Efficacy of 5-HT1F agonist versus CGRP-antagonists for treatment of acute migraine: A systematic review and network meta-analysis

Background: Two new classes of drugs approved by USFDA for the treatment of acute migraine are non-peptide Calcitonin Gene-Related Peptide (CGRP) receptor antagonists (rimegepant and ubrogepant) and 5-HT1F receptor agonist lasmiditan. There are no clinical trials comparing these two classes of newer drugs. Aim and Objectives: The present network meta-analysis was conducted with the objective to compare the efficacy of orally administered lasmiditan versus CGRP-receptor antagonists (rimegepant and ubrogepant) in the treatment of acute migraine. Materials and Methods: Electronic database search in PUBMED and Cochrane library was conducted using MeSH search terms “Lasmiditan” AND “Migraine” for articles on lasmiditan; while MeSH terms “Ubrogepant” AND “Migraine;” “Rimegeapnt” AND “Migraine” were used for articles on CGRP-antagonists. Randomized or cross-over studies comparing efficacy of oral lasmiditan and two FDA approved CGRP-antagonists (rimegepant, and ubrogepant) versus other active treatment or placebo in adults with acute attack of migraine were included in the analysis. Incidence of 2 h pain-free event was the primary outcome measure while the incidence of 24 h pain-free was the secondary outcome measure compared. Both frequent and Bayesian network meta-analysis were conducted by CRSU MetaInsight software. Results: In 12 eligible studies, seven interventions were compared with total 13795 patients analyzed in the network. Higher treatment ranking for 2 h and 24 h pain-free events was observed for lasmiditan 200 mg and rimegepant 150 mg, respectively. Conclusions: There is strong evidence to conclude that lasmiditan at 200 mg is better drug for immediate (2 h) headache freedom. There is limited evidence to support rimegepant for sustained effect (beyond 24 h).

Analgesic Effect of Intrathecal 2R， 6R-HNK on Neuropathic Pain in Female Mice / 中山大学学报(医学科学版)

ObjectiveTo investigate the analgesic action and mechanism of intrathecal 2R， 6R-hydroxynorketamine （2R， 6R-HNK） on spared nerve injury （SNI）-induced chronic neuropathic pain （CNP） in female mice. MethodsSNI was used to establish acute and chronic CNP models in female mice. The mice were randomly divided into different groups with administration of vehicle， 2R， 6R-HNK or S-ketamine （10 mg/kg intraperitoneal injection/i.p. or 7， 21 μmol/L intrathecal injection/i.t.） at 3 weeks after or 30 min/1 d before operation （n = 3 - 7 mice/group）. The curative or preventive effect of 2R， 6R-HNK was evaluated by mechanical paw withdrawal threshold （PWT） and the analgesic efficiency. Finally， immunofluorescence and RT-PCR of dorsal root ganglion （DRG） and spinal dorsal horn （SDH） were used to explore the possible mechanisms. ResultsCompared with vehicle， intrathecal injection of 2R， 6R-HNK largely reversed SNI-induced bilateral mechanical allodynia in a delayed-and-dose-dependent way. Among them， 21 μmol/L 2R， 6R-HNK reached its maximum analgesic efficiency （75.32±7.69） % at 2 d. Pre-intrathecal delivery of 2R， 6R-HNK also delayed the development of bilateral mechanical hypersensitivity 2 - 3 d induced by SNI. Mechanically， 2R， 6R-HNK reversed not only the abnormal excitability of neurons in bilateral DRG and superficial SDH， but also the upregulation of calcitonin gene-related peptide （CGRP） and brain-derived nerve growth factor （BDNF） in DRG. ConclusionIntrathecal administration of 2R， 6R-HNK exerts an analgesic effect against CNP， probably via suppressing abnormal neuronal excitability in ascending pain pathway as well as down-regulating CGRP and BDNF expression in DRG neurons.

