Headache Currents最新文献

{"title":"Basic Science: Prejunctional and Presynaptic Trigeminovascular Targets: What Preclinical Evidence Is There?","authors":"Peter J. Goadsby MD., Ph.D.","doi":"10.1111/j.1743-5013.2004.10103.x","DOIUrl":"10.1111/j.1743-5013.2004.10103.x","url":null,"abstract":"<p> <i>Inhibition of trigeminovascular nociceptive traffic by a prejunctional/presynaptic mechanism is an attractive approach for the treatment of migraine. It has been shown that blocking the presumed postsynaptic actions of calcitonin gene-related peptide (CGRP) is an effective acute antimigraine strategy, so that blockade of CGRP release by presynaptic inhibition also seems promising. A number of targets are reviewed including serotonin 5-HT_1F and 5-HT_1D receptor agonists, adenosine A₁ receptor agonists, nociceptin, and vanilloid VR1 receptors. For each, the preclinical rationale for their involvement in prejunctional/presynaptic mechanisms is reviewed. Development of one or more such compounds offers the exciting prospect of new nonvasoconstrictor treatments for migraine and cluster headache.</i> </p>","PeriodicalId":100600,"journal":{"name":"Headache Currents","volume":"1 1","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2004-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1743-5013.2004.10103.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76431623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glutamate Receptor Antagonists","authors":"Marcelo E. Bigal \u0000 MD, PhD","doi":"10.1111/j.1743-5013.2004.10102B.x","DOIUrl":"10.1111/j.1743-5013.2004.10102B.x","url":null,"abstract":"<div>\u0000 \u0000 \u0000 \u0000 <p>BACKGROUND: L-glutamate activates neurons in the trigeminal nucleus caudalis (TNC). Furthermore, non-NMDA ionotropic glutamate receptors such as GluR5 are expressed in rat trigeminal ganglion (TG), and GluR5 receptors play an important role in central sensitization (CS). CS is implicated in, and the trigeminal system is at the core of, migraine. Therefore, we hypothesized that GluR5 receptor antagonists would be effective in preclinical models of migraine.</p>\u0000 <p>OBJECTIVES: 1) To test the potency and efficacy of GluR5 antagonists with varying degrees of affinity and selectivity for the GluR5/kainate receptor in the dural plasma protein extravasation (PPE) and the c-fos models of migraine. 2) To test these GluR5 receptor antagonists for their ability to contract the rabbit saphenous vein (RSV) in <i>vitro.</i></p>\u0000 <p>METHODS: GluR5 antagonists were synthesized in the Lilly Research Laboratories. Ligand binding studies using recombinant human non-NMDA receptors expressed in HEK293 cell membranes were used to determine compound affinity. We evaluated parenterally administered compounds in the PPE and the c-fos models induced by electrical stimulation of male rats TG. Fos protein in the TNC was measured in the c-fos experiment. Ring preparations of RSV were suspended in tissue baths and isometric contractions were recorded following incremental increases in the concentration of the test compound. Sumatriptan was used as a positive control for the RSV studies.</p>\u0000 <p>RESULTS: LY293558, LY382884 and LY435735 dose-dependently blocked protein extravasation in the PPE model. The rank order of potency correlated with affinity for GluR5. In contrast, LY300168, a potent and selective AMPA antagonist, did not block protein extravasation, even at relatively high doses. LY293558 and LY435735 also blocked c-fos expression in the TNC. LY293558 and LY382884 did not contract the tissue in the RSV assay at concentrations up to 100 mM.</p>\u0000 <p>CONCLUSIONS: The inhibitory effects of GluR5 antagonists in the PPE and c-fos preclinical models of migraine suggest a novel role for GluR5 antagonism in migraine therapy. The lack of efficacy of the selective AMPA antagonist LY300168 in PPE does not support a role for this mechanism in migraine. The lack of activity of these compounds in the RSV provides a therapeutic advantage of GluR5 antagonists over current vasoactive migraine therapies. These pharmacological properties of GluR5 antagonists suggest that they could be used in the treatment of acute migraine without a cardiovascular liability.</p>\u0000 </div>","PeriodicalId":100600,"journal":{"name":"Headache Currents","volume":"1 1","pages":"20-21"},"PeriodicalIF":0.0,"publicationDate":"2004-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1743-5013.2004.10102B.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74948581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Science: Peripheral and Central Trigeminal Targets for Acute Migraine Therapy: Early Clinical Trial Results","authors":"Nabih M. Ramadan M.D.,&nbsp;Thomas M. Buchanan M.S.,&nbsp;Starr H. Pearlman Ph.D.","doi":"10.1111/j.1743-5013.2004.10104.x","DOIUrl":"10.1111/j.1743-5013.2004.10104.x","url":null,"abstract":"<p> <i>In the decade since the introduction of sumatriptan on the market, second- and third-generation triptans have been advanced with the goal of reducing side effects while maintaining or improving efficacy. While these efforts have yielded relatively minor changes to the sumatriptan molecule, the new triptans enhance the ability of clinicians to individualize therapy. More recent strategies focus on novel neuronal targets for acute migraine treatments without the liability of adverse cardiovascular effects. Current research is focusing on calcitonin gene-related peptide antagonists, glutamate modulators, selective serotonin 1F or 1D agonists, and adenosine type 1 agonists. Clinical data on these approaches are emerging and seem encouraging. However, these potential therapies are in an early stage of development, and to date, none has reached phase III clinical research.