Recent advances in targeting calcitonin gene-related peptide for the treatment of menstrual migraine: A narrative review

Menstrual migraine (MM) has a longer duration and higher drug resistance than non-perimenstrual migraine. Calcitonin gene-related peptide (CGRP) and CGRP receptors are expressed in the peripheral and central nervous systems throughout the trigeminovascular system. The CGRP/CGRP receptor axis plays an important role in sensory physiology and pharmacology. CGRP receptor antagonists and anti-CGRP monoclonal antibodies (mAbs) have shown consistent efficacy and tolerability in the prevention of chronic or episodic migraine and are now approved for clinical use. However, few studies have reported the use of these drugs in MM, and no specific treatment for MM has been approved. This review aimed to shed light on the recent advances in targeting calcitonin gene-related peptides for the treatment of menstrual migraines in PubMed. In this review, we first discuss the axis of the CGRP/CGRP receptor. We then discuss the role of CGRP receptor antagonists and anti-CGRP mAbs in MM treatment. Finally, we discuss the role of the combination of anti-CGRP mAbs and CGRP receptor antagonists in migraine treatment and the drugs that inhibit CGRP release. Altogether, the anti-CGRP mAbs or CGRP receptor antagonists showed good efficacy and safety in the treatment of MM.     

Calcitonin gene-related peptide mediates acid-induced lung injury in mice

BACKGROUND AND OBJECTIVE: Acid-induced lung injury from aspiration is one of the most important causes of ARDS. Calcitonin gene-related peptide (CGRP) is a neuropeptide that has various biological actions. The current study investigated whether CGRP might have pathophysiological roles in acid-induced lung injury. METHODS: The investigations employed CGRP gene-disrupted mice--mutant mice (CGRP(-/-)) and their littermate controls (CGRP(+/+)). Anaesthetized and mechanically ventilated mice received 2 mL/kg HCl (pH = 1.5) intratracheally. Lung wet-to-dry weight ratios were calculated to assess pulmonary oedema, total and differential cell counts of the BALF were determined, and measurements of myeloperoxidase activity were performed. RESULTS: Acid-induced lung injury was characterized by an increase in lung permeability and respiratory failure. Disruption of the CGRP gene significantly attenuated acid-induced injury, oedema and respiratory failure. CONCLUSIONS: This study suggests that CGRP is involved in the pathogenesis of acute lung injury caused by acid aspiration and CGRP mutant mice may provide an appropriate model to study molecular mechanisms in this context.     

急性脑梗死患者血浆降钙素基因相关肽分析

目的　了解急性脑梗死患者血浆降钙素基因相关肽 ( CGRP)动态变化及与病情的关系。方法　脑梗死患者按病情分为轻、中、重三组 ,分别在发病 3d内、 2 w末、 4 w末采血 ,放免法测定血浆 CGRP浓度 ,并与对照组比较。　结果　血浆 CGRP浓度脑梗死发病 3d内显著降低 ,2 w末、 4 w末依次增高接近对照组 ,急性期病情重者比轻者的 CGRP浓度低。　结论　脑梗死患者存在着血浆 CGRP水平的规律性变化 ,其浓度与脑梗死病理过程以及病变程度有关。     

Calcitonin gene-related peptide released by capsaicin suppresses myoelectrical activity of gastric smooth muscle

BACKGROUND: It is widely accepted that the inhibition of gastric motor activity as well as the maintenance of gastric mucosal blood flow and mucous secretion are important for the homeostasis of the gastric mucosa. The present study was performed to ascertain whether or not capsaicin, which can protect the stomach from noxious stimuli, affects gastric motor activity. METHODS: Male Sprague-Dawley rats were anesthetized with urethane, and the stomach was cannulated by two catheters from esophageal and duodenal sides. A biopolar electrode was fixed to the serosal surface of the antrum and myoelectrical activity was recorded during the instillation of a small volume of solutions. RESULTS: The myoelectrical activity of rat gastric smooth muscle was increased at intragastric pressures of >2 cmH(2)O. Replacement of intragastric physiological saline with 1.6 mmol/L capsaicin solution significantly suppressed this myoelectrical activity by 50%. Intragastric capsaicin administration caused a significant release of substance P (SP) and calcitonin gene-related peptide (CGRP). The maximum released levels of CGRP in the gastric perfusates were 100-fold those of SP. The myoelectrical activity observed at an intragastric pressure of 2 cmH(2)O was avoided by continuous infusion of CGRP (0.1-3.0 nmol/kg per min) into the gastric artery in a dose-dependent manner, but not by that of SP (1.0 nmol/kg per min). Continuous CGRP-(8-37) infusion into the gastric artery completely blocked the reduction by intragastric capsaicin of myoelectrical activity. CONCLUSION: These results suggest that the suppression of the myoelectrical activity of gastric smooth muscle by capsaicin is attributable to the endogenous CGRP released.     