Epitope identification of calcitonin gene-related peptide antibodies based on ELISA and NMR methods / 中国生物制品学杂志

@#Objective To develop an indirect ELISA-based peptide scanning method combined with nuclear magnetic resonance(NMR)technique for the epitope identification of calcitonin gene-related peptide(CGRP)antibodies.Methods The antigen binding activities of two antibodies(new CGRP antibody and control antibody)were determined by indirect ELISA using each truncated CGRP fragment as coating antigen,and the linear epitope was analyzed according to the EC50value of four-parameter curve. Two-dimensional hydrogen-nitrogen correlation(2D1H-15N HSQC)spectrum of CGRP were acquired by NMR technique,and the binding of antibodies to the arginine of CGRP were analyzed through the disturbance of the antibodies to CGRP signals. Specific arginine modifications were detected by liquid chromatography-mass spectrum(LCMS) and NMR technique,and two arginine resonances were assigned on CGRP by correlating the rank order of the modification rate.ResultsThe antigen binding activities of two antibodies with CGRP(1-37),CGRP(19-37)and CGRP(25-37)showed dose-response relationships,and were fitted with four-parameter equation. However,there were no significant antigen binding with CGRP(1-18),CGRP(19-24)and CGRP(25-37)without C-terminal amide. The linear epitopes of both antibodies were located at the C-terminal of CGRP. The resonances of arginine ε-NH in 2D1H-15N HSQC spectrum disappeared in the presence of the control antibody;and the resonances appeared in the presence of the new antibody. The arginine R11 and R18 of CGRP could bind to the control antibody,but not to the new antibody. The NMR assignment for the arginine resonances were made by correlating the relative ranking of the modification rate where signals A and B arose from R11 ε-NH and R18 ε-NH respectively.ConclusionIn this study,the linear and conformational epitopes of new CGRP antibody and control antibody were identified based on the methods of ELISA and NMR,which may provide a theoretical basis for the design of the candidate therapeutic CGRP antibodies.

Evaluation of the use of CGRP monoclonal antibodies (mAbs) in migraine prophylaxis in a private clinic / Avaliação do uso de anticorpos monoclonais (mAbs) CGRP na profilaxia de enxaqueca em clínica privada

Introduction: Migraine is considered the second most prevalent neurological disorder in the population and highly disabling. Objective: The aim of this study is to evaluate the use of calcitonin gene-related peptide (CGRP) monoclonal antibodies in migraine prophylaxis, with emphasis on therapeutic response, adverse effects, and impacts on quality of life. Method; A quantitative, retrospective, and descriptive study was carried out, through the analysis of medical records and telephone interviews with patients seen at the Serviço de Neurologia e Neurocirurgia, in the city of Passo Fundo, RGS, Brazil, currently or previously having used at least one dose of the medication. Conclusion: Thus, it is understood that CGRP monoclonal antibodies are able to reduce monthly headache days, reduce pain intensity and promote improvement in work capacity. Therefore, they can be considered effective, safe and well-adhered medications for migraine prophylaxis.

Introdução: A enxaqueca é considerada o segundo distúrbio neurológico mais prevalente na população e altamente incapacitante. Objetivo: O objetivo deste estudo é avaliar o uso de anticorpos monoclonais do peptídeo relacionado ao gene da calcitonina (CGRP) na profilaxia da enxaqueca, com ênfase na resposta terapêutica, efeitos adversos e impactos na qualidade de vida. Método; Foi realizado um estudo quantitativo, retrospectivo e descritivo, por meio de análise de prontuários e entrevistas telefônicas com pacientes atendidos no Serviço de Neurologia e Neurocirurgia, na cidade de Passo Fundo, RGS, Brasil, que já usaram ou usaram pelo menos uma dose do medicamento. Conclusão: Assim, entende-se que os anticorpos monoclonais CGRP são capazes de reduzir os dias mensais de cefaleia, reduzir a intensidade da dor e promover melhora na capacidade de trabalho. Portanto, podem ser considerados medicamentos eficazes, seguros e de boa adesão para a profilaxia da enxaqueca.