</i> </p>","PeriodicalId":100600,"journal":{"name":"Headache Currents","volume":"1 1","pages":"7-12"},"PeriodicalIF":0.0,"publicationDate":"2004-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1743-5013.2004.10104.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77789322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NOS Inhibition","authors":"Marcelo E. Bigal \u0000 MD, PhD","doi":"10.1111/j.1743-5013.2004.10102D.x","DOIUrl":"https://doi.org/10.1111/j.1743-5013.2004.10102D.x","url":null,"abstract":"<div>\u0000 \u0000 \u0000 \u0000 <p>BACKGROUND: Nitric oxide (NO) is an almost ubiquitous messenger molecule and is implicated in several disorders. NG monomethyl L-arginine (L-NMMA:546C88) is an inhibitor of all three NO synthases (NOS), the enzymes that catalyse the production of NO. The present study was performed to evaluate the dose-response relation of L-NMMA to improve the design and interpretation of studies in migraine sufferers and other diseases.</p>\u0000 <p>METHODS: In a double-blind, placebo-controlled, cross-over design, six healthy volunteers were randomised to receive three different doses of L-NMMA (0.3 mg/kg, 1 mg/kg, 3 mg/kg) or placebo (5% dextrose) intravenously (iv) over 5 min on four different days. On a fifth study day, in an open design, the same subjects received L-NMMA in the dose 6 mg/kg iv over 15 min. The effect of L-NMMA on the maximal mean blood velocity (Vmean) in the middle cerebral artery (MCA) (transcranial Doppler), the luminal diameter of the radial artery (high-frequency ultrasound), mean arterial blood pressure (MAP), heart rate and electrocardiogram were repeatedly followed every 5 min until 60 min after start of the infusion, then every 15 min during the following hour, and at 3 h and 4 h.</p>\u0000 <p>RESULTS: Inhibition of NOS had no effect on Vmean in MCA or on the diameter of the radial artery, but MAP increased and heart rate decreased dose dependently. With a dose of 6-mg/kg L-NMMA infused over a 15-min period, the maximum MAP increase was 20% 20 min after the start of L-NMMA infusion. The maximum decrease of heart rate was 24% 15 min after start of the L-NMMA infusion.</p>\u0000 <p>CONCLUSION: L-NMMA in a dose that caused marked changes in systemic blood pressure and heart rate had no effect on cerebral and radial arteries in man.</p>\u0000 </div>","PeriodicalId":100600,"journal":{"name":"Headache Currents","volume":"1 1","pages":"23"},"PeriodicalIF":0.0,"publicationDate":"2004-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1743-5013.2004.10102D.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"109165293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glutamate","authors":"F. Michael Cutrer \u0000 MD","doi":"10.1111/j.1743-5013.2004.10101D.x","DOIUrl":"https://doi.org/10.1111/j.1743-5013.2004.10101D.x","url":null,"abstract":"<div>\u0000 \u0000 \u0000 \u0000 <p>Expression of Fos protein is an indicator of neuronal perturbation and is readily observed in the caudal medulla and the spinal cord following trigeminovascular nociceptive activation by electrical stimulation of the superior sagittal sinus (SSS) in the cat. It has been shown in the rat that N-methyl-D-aspartate (NMDA) receptor blockade causes a reduction in Fos protein expression after generalized meningeal irritation. We wished to examine if the same relationship was true in the cat, using the same non-competitive NMDA receptor antagonist MK-801, and a trigeminovascular-specific stimulus. A group of experimental animals underwent stimulation following blinded administration of MK-801 (4 mg/kg i.v.); control animals underwent stimulation minus MK-801, and a non-stimulated control animal underwent surgery alone. The regions examined for Fos-like immunoreactivity were the trigeminal nucleus caudalis (TNC) and its caudal extension into the C(1) and C(2) levels of the upper cervical spinal cord. The Fos-positive cell counts for the three regions (TNC, C(1) and C(2)) were grouped together for analysis. In the control stimulated group a median of 78 (56-99, quartile range, n = 4) cells were Fos-positive. In the group treated with MK-801 the median number of Fos-positive cells was reduced to 40 (30-48; P &lt; 0.03, n = 7). The large reduction that was observed in SSS stimulation-evoked Fos protein expression following the administration of MK-801, taken together with electrophysiological data, indicates a role for glutamate in neurotransmission within the trigeminocervical complex. Understanding glutamatergic mechanisms in the trigeminocervical complex offers mechanistic insight and therapeutic possibilities for primary neurovascular headaches, such as migraine.</p>\u0000 </div>","PeriodicalId":100600,"journal":{"name":"Headache Currents","volume":"1 1","pages":"18"},"PeriodicalIF":0.0,"publicationDate":"2004-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1743-5013.2004.10101D.