Serotonin,calcitonin and calcitonin gene-related peptide in acute pancreatitis

Objective: The aim of this study was to investigate plasma levels of serotonin, calcitonin and calcitonin gene-related peptide (CGRP) in the course of acute pancreatitis (AP) taking organ failure, etiology and severity into consideration.

Material and methods: Sixty consecutive patients with alcohol- or gallstone-induced AP were included over a 15-month period. Patients were treated according to a standardized algorithm and monitored for organ specific morbidity and mortality. Organ functions and blood samples were assessed on days 0, 1, 2 and 14 after hospital admission. Twenty healthy volunteers, matched for age and gender, comprised the reference group.

Results: Lower levels of serotonin were observed in patients at admission compared to healthy volunteers (p?=?.021). Serotonin levels increased from day 2 to 14 (p?<?.001), but with no relation to severity, etiology or organ failure. No difference in calcitonin levels was found in patients at admission compared to healthy volunteers. However, calcitonin levels decreased over time (p?<?.001) and higher levels were found in patients with respiratory failure (p?=?.039). No difference was observed in relation to severity or etiology. CGRP levels in patients at admission did not differ from healthy volunteers, nor did CGRP change over time or show any relationship to severity, etiology or organ failure.

Conclusion: Our data suggest serotonin and calcitonin levels to be associated to time-course of AP, and calcitonin levels to organ dysfunction. We hypothesize that serotonin plays a pathogenic role in the compromised pancreatic microcirculation, and calcitonin a role as a biomarker of severity in AP.     

Intracerebroventricular administration of human calcitonin and human calcitonin gene-related peptide inhibits meal-stimulated gastric acid secretion in the dog

This study was designed to assess the central nervous system actions of human calcitonin (hCalc) and human calcitonin gene-related peptide (hCGRP) on meal-stimulated gastric acid secretion in awake beagle dogs. hCalc (0.1–1.0 nmol/kg) and hCGRP (0.01–1.0 nmol/kg) injected into the third cerebral ventricle significantly inhibited gastric acid secretion stimulated by an 8% peptone meal. hCGRP was ten times more potent than hCalc in inhibiting gastric secretion. Neither hCalc nor hCGRP significantly altered plasma gastrin concentrations compared to control values. Truncal vagotomy did not prevent the gastric inhibitory actions of hCalc and hCGRP. Ganglionic blockade with chlorisondamine completely abolished the gastric inhibitory action of hCalc but had no effect on gastric acid inhibition induced by hCGRP. The results of this study indicate that intracerebroventricular administration of hCalc and hCGRP inhibits meal-stimulated gastric acid secretion in awake dogs. Inhibition of gastric acid secretion by hCalc and hCGRP in the dog is not mediated by inhibition of gastrin release or by the vagus nerves. Human Calc but not human CGRP appears to inhibit meal-stimulated gastric acid secretion in the dog by activation of the autonomic (sympathetic) nervous system.     

小胶质细胞在偏头痛大鼠中枢敏化过程中的作用

目的观察二甲胺四环素(MC)对偏头痛大鼠痛觉超敏行为、颈髓后角小胶质细胞及神经元激活的影响,探讨小胶质细胞在偏头痛大鼠模型中枢敏化过程中的作用。方法 66只雄性SD大鼠随机分为空白组、假手术组、生理盐水组(NS组)、新型致炎剂(IS)4d组(IS4组)、IS 7d组(IS7组)、IS/MC预防组、IS/NS预防组、NS/NS预防组、IS/MC治疗组、IS/NS治疗组、NS/NS治疗组。每组6只。采用Vonfrey纤维丝测定各组大鼠眶周痛觉阈值,免疫荧光染色测定颈髓后角小胶质细胞及神经元激活情况。结果硬脑膜给予IS第3天眶周痛觉阈值较NS组明显下降(P<0.01)。IS/MC预防组眶周痛觉阈值明显高于IS/NS预防组(P<0.01)。IS4组、IS7组小胶质细胞平均荧光密度值高于假手术组(P<0.01)。IS/MC预防组、IS/MC治疗组小胶质细胞平均荧光密度值分别低于IS/NS预防组、IS/NS治疗组(P<0.01)。IS/MC预防组C-fos平均荧光密度值明显低于IS/NS预防组(P<0.01)。结论在慢性硬脑膜炎症所致的中枢敏化过程中小胶质细胞可能仅在启动阶段起作用,对于痛觉超敏的维持无作用。MC能有效预防偏头痛大鼠模型痛觉超敏的发生,但对已存在的痛觉超敏无治疗作用。     