Migraine treatment with biological therapies. The state of the art / Tratamento da enxaqueca com terapias biológicas. O Estado da arte

Migraine is a highly prevalent and debilitating neurological disorder. Most patients do not receive a correct diagnosis and effective treatments. Apart of the few specialists and tertiary centers worldwide, the treatment of migraine is usually symptomatic and prevention, as well as treatments of the underlying mechanisms, are not aimed. It results in frustration and substantial burden. The last few years witnessed the releasing of specific biological therapies, mostly addressing one of the peptides involved in migraine pathophysiology, the calcitonin gene-related peptide (CGRP). Either the small molecules as well as the monoclonal antibodies against CGRP or its canonical receptor have been launched in markets across the globe and represent interesting options for the treatment of migraine. Onabotulinumtoxin A has also been proposed for chronic migraine as well, but not for episodic migraine, based on its unique ability to inhibit the SNARE complex formation and the release of numerous potential mediators of migraine. However, despite the favorable figures on efficacy and tolerability of these compounds, the regulations, and particulars of different countries, regarding the structures and reimbursement of medical care, demonstrated different adhesion profiles of chosen populations to receive these emerging weapons against migraine-imposed suffering. This review addresses the use and characteristics of biological therapies used in migraine treatment.

A enxaqueca é um distúrbio neurológico altamente prevalente e debilitante. A maioria dos pacientes não recebe um diagnóstico correto e tratamentos eficazes. Com exceção dos poucos especialistas e centros terciários em todo o mundo, o tratamento da enxaqueca é geralmente sintomático e a prevenção, bem como o tratamento dos mecanismos subjacentes, não são direcionados. Isso resulta em frustração e fardo substancial. Os últimos anos testemunharam o lançamento de terapias biológicas específicas, abordando principalmente um dos peptídeos envolvidos na fisiopatologia da enxaqueca, o peptídeo relacionado ao gene da calcitonina (CGRP). Tanto as pequenas moléculas como os anticorpos monoclonais contra CGRP ou o seu receptor canônico foram lançados em mercados em todo o mundo e representam opções interessantes para o tratamento da enxaqueca. A onabotulinumtoxina A também foi proposta para enxaqueca crônica, mas não para enxaqueca episódica, com base em sua capacidade única de inibir a formação do complexo SNARE e a liberação de numerosos mediadores potenciais da enxaqueca. No entanto, apesar dos números favoráveis ​​sobre a eficácia e tolerabilidade destes compostos, os regulamentos e particularidades de diferentes países, no que diz respeito às estruturas e reembolso dos cuidados médicos, demonstraram diferentes perfis de adesão das populações escolhidas para receber estas armas emergentes contra o sofrimento imposto pela enxaqueca. Esta revisão aborda o uso e as características das terapias biológicas utilizadas no tratamento da enxaqueca.

Modulating effects of RAMPs on signaling profiles of the glucagon receptor family

Receptor activity-modulating proteins (RAMPs) are accessory molecules that form complexes with specific G protein-coupled receptors (GPCRs) and modulate their functions. It is established that RAMP interacts with the glucagon receptor family of GPCRs but the underlying mechanism is poorly understood. In this study, we used a bioluminescence resonance energy transfer (BRET) approach to comprehensively investigate such interactions. In conjunction with cAMP accumulation, Gα q activation and β-arrestin1/2 recruitment assays, we not only verified the GPCR-RAMP pairs previously reported, but also identified new patterns of GPCR-RAMP interaction. While RAMP1 was able to modify the three signaling events elicited by both glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), and RAMP2 mainly affected β-arrestin1/2 recruitment by GCGR, GLP-1R and glucagon-like peptide-2 receptor, RAMP3 showed a widespread negative impact on all the family members except for growth hormone-releasing hormone receptor covering the three pathways. Our results suggest that RAMP modulates both G protein dependent and independent signal transduction among the glucagon receptor family members in a receptor-specific manner. Mapping such interactions provides new insights into the role of RAMP in ligand recognition and receptor activation.

Effect of moxibustion on colonic mucosal injury and expression of CGRP positive nerve fibers of distal colonic mucosa in ulcerative colitis mice / 中国针灸

OBJECTIVE@#To observe the effect of moxibustion at "Zusanli" (ST 36) on distal, middle and proximal colonic mucosal injury and expression of calcitonin gene-related peptide (CGRP) positive nerve fibers of distal colonic mucosa in ulcerative colitis (UC) mice at different time points.@*METHODS@#A total of 51 C57BL/6N mice were randomized into a 7-day control group (@*RESULTS@#Mucosal injury can be observed in mice after modeling, displaying epithelial layer disappearance, abnormal crypt structure or crypt disappearance. Compared with the 7-day control group, colon length was shortened (@*CONCLUSION@#Moxibustion at "Zusanli" (ST 36) can reduce the expressions of positive nerve fibers of colonic mucosa and CGRP positive nerve fibers of distal colonic mucosa, thus, improve the colonic mucosal injury.

