BACKGROUND: The role of beta calcitonin gene-related peptide (beta-CGRP) in gastrointestinal tract is obscure, but experimental models suggest an effect on the homeostasis of the intestinal mucosa. We measured beta-CGRP circulating levels in a large series of subjects with a recent diagnosis of inflammatory bowel disease (IBD), in order to assess the potential role of this neuropeptide in IBD pathogenesis.
METHODS: Morning serum beta-CGRP levels were measured by ELISA (CUSABIO, China) in 96 patients recently diagnosed of IBD and compared with those belonging from 50 matched healthy controls (HC) and 50 chronic migraine (CM) patients.
RESULTS: Beta-CGRP levels were lower in patients with IBD (3.1 ± 1.9 pg/mL; 2.9 [2.4-3.4] pg/mL) as compared to HC (4.7 ± 2.6; 4.9 [4.0-5.8] pg/mL; p < 0.001) and to CM patients (4.6 ± 2.6; 4.7 [3.3-6.2] pg/mL; p < 0.001). Beta-CGRP levels in CM were not significantly different to those of HC (p = 0.92). Regarding IBD diagnostic subtypes, beta-CGRP levels for ulcerative colitis (3.0 ± 1.9pg/mL; 2.5 [2.1-3.4] pg/mL) and Crohn\'s disease (3.3 ± 2.0 pg/mL; 3.2 [2.4-3.9] pg/mL) were significantly lower to those of HC (p < 0.01 and p < 0.05, respectively) and CM (p < 0.01 and p < 0.05, respectively).
CONCLUSIONS: We have found a significant reduction in serum beta-CGRP levels in patients with a recent diagnosis of all kinds of IBD as compared to two control groups without active intestinal disease, HC and CM, which may suggest a role for this neuropeptide in the pathophysiology of IBD. Our data indicate a protective role of beta-CGRP in the homeostasis of the alimentary tract.

Calcitonin gene-related peptide (CGRP) inhibitors, in the form of injectable monoclonal antibodies, are a newer class of drugs for the prevention of migraine headaches. In clinical trials, they have been found to be effective with good tolerance and few adverse effects. Alopecia has been increasingly noted as a post-marketing event associated with CGRP inhibitor injectables. Of the case reports available on this topic, alopecia has commonly been localised to the scalp and associated with erenumab use; however, not as much has been reported for fremanezumab nor for injection site-related alopecia. We report an occurrence of persistent lower extremity localised injection site alopecia in a patient within our headache clinic who used fremanezumab. The possible mechanism of alopecia may be related to the failure of hair follicle immune privilege in the absence of CGRP immunomodulatory effects.

Headache is the most common condition encountered in neurological practice. However, despite the burden to patients, migraine, a typical primary headache, is not life-threatening, and evaluation shows no abnormalities; therefore, it is often treated using analgesics. Moreover, patients often do not visit hospitals and clinics because over-the-counter analgesics, such as nonsteroidal anti-inflammatory drugs are easily available. However, many patients continue to experience headaches. Migraine therapy has progressed remarkably following the advent of calcitonin gene-related peptide antibody drugs in recent years. Many patients with migraine do not visit hospitals and clinics and do not receive appropriate treatment. Therefore, in the future, neurologists will need to play a key role in patient education and in training physicians to enable accurate diagnosis of headaches.

The effects of calcitonin gene-related peptide (CGRP) on atherosclerosis remain unclear. We used apolipoprotein E-deficient (ApoE-/-) mice to generate double-knockout ApoE-/-:CGRP-/- mice lacking alpha CGRP. ApoE-/-:CGRP-/- mice exhibited larger atherosclerotic plaque areas, peritoneal macrophages with enhanced migration functions, and elevated levels of the inflammatory cytokine tumor necrosis factor (TNF)-⍺. Thus, we also explored whether inhibiting TNF-⍺ could improve atherosclerosis in ApoE-/-:CGRP-/- mice by administering etanercept intraperitoneally once a week (5 mg/kg) alongside a high-fat diet for 2 weeks. This treatment led to significant reductions in aortic root lesion size, atherosclerotic plaque area and macrophage migration in ApoE-/-:CGRP-/- mice compared with mice treated with human IgG (5 mg/kg). We further examined whether results observed in ApoE-/-:CGRP-/- mice could similarly be obtained by administering a humanized monoclonal CGRP antibody, galcanezumab, to ApoE-/- mice. ApoE-/- mice were subcutaneously administered galcanezumab at an initial dose of 50 mg/kg, followed by a dose of 30 mg/kg in the second week. Galcanezumab administration did not affect systolic blood pressure, serum lipid levels, or macrophage migration but led to a significant increase in lipid deposition at the aortic root. These findings suggest that alpha CGRP plays a critical role in inhibiting the progression of atherosclerosis.

OBJECTIVE: To observe the effects of acupuncture at \"antihypertensive acupoint prescription\" on endothelial active factors and related autonomic neurotransmitters in spontaneous hypertension rats, and explore the vascular regulation and central regulation mechanisms of acupuncture for anti-hypertension.
METHODS: Thirty SPF grade male spontaneous hypertension rats were randomly divided into a model group (15 rats) and an acupuncture group (15 rats). Besides, 15 Wistar Kyoto rats were collected as a blank control group (normal group). In the acupuncture group, acupuncture was delivered at the \"antihypertensive acupoint prescription\" (bilateral \"Renying\" [ST 9], \"Quchi\" [LI 