高原急性重症脑功能损伤血浆肾上腺髓质素和降钙素基因相关肽测定及意义

目的研究高原急性重症脑功能损伤患者血浆肾上腺髓质素(ADM)和降钙素基因相关肽(CGRP)的变化并探讨其作用及临床意义。方法测定35例高原急性重症脑功能损伤患者(脑功能损伤组)发病第12、、3天血浆ADM、CGRP水平,同时测定20例高原健康体检者(高原对照组)、20例平原健康体检者(平原对照组)血浆ADM、CGRP水平。结果脑功能损伤组患者血浆ADM、CGRP发病3天内的水平均高于高原对照组及平原对照组(P<0.05),而发病3天之间患者的ADM、CGRP水平无明显差异(P>0.05);高原对照组血浆ADM、CGRP均高于平原对照组(P<0.05)。脑功能损伤组血浆ADM与CGRP之间呈显著正相关(P<0.05),大脑中动脉收缩期流速(SV)与发病第1天血浆ADM、CGRP呈负相关(P<0.05)。死亡病例发病第1天血浆ADM、CGRP均高于非死亡病例(P<0.05)。结论ADM和CGRP参与了急性重症脑功能损伤的发生发展过程,对损伤时脑组织起代偿性保护作用;血浆ADM、CGRP值亦可间接反映脑损伤程度。     

Calcitonin gene-related peptide potentiates substance P-induced plasma extravasation in the rat trachea

Antidromic stimulation of vagal sensory nerves is known to produce plasma extravasation in the rat trachea. This neurogenic inflammation is thought to be mediated by substance P or other tachykinins released from sensory nerve endings. We sought to determine whether calcitonin gene-related peptide (CGRP), which is also released from sensory nerve endings, can potentiate substance P-induced plasma extravasation in the rat trachea. To accomplish this, we measured the amounts of Evans blue dye extravasated into the trachea after intravenous injections of substance P alone and combined with CGRP. We found that when substance P and CGRP were injected together, the amount of plasma extravasation produced in the trachea was substantially greater than the amount produced when substance P was injected alone. This potentiation was critically dependent on the dosage of CGRP and was not observed when relatively high dosages were used. We also found that CGRP had a potent hypotensive effect and speculate that reduced blood pressure may account for the lack of potentiation observed at the higher CGRP dosages. Based on these findings, we conclude that CGRP can potentiate substance P-induced plasma extravasation in the rat trachea and may therefore play a role in modulating neurogenic inflammation of the airways. Offprint requests to: J.J. Brokaw     

Calcitonin gene-related peptide activates the K+ channels of vascular smooth muscle cells via adenylate cyclase

The aim of the present study was to examine the effects of calcitonin gene-related peptide (CGRP) on the K⁺ channels of vascular smooth muscle cells. Cultured smooth muscle cells from a porcine coronary artery were studied using the patch-clamp technique. Extracellular application of 100 nM CGRP activated two types of K⁺ channels the Ca²⁺-activated K⁺ channel (K_Ca channel) and the ATP-sensitive K⁺ channel (K_ATP channel) in cell-attached patch configurations. In cells pretreated with Rp-cAMPS, a membrane-permeable inhibitor of cAMP-dependent protein kinase (PKA), extracellular application of 100 nM CGRP could not activate the K_Ca or K_ATP channel, indicating that the activation of the K⁺ channels by CGRP occurs in connection with PKA. In the cell-attached patch configurations, extracellular application of 1 mM dibutyryl cAMP, a membrane permeable cAMP, activated K_Ca and K_ATP channels. In inside-out patch configurations, application of PKA to the cytosolic side activated both the K_Ca and K_ATP channels. These results indicate that CGRP modulates the K⁺ channels of vascular smooth muscle cells via adenylate cyclase, i.e., cAMP-PKA pathway, and contributes to control of vascular tone.     