A standardized extract of Centella asiatica (ECa 233) prevents temporomandibular joint osteoarthritis by modulating the expression of local inflammatory mediators in mice

Abstract Objectives To investigate the effect of a standardized extract of Centella asiatica (ECa 233), which has anti-inflammatory properties, on the local expression of the transient receptor potential vanilloid 1 (TRPV1), the acid-sensing ion channel subunit 3 (ASIC3), and the calcitonin gene-related peptide (CGRP) in the temporomandibular joint (TMJ) structure 21 days after injecting the TMJ with complete Freund's adjuvant (CFA). Methodology A mouse model was induced by analyzing the CFA-injected TMJ on days 7, 14, and 21. We assessed TMJ histology by the osteoarthritis cartilage grade score. Then, we observed the effect of different ECa 233 concentrations (30, 100, and 300 mg/kg) and of 140 mg/kg ibuprofen doses on TRPV1, ASIC3, and CGRP local expression on day 21. Results Osteoarthritis cartilage scores were 1.17±0.37 and 3.83±0.68 on days 14 and 21, respectively, in the CFA group (n=5). On day 21, TRPV1, ASIC3, and CGRP expression significantly increased in the CFA group. In the ibuprofen-treated group, TRPV1 expression significantly decreased, but ASIC3 and CGRP showed no significant difference. All ECa 233 doses reduced TRPV1 expression, but the 100 mg/kg ECa 233 dose significantly decreased ASIC3 expression. Conclusions TRPV1, ASIC3, and CGRP expression increased in mice with TMJ-OA on day 21. All ECa 233 and ibuprofen doses inhibited pathogenesis by modulating the local expression of TRPV1 and ASIC3. Therefore, ECa 233 was more effective than ibuprofen.

Erenumab aooe: a milestone for the preventive treatment of migraine

Migraine is a complex neurological condition, which can affect the whole body and can result in many symptoms as nausea, vomiting, photophobia (Increased sensitivity to light), phonobhobia (Increased sensitivity to sound) and osmophobia (Increased sensitivity to smell). Neurological symptoms that include visual disturbances such as blind spots, distorted vision, flashing lights or zigzag patterns. Other common symptoms includes- dizziness, vertigo, tingling sensations in the limbs, an inability to concentrate, confusion, difficulty in speaking, paralysis or loss of consciousness (in very rare cases). These symptoms, often called ‘aura’. Migraine attacks may differ in their frequency, duration and severity, although, normally they last between 4 and 72 hours, and most people are symptom-free between attacks. There are many drugs for the treatment of acute attack of migraine which can be divided into mild, moderate and severe attacks. In mild case NSAIDs like Paracetamol, Ibuprofen are prescribed. In moderate cases Anti-emetics like metoclopramide, domperidone can be prescribe with combinations of NSAIDs or triptans as sumatriptan. In case of severe cases triptans can be prescribed with ergot alkaloids and antiemetics. Following drugs are prescribed for the prophylaxis of migraine as sodium valproate, amitriptyline (Tricyclic antidepressant), propranolol and metoprolol (beta blockers). Erenumab-aooe is a calcitonin gene-related peptide receptor antagonist. It is specifically indicated for the preventative treatment of migraine in adults. Erenumab-aooe is supplied as an injection for subcutaneous use. The recommended dosage is 70 mg injected subcutaneously once monthly. Some patients may benefit from a dosage of 140 mg injected subcutaneously once monthly, which is administered as two consecutive subcutaneous injections of 70 mg each. Erenumab-aooe is a human monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) receptor and antagonizes CGRP receptor function.

Progress in drug prevention and treatment of migraine / 中国临床药理学与治疗学

Migraine is a common nervous system disease, which could seriously affect the quality of life. However, the medical treatment of migraine cannot meet the clinical needs at present. With the deepening of research, serotonin 1F receptor agonists and drugs targeting CGRP are more and more developed and marketed. In this paper, the mechanism of action, safety and efficacy, metabolic characteristics of these drugs were systematically evaluated to provide a more scientific basis for clinical prevention and treatment of migraine.