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"109165294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CGRP Receptors","authors":"F. Michael Cutrer \u0000 M.D.","doi":"10.1111/j.1743-5013.2004.10101A.x","DOIUrl":"https://doi.org/10.1111/j.1743-5013.2004.10101A.x","url":null,"abstract":"<div>\u0000 \u0000 \u0000 \u0000 <p>We examined the regulation of calcitonin gene-related peptide (CGRP) promoter activity in primary cultures of rat trigeminal ganglia neurons. A viral vector was used to circumvent the potential complication of examining only a small subpopulation of cells in heterogeneous cultures. Infection with high titers of recombinant adenovirus containing 1.25 kb of the rat CGRP promoter linked to the beta-galactosidase reporter gene (AdCGRP-lacZ) yielded expression in about 50% of the CGRP-expressing neurons. The CGRP-lacZ reporter gene was preferentially expressed in neurons, with 91% co-expression with endogenous CGRP. In contrast, an adenoviral vector containing a CMV-lacZ reporter was predominantly expressed in non-neuronal cells, with only 29% co-expression with CGRP. We then asked whether the CGRP promoter in the viral vector could be regulated by serotonin receptor type 1 (5-HT(1)) agonists. Promoter activity was decreased two- to threefold by treatment with five 5-HT(1B/D) agonists, including the triptan drugs sumatriptan, eletriptan, and rizatriptan that are used for migraine treatment. As controls, CMV promoter activity was not affected, and 5-HT(1B/D) receptor antagonists blocked the repression caused by sumatriptan and eletriptan. Thus, adenoviral gene transfer can be used in trigeminal ganglia neurons for studying the mechanisms of triptan drug action on CGRP synthesis.</p>\u0000 </div>","PeriodicalId":100600,"journal":{"name":"Headache Currents","volume":"1 1","pages":"13"},"PeriodicalIF":0.0,"publicationDate":"2004-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1743-5013.2004.10101A.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"109165452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitric Oxide","authors":"F. Michael Cutrer \u0000 M.D.","doi":"10.1111/j.1743-5013.2004.10101B.x","DOIUrl":"https://doi.org/10.1111/j.1743-5013.2004.10101B.x","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Nuclear Factor-kappaB as a Molecular Target for Migraine Therapy</h3>\u0000 \u0000 \u0000 \u0000 <p>Nitric oxide (NO) generated from inducible NO synthase (iNOS) participates in immune and inflammatory responses in many tissues. The NO donor glyceryl trinitrate (GTN) provokes delayed migraine attacks when infused into migraineurs and also causes iNOS expression and delayed inflammation within rodent dura mater. Sodium nitroprusside, a NO donor as well, also increases iNOS expression. Because inflammation and iNOS are potential therapeutic targets, we examined transcriptional regulation of iNOS following GTN infusion and the consequences of its inhibition within dura mater. We show that intravenous GTN increases NO production within macrophages. L-N(6)-(1-iminoethyl)lysine, a selective iNOS inhibitor, attenuates the NO signal, emphasizing the importance of enzymatic activity to delayed NO production. iNOS expression is preceded by significant nuclear factor kappa B (NF-kappaB) activity, as reflected by a reduction in the inhibitory protein-kappa-B-alpha (IkappaBalpha) and activation of NF-kappaB after GTN infusion. I-kappa-B-alpha degradation, NF-kappaB activation, and iNOS expression were attenuated by parthenolide (3mg/kg), the active constituent of feverfew, an anti-inflammatory drug used for migraine treatment. These findings suggest that GTN promotes NF-kappaB activity and inflammation with a time course consistent with migraine attacks in susceptible individuals. We conclude, based on results with this animal model, that blockade of NF-kappaB activity provides a novel transcriptional target for the development of anti-migraine drugs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Effects of the Nitric Oxide Donor, DEA/NO on Cortical Spreading Depression</h3>\u0000 \u0000 \u0000 \u0000 <p>Cortical spreading depression (CSD) is a transient disruption of local ionic homeostasis that may promote migraine attacks and the progression of stroke lesions. We reported previously that the local inhibition of nitric oxide (NO) synthesis with Nomega-nitro-L-arginine methyl ester (L-NAME) delayed markedly the initiation of the recovery of ionic homeostasis from CSD. Here we describe a novel method for selective, controlled generation of exogenous NO in a functioning brain region. It is based on microdialysis perfusion of the NO donor, 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA/NO). As DEA/NO does not generate NO at alkaline pH, and as the brain has a strong acid-base buffering capacity, DEA/NO was perfused in a medium adjusted at alkaline (but unbuffered) pH. Without DEA/NO, such a microdialysis perfusion medium did not alter CSD. DEA/NO (1, 10 and 100 microM) had little effect on CSD by itself, but it reversed in a concentration-dependent manner the effects of NOS inhibition by 1 mM L-NAME. These data ","PeriodicalId":100600,"journal":{"name":"Headache Currents","volume":"1 1","pages":"14-15"},"PeriodicalIF":0.0,"publicationDate":"2004-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1743-5013.2004.10101B.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"109165295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}