降钙素基因相关肽的血液动力学作用及其机理

静脉注射降钙素基因相关肽（ＣＧＲＰ），可使麻醉大鼠血压明显下降，在注射后１ｍｉｎ出现作用，５ｍｉｎ最明显（平均动脉压下降１５．５％），１０ｍｉｎ后恢复。在用药后心率最快时增加９．４％，持续３０ｍｉｎ，左室收缩压峰值和左室压上升最大速度分别增加１０％和１５％。ＣＧＲＰ的降压作用不能被阿托品阻断，且心率加快，心肌收缩性增强。预先用利血平阻断交感神经后再注射ＣＧＲＰ，心率无变化，平均动脉压、左室收缩压峰值、左室压上升最大速度均显著降低，且作用持续时间长。结果表明，ＣＧＲＰ的作用与交感神经的调控有密切关系．它的正性变力和变时的作用可能是通过交感神经释放递质引起的。     

Calcitonin-related peptides in patients with acute leukemia: association of human calcitonin with poor prognosis

Elevated serum levels of peptides hormones in patients with acute leukemia and production of these agents by the leukemic blasts have been described. In 77 patients with acute leukemia the influence of common risk factors and elevations of serum levels of calcitonin-related peptides on clinical outcome was evaluated. By multivariate analysis, only age and elevated serum level of h-CT were found to be significantly correlated to survival. CGRP and s-CT showed no influence on outcome. Closer inspection of the clinical course of these patients showed that patients with elevated h-CT are not likely to survive the first 4 weeks after diagnosis. The possibility that this hormone may influence the biological behavior of the leukemic cells is discussed.     

Efficacy and safety of cutting therapy in the treatment of migraine: A protocol for systematic review and meta-analysis

Background:Migraine is a chronic paroxysmal neurovascular disease in which pain on one or both sides of the head is the main manifestation and is accompanied by other neurological manifestations. Clinical practice has shown that cutting therapy as a complementary alternative medicine can play a role in relieving migraine attacks. However, there is no consensus on the efficacy of cutting treatment in the treatment of migraine. The aim of this study was to conduct a meta-analysis to systematically evaluate the efficacy and safety of cutting therapy in the treatment of migraine.Methods:First, databases were searched for relevant literature. The main databases we searched were PubMed, the Web of Science, MEDLINE, Embase, Cochrane Library, the Chinese National Knowledge Infrastructure, the Chinese Science Journal Database, Wanfang Data, and the Chinese Biomedical Literature Database. The keywords searched were “cutting treatment,” “ traditional Chinese medicine cutting treatment,” and “migraine.” The search was conducted from inception to November 2021. Second, 2 reviewers independently completed the process of study selection, data extraction, risk of bias assessment and data synthesis in strict accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols statement guidelines. Finally, we will use Review Manager Version 5.3 software for meta-analysis.Results:This study will provide the most recent evidence related to the treatment of migraine by cutting therapy.Conclusion:The results of this systematic evaluation will provide an objective evidence-based framework for judging the effectiveness and safety of cutting therapy in the treatment of migraine.     

Plasma concentrations of calcitonin gene-related peptide increase during haemodialysis: relation to blood pressure

The authors measured the plasma levels of calcitonin gene-related peptide (CGRP), the most potent vasodilatator known, during sequential ultrafiltration and haemodialysis in 12 patients using a radio-immunoassay method. Mean plasma levels of CGRP were 70.3 +/- 16.5 (mean +/- SE) pmol l-1 at the start of treatment, it increased to 85.3 +/- 17.6 pmol l-1 during ultrafiltration and to 114.5 +/- 25.3 pmol l-1 during dialysis. Systolic blood pressure decreased during haemodialysis. Plasma levels of CGRP were negatively correlated to systolic blood pressure before and at the end of dialysis, and changes in plasma levels of CGRP were strongly correlated to changes in systolic blood pressure. The increase in CGRP levels was not correlated to the fluid removal, toxin removal or changes in osmolality. The increase in plasma levels of CGRP observed during dialysis may be an important cause of dialysis induced vasodilatation and fall in blood pressure.     