Protective role of berberine on ulcerative colitis through modulating enteric glial cells-intestinal epithelial cells-immune cells interactions

Ulcerative colitis (UC) manifests as an etiologically complicated and relapsing gastrointestinal disease. The enteric nervous system (ENS) plays a pivotal role in rectifying and orchestrating the inflammatory responses in gut tract. Berberine, an isoquinoline alkaloid, is known as its anti-inflammatory and therapeutic effects in experimental colitis. However, little research focused on its regulatory function on ENS. Therefore, we set out to explore the pathological role of neurogenic inflammation in UC and the modulating effects of berberine on neuro-immune interactions. Functional defects of enteric glial cells (EGCs), with decreased glial fibrillary acidic protein (GFAP) and increased substance P expression, were observed in DSS-induced murine UC. Administration of berberine can obviously ameliorate the disease severity and restore the mucosal barrier homeostasis of UC, closely accompanying by maintaining the residence of EGCs and attenuating inflammatory infiltrations and immune cells overactivation. , berberine showed direct protective effects on monoculture of EGCs, bone marrow-derived dendritic cells (BMDCs), T cells, and intestinal epithelial cells (IECs) in the simulated inflammatory conditions. Furthermore, berberine could modulate gut EGCs-IECs-immune cell interactions in the co-culture systems. In summary, our study indicated the EGCs-IECs-immune cell interactions might function as a crucial paradigm in mucosal inflammation and provided an infusive mechanism of berberine in regulating enteric neurogenic inflammation.

Systematic Review on the Efficacy and Safety of Erenumab for the Prevention of Migraine

OBJECTIVE: This study aimed to provide efficacy and safety information on the use of erenumab for prevention of episodic and chronic migraines. METHODS: The keywords “Erenumab and migraine” were used to search the PubMed database to then compile efficacy and safety data for erenumab. Data from relevant Phase 2 and Phase 3 clinical trials were analyzed, using RevMan for statistical analysis. RESULTS: Three clinical trials (one Phase 2 and two Phase 3 studies) were retrieved. All three trials used the same primary endpoint (change from baseline in monthly migraine days (CBMD)) to evaluate efficacy and safety of erenumab use for prevention of episodic and chronic migraines. Subcutaneous doses of erenumab (70 or 140 mg) were administered monthly in each trial, for 3 months (Studies 2, and 3) or 6 months (Study 1). The mean differences in CBMD in the 70 mg and 140 mg erenumab arms were −1.36 and −1.98, respectively, compared to that in the placebo arm. Some adverse events, such as nasopharyngitis and upper respiratory tract infection, were reported, but no differences in safety between erenumab and placebo were found to be significant. CONCLUSIONS: Erenumab showed superior efficacy in prevention of migraines compared to placebo. However, additional information regarding the long-term safety of erenumab should be collected. Therefore, post-marketing surveillance for adverse events is needed.

Protective Effects of Tilianin on Brain Tissue in Cerebral Ischemia-reperfusion Injury Model Rats / 中国药房

OBJECTIVE:To study the effects of tilianin(TIL)on brain tissue in rats with cerebral ischemia-reperfusion injury. METHODS:Totally 120 male SD rats were randomly divided into sham operation group(0.9% sodium chloride solution),model group(0.9% sodium chloride solution),nimodipine group(32 mg/kg)and TIL low-dose and medium-dose,high-dose groups(4, 8,16 mg/kg),with 20 rats in each group. The rats were given relevant medicine intragastrically,once a day,for consecutive 7 d. 15 min after last medication,cerebral ischemia-reperfusion injury model was established by reforming suture-occluded method. The neurological deficit score in rats were evaluated, and percentage of cerebral infarction volume of rats was determined. Histopathological changes of brain tissue were observed by HE staining. The activities of SOD,CAT and LDH,MDA content in cerebral tissue of rats were determined. The expression of calcitonin gene-related peptide(CGRP)and peripheral vascular endothelial growth factor receptor 2 (VEGFR2) protein were determined by Western blot assay. RESULTS:Compared with sham operation group,neurological deficit score and percentage of cerebral infarction volume of model group were increased significantly(P＜0.01);the nerve cells in brain tissue were significantly reduced and the interstitial edema was obvious. SOD and CAT activities were decreased significantly,LDH activity was increased significantly,MDA content was decreased significantly,protein expression of CGRP and VEGFR2were increased significantly(P＜0.05 or P＜0.01). Compared with model group,neurological deficit score of nimodipine group,TIL medium-dose and high-dose groups were decreased significantly;percentage of cerebral infarction volume was decreased significantly (P＜0.05 or P＜0.01);above pathological conditions of cerebral tissue in rats were relieved significantly;SOD and CAT activities were strengthened significantly,MDA content and LDH activities were decreased significantly,protein expression of CGRP and VEGFR2were increased significantly (P＜0.05 or P＜0.01). CONCLUSIONS: TIL has certain protective effects on cerebral ischemia-reperfusion injury model rats,and its mechanism may be related to the up-regulation of CGRP and VEGFR2expression.

