu, Hantao / Warfvinge, Karin / Shi, Licheng / Dovlatyan, Mary / Xu, Cen / Edvinsson, Lars. ·Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320 and 360 Binney Street, Cambridge, MA 02142, USA. Electronic address: silkem@amgen.com. · Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320 and 360 Binney Street, Cambridge, MA 02142, USA. · University of Lund, Institute of Clinical Sciences at Lund University Hospital, House A13, Sölvegatan, Lund 22184, Sweden. ·Neuroscience · Pubmed #27155150.

ABSTRACT: Calcitonin gene-related peptide (CGRP) is a potent vasodilator and a neuromodulator implicated in the pathophysiology of migraine. It binds to the extracellular domains of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein (RAMP) 1 that together form the CGRP receptor. Antagonist antibodies against CGRP and its binding site at the receptor are clinically effective in preventing migraine attacks. The blood-brain barrier penetration of these antagonist antibodies is limited, suggesting that a potential peripheral site of action is sufficient to prevent migraine attacks. To further understand the sites of CGRP-mediated signaling in migraine, we used immunohistochemical staining with recently developed antagonist antibodies specifically recognizing a fusion protein of the extracellular domains of RAMP1 and CLR that comprise the CGRP binding pocket at the CGRP receptor in monkey and man. We confirmed binding of the antagonist antibodies to human vascular smooth muscle cells (VSMCs) of dural meningeal arteries and neurons in the trigeminal ganglion, both of which are likely sites of action for therapeutic antibodies in migraine patients. We further used one of these antibodies for detailed mapping on cynomolgus monkey tissue and found antagonist antibody binding sites at multiple levels in the trigeminovascular system: in the dura mater VSMCs, in neurons and satellite glial cells in the trigeminal ganglion, and in neurons in the spinal trigeminal nucleus caudalis. These data reinforce and clarify our understanding of CGRP receptor localization in a pattern consistent with a role for CGRP receptors in trigeminal sensitization and migraine pathology.

22 Article Experimental inflammation following dural application of complete Freund's adjuvant or inflammatory soup does not alter brain and trigeminal microvascular passage. 2015

Lundblad, Cornelia / Haanes, Kristian A / Grände, Gustaf / Edvinsson, Lars. ·Department of Medicine, Institute of Clinical Sciences, University Hospital, Lund University, 22185, Lund, Sweden. · Department of Clinical Experimental Research, Copenhagen University Hospital, Glostrup, Denmark. · Department of Medicine, Institute of Clinical Sciences, University Hospital, Lund University, 22185, Lund, Sweden. Lars.Edvinsson@med.lu.se. · Department of Clinical Experimental Research, Copenhagen University Hospital, Glostrup, Denmark. Lars.Edvinsson@med.lu.se. ·J Headache Pain · Pubmed #26512021.

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.

23 Article The Journey to Establish CGRP as a Migraine Target: A Retrospective View. 2015

Edvinsson, Lars. ·Department of Medicine, Institute of Clinical Sciences, Lund University and Lund University Hospital, Lund, Sweden. ·Headache · Pubmed #26368117.

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.

24 Article Dural administration of inflammatory soup or Complete Freund's Adjuvant induces activation and inflammatory response in the rat trigeminal ganglion. 2015

Lukács, M / Haanes, K A / Majláth, Zs / Tajti, J / Vécsei, L / Warfvinge, K / Edvinsson, L. ·Department of Medicine, Institute of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Sölvegatan 17, SE 221 84, Lund, Sweden. ·J Headache Pain · Pubmed #26329487.

ABSTRACT: BACKGROUND: Migraine is a painful disorder with a huge impact on individual and public health. We hypothesize that migraine pain originates from a central mechanism that results secondarily in hypersensitivity in peripheral afferents associated with the cerebral and cranial blood vessels. It has previously been shown that application of inflammatory or algesic substances onto the dura mater or chemical stimulation of the dural receptive fields causes hypersensitivity to mechanical and thermal stimulation together with direct activation of the TG. We asked whether local inflammation of dura mater induces inflammatory activation in the trigeminal ganglion. METHODS: We performed topical administration of inflammatory soup (IS) or Complete Freund's Adjuvant (CFA) onto an exposed area of the rat dura mater in vivo for 20 min. The window was closed and the rats were sacrificed after 4 h and up to 7 days. Myography was performed on middle meningeal arteries. The trigeminal ganglia were removed and processed for immunohistochemistry or Western blot. RESULTS: Both CFA and IS induced enhanced expression of pERK1/2, IL-1β and CGRP in the trigeminal ganglia. The pERK1/2 immunoreactivity was mainly seen in the satellite glial cells, while IL-1β reactivity was observed in the neuronal cytoplasm, close to the cell membrane, seemingly as sign of neuro-glial interaction. The CGRP expression in the neurons and nerve fibres was enhanced after the application of either inflammatory agent. Myography resulted in a strong vasoconstrictor response to IS, but not to CFA. CONCLUSIONS: These results suggest that the application of IS or CFA onto the dura mater causes long-term activation of the TG and demonstrate the importance of the neuro-glial interaction in the activation of the trigeminovascular system.

25 Article Modulation of inflammatory mediators in the trigeminal ganglion by botulinum neurotoxin type A: an organ culture study. 2015

Edvinsson, Jacob / Warfvinge, Karin / Edvinsson, Lars. ·Department of Medicine, Lund University, Lund, Sweden, jacob.edvinsson@hotmail.com. ·J Headache Pain · Pubmed #26245187.

ABSTRACT: BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

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