Effect of CGRP antagonist,alpha-CGRP 8-37, on acid secretion in the dog

The recently synthesized calcitonin gene-related peptide (CGRP) antagonist, human alpha-CGRP 8-37, was used to study its effects on gastric acid secretion. Four dogs with gastric fistula were used to measure the antagonist's physiologic effects in the stomach. All dogs received a bactopeptone dextrose meal (intragastric titration to pH 5.5) with either continuous CGRP 8-37 (1000 pmol/kg/hr) or saline (control). Additionally, intravenous bombesin (75–600 ng/kg/hr) and bethanecol (12.5–100 µg/kg/hr) was tested in the presence of the antagonist. Plasma gastrin levels also were measured via radioimmunoassay (RIA) in control and CGRP 8-37-stimulated animals. Gastric acid secretion increased by 100% with infusion of 1000 pmol/kg/hr CGRP 8-37 when compared to the control. Acid output increased 98% with both intravenous antagonist and 600 ng/kg/hr bombesin when compared to bombesin alone. However, no augmentation of acid secretion by CGRP 8-37 was shown with 25 µg/kg/hr bethanecol. RIA of plasma gastrin demonstrated no effect with the antagonist when given alone and did not increase bombesin-stimulated gastrin release. We conclude that CGRP 8-37 blocks native CGRP inhibitory effects on gastric acid secretion. Our findings of potentiation of acid secretion by bombesin as well as no change in gastrin levels in the presence of the antagonist is likely due to a blockage in a noncholinergic neuron to the somatostatin cell. Furthermore, CGRP 8-37 did not increase bethanecolstimulated acid secretion, most likely due to bethanecol's (acetylcholine) nearly ubiquitous positive effects on acid secretion.Funded by NIH Grant DK 40790.     

降钙素基因相关肽对犬冠脉流量及冠状动脉的作用

本研究通过整体及离体灌流实验观察到重庆冠脉狭窄时，犬冠脉流量（ＣＢＦ），平均动脉压（ＭＡＰ）明显减小，而心率（ＨＲ）则增加。狭窄３０ｍｉｎ后由冠状动脉注射降钙素基因相关肽（ＣＧＲＰ）０．３μｇ／ｋｇ后，ＣＢＦ、ＭＡＰ和ＨＲ可恢复正常水平。同时，缺血犬的离体冠状动脉对ＣＧＲＰ的反应也出现改变。大冠脉舒张反应明显降低，而小冠脉的舒张反应与正常相比，无明显改变，这可能与缺血后大冠脉的内皮细胞容易损伤有关。同时也提示:急性心肌缺血时，冠脉流量的减少，主要由于小冠状动脉收缩所致。     

Prevention of glomerular hyperfiltration in rats with streptozotocin-induced diabetes by an atrial natriuretic peptide receptor antagonist

Summary The contribution of atrial natriuretic peptide (ANP) to the development of glomerular hyperfiltration in diabetes was investigated by examining the effects of HS-142-1, a non-peptide antagonist of biological receptors for ANP, on glomerular filtration rate (GFR) and renal plasma flow (RPF) in rats with streptozotocin-induced diabetes. Three to four weeks after streptozotocin injection, the plasma concentration of ANP, urinary cyclic GMP excretion rate, GFR, and RPF were significantly higher in diabetic rats than in control rats. The increase in GFR and RPF in diabetic rats was significantly reduced, in a dose-dependent manner, by a single intravenous injection of HS-142-1; the maximal effect was apparent at a dose of 10 mg per kg of body weight. Continuous subcutaneous administration of HS-142-1 with an osmotic minipump for 3 to 4 weeks, beginning 2 days after streptozotocin injection, prevented the increases in urinary cyclic GMP excretion rate, GFR, and RPF observed in untreated diabetic rats. These results highlight the importance of ANP in the development of diabetic glomerular hyperfiltration and indicate that this condition can be prevented by continuous inhibition of the action of ANP.Abbreviations ANP Atrial natriuretic peptide - GFR glomerular filtration rate - RPF renal plasma flow - PAH para-aminohippurate     

偏头痛病人血浆内皮素及降钙素基因相关肽测定的临床意义

目的测定偏头痛病人血浆内皮素(ET)和降钙素基因相关肽(CGRP)含量,探讨其在偏头痛发生与发展中的意义.方法选择34例诊断明确的偏头痛病人,按发病时间分为发作期和间歇期,抽取肘静脉血2 mL,采用放免分析技术(RIA)分别测定ET及CGRP含量,并与31名同期健康人作对照.结果偏头痛组ET及CGRP含量显著高于正常对照组(P<0.01);重度发作组与轻中度组及间歇期组相比,ET的水平前者高于后两者(P<0.05或P<0.01);CGRP轻中度组及间歇期组与正常对照组相比,有统计学意义(P<0.01或P<0.05),ET轻中度组有统计学意义(P<0.05).对照组(r=0.5860,P<0.01)和间歇期组(r=0.6047,P<0.05)ET和CGRP含量变化呈正相关.结论偏头痛病人血浆ET及CGRP水平的变化可能参与了偏头痛的发病过程.