Effects of Naoluo Xintong Decoction on vascular dementia rats' memory and learning, and hippocampal neuronal intracellular calcium concentration / 中成药

AIM To study the effects of Naoluo Xintong Decoction (NLXTD) on vascular dementia (VD)rats' memory and learning,and hippocampal neuronal intracellular calcium concentration.METHODS Rats were divided randomly into model group,NLXTD group (8.54 g/kg),Huperzia-A group (0.06 mg/kg) and sham group.They were made into vascular dementia rats by the improved bilateral carotid artery ligation method (2-VO)thereafter if necessary.After one-month corresponding intragastric administration,the rats were ethologically evaluated by the Morris water maze experiment;their fluorescence intensity of hippocampal neuronal intracellular calcium concentration was determined by flow cytometry,and the expression levels of calcitonin gene related peptide (CGRP) and its hippocampus receptor were detected by enzyme-linked immunosorbent assay (ELISA).RESULTS Compared with the model group,rats in NLXTD group displayed overall superiority to those of the model group in terms of significantly shortened time of escape latency (P ＜0.01),significantly increased number through the platform and the times in the fourth quadrant (P ＜ 0.01),a lower fluorescence intensity indicating a lower hippocampal neuronal intracellular calcium concentration (P ＜ 0.05).CONCLUSION The significant improvement of memory and learning observed among VD rats' due to NLXTD intervention may be attributable to its efficacy in reducing the hippocampal neuronal intracellular calcium concentration by enhancing the expression levels of CGRP and its receptor.

Effects of active components extracted from Dachuanxiong Decoction on the expressions of CGRP and its receptors in rats with migraine / 中成药

AIM To study the effects of active components extracted from Dachuanxiong Decoction (DCXD,Chuanxiong Rhizoma,Gastrodiae Rhizoma) on the expressions of calcitonin gene-related peptide (CGRP) and its receptors in hypothalamus and periaqueductal gray (PAG) of rats with migraine.METHODS Seventy-two rats were evenly assigned to six groups at random,normal group,model group,positive drug group,groups of highdose,middle-dose and low-dose DCXD.Each group was then divided into Subgroup A and Subgroup B.The migraine rat model was established by subcutaneous nitroglycerin injection.The expressions of CGRP in Subgroup B's rat hypothalamus and PAG were observed by immunohistochemical staining,while the levels of CGRP in rat plasma,hypothalamus and PAG in Subgroup A were detected by ELISA.All the gene expressions of CGRP and its receptors (CRLR,RCP,RAMP1) in Subgroup A's rat hypothalamus and PAG were assessed by real-time PCR.RESULTS There was a more significant CGRP level increase in plasma,hypothalamus and PAG in the model group than that in the normal group (P ＜ 0.01).The modelled rats found their up-regulated expressions of CGRP and RCP in hypothalamus (P ＜ 0.05),up-regulated expressions of CGRP and CRLR in PAG,and down-regulated expression of RCP (P ＜ 0.05).All low-dose,middle-dose,high-dose active components worked in decreasing the CGRP levels in plasma,hypothalamus and PAG.The middle-dose led to down-regulation of CGRP,RCP expressions in hypothalamus (P ＜0.05,P ＜0.01),down-regulation of CGRP,CRLR expressions in PAG (P ＜0.05),and up-regulation of RCP expression in PAG (P ＜ 0.05).CONCLUSION The mechanism of active components extracted from DCXD in migraine management may associate with its capability in down-regulating CGRP expressions in hypothalamus and PAG,reducing CGRP synthesis and inhibiting neurogenic inflammation.

The role of calcitonin gene-related peptide in migraine prevention by botulinum toxin type A

@#Objectives: Calcitonin gene-related peptide (CGRP) is currently considered to be a major contributing factor in migraine headache. Botulinum toxin type A (BTXA) was found to be effective in migraine prevention. However, the mechanism of action in patients was unknown. Using injection as in clinical setting, the study aimed to determine whether BTXA could decrease the sensitization of the trigeminovascular nociceptive system through the reduction of CGRP action. Methods: Adult male Wistar rats were pretreated with normal saline solution or BTXA before KCl application to induce cortical spreading depression (CSD) or NaCl application as a control. Regional cerebral blood flow at parietal cortex was measured for 90 min after KCl or NaCl application. Tissues from trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) were then collected for CGRP and c-Fos measurement respectively. Results: BTXA pretreatment significantly decreased the cumulative blood flow and number of hyperemic peaks induced by KCl. Numbers of CGRP positive cells at TG and c-Fos positive cells at TNC were also reduced by BTXA.Conclusion: BTXA pretreatment reduced CGRP production and release from the TG leading to lessen CSD production and persistent activation of TNC which played a major role in migraine headache.

Association of CALCA and RAMP1 gene polymorphisms with migraine in a Chinese population

Background & Objective: The calcitonin gene-related peptide (CGRP) has a central role in the pathogenesis of migraine, but variations in CGRP-related genes, including the calcitonin gene-related polypeptide-alpha (CALCA) gene and the receptor activity modifying 1 (RAMP1) gene, have not been found to link with migraine in Australian population. The goals of this study were to determine whether variants in the two genes are related to migraine in Chinese population. Methods: Using a case-control approach, rs3781719 and rs145837941 in the CALCA gene and rs3754701 and rs7590387 at the RAMP1 locus was analyzed in a cohort of 504 migraine cases and 529 ethnically matched controls. Genotyping was performed using Sequenom MALDI-TOF mass spectrometry iPLEX platform. Results: The CALCA gene rs145837941 variant was not found in migraine or control group. No significant difference in genotypic and allelic distribution was observed in the other three polymorphisms between migraine cases and controls. All the three SNPs were also not selected as significant factors that independently contributed to susceptibility to migraine in multivariate analysis. In the subgroup analysis, the CALCA rs3781719 seemed to be a significant risk for migraine with aura, but was not statistically significant after FDR correction. Moreover, there was no synergistic relationship between the three SNPs in the multifactor dimensionality reduction analysis for explore locus–locus interactions. Conclusion: Our data suggested that variants in CALCA gene and RAMP1 gene were not associated with migraine in the Han-Chinese population.

Clinical efficacy and mechanism of oxycodone in cancerous neuropathic pain in advanced colon cancer / 中国生化药物杂志

Objective To investigate the effect and mechanism of oxycodone on the treatment of cancerous neuropathic pain in advanced colon cancer.Methods 80 cases of advanced colon cancer in department of anorectal of Shaoxing Second Hospital of Zhejiang Province from March 2015 to March 2016 were selected and randomly divided into two groups with 40 cases in each group.The control group were treated with routine clinical treatment, and the experiment group were treated with oxycodone treatment on the basis of the control group.The levels of pain score, quality of life score, serum β-EP, calcitonin gene related peptide (CGRP) and prostaglandin E2(PGE2), clinical efficacy and adverse reaction incidence rate changes were compared between two groups before and after treatment.Results Compared with before treatment, levels of the pain score, serum β-EP, CGRP and PGE2 decreased in two groups after treatment, after treatment, the experiment group pain score (2.38 ±0.34), quality of life score (28.39 ± 3.97), serumβ-EP (228.71 ±34.92), CGRP (22.46 ±3.15), PGE2 level (2.45 ±0.35) and the incidence of adverse reactions was 17.50%, were lower than that of the control group the pain score (3.51 ±0.51), the quality of life score (33.53 ±4.76), serum β-EP (246.67 ±34.83), CGRP (30.36 ±4.25), PGE2(3.36 ±0.47) and the incidence of adverse reactions was 40.00%, the difference was statistically significant (P<0.05), the total effective rate of the experiment group was 87.50%, higher than that of the control group, the total effective rate was 60.00%, the difference was statistically significant (P<0.05).Conclusion Oxycodone can effectively reduce pain in patients with advanced colon cancer neuropathic pain score, improve the quality of life, and has high clinical efficacy and safety.

Effect of Acupuncture plus Medication on Serum 5-HT, CGRP and ET in IBS-D / 上海针灸杂志

Objective To observe the efficacy of acupuncture plus medication in treating diarrhea-irritable bowel syndrome (IBS-D) due to liver depression and spleen deficiency, and its effect on serum 5-hydroxytryptamine (5-HT), calcitonin gene-related peptide (CGRP) and endothelin (ET). Method Sixty IBS-D (liver depression and spleen deficiency) were recruited and randomized into an observation group and a control group, 30 cases each. Patients in the observation group were intervened by acupuncture plus modified Bai Zhu Shao Yao powder, while the control group was intervened by acupuncture alone. The total effective rate, change of syndrome score of traditional Chinese medicine (TCM) and diarrhea-irritable bowel syndrome quality of life scale (IBS-QOL), as well as the levels of serum 5-HT, CGRP and ET, were observed. Result The total effective rate was 83.3% in the observation group, significantlyhigher than 63.3% in the control group (P0.05). The global and component TCM symptoms scores and IBS-QOL dropped significantly in both groups after the intervention (P0.05) before the treatment. The levels of 5-HT, CGRP and ET decreased significantly after the treatment in both groups (P<0.05); after the intervention, the levels of 5-HT, CGRP and ET in the observation group were significantly lower than those in the control group (P<0.05). Conclusion Acupuncture plus medication can effectively mitigate the symptoms in IBS-D (liver depression and spleen deficiency) and enhance the quality of life, which is possibly achieved by down-regulating the serum 5-HT, CGRP and ET levels.

The effect and mechanism of capsaicin prevented acute gastric mucosal injury by indomethacin / 实用医学杂志

Objective The study of capsaicin (CAP) on the effect and mechanism of indomethacin induced acute gastric mucosal injury in different period.Methods 80 SD rats were randomly divided into 8 groups with 10 rats in each group.The experiment was completed in two phases,and the Ⅰ period was 2 weeks,the Ⅱ period was 4 weeks.The Ⅰ period including group A1 (control group),group B1 (model group),group C1 (CAP group),group D1 (CAP + indomethacin group).The grouping method of the two periods were the same.The rats' gastric mucosa were damaged by indomethacin,and then killed the rats 4 hours later.Last,astric juice was collected to determine the total acidity of gastric acid,counted thegastric mucosal injury index,observed the gastric mucosa pathological injury,detected the expression of TRPV 1、CGRP、MDA、SOD and PGI2.Results The Ⅰ period:the gastric mucosa of group A1 and C1 had no damage.Group D1 compared with group B1,there was no significant difference in gastric mucosa injury (P ＞ 0.05),total acidity decreased significantly (P ＜ 0.05),MDA was no significant difference (P ＞ 0.05),SOD、PGI2 increased significantly (P ＜ 0.05),the expression of TRPV1、CGRP increased significantly (P ＜ 0.05).The Ⅱperiod:the gastric mucosa of group A2 and C2 had no damage.Group D2 compared with group B2,the gastric mucosa injury were significantly reduced (P ＜ 0.05),total acidity decreased significantly (P ＜ 0.05),MDA decreased significantly (P ＜ 0.05),SOD、PGI2 increased significantly (P ＜ 0.05),the expression of TRPV1、CGRP increased significantly (P ＜ 0.05).Conclusion There was no damage to the general morphology and histology of gastricmucosa in rats by intragastric CAP 1 mg/(kg· d) for 2 weeks and 4 weeks.2.It could prevent that indomethacininduced acute gastric mucosal injury in rats by pretreated with CAP 1 mg(kg· d) for 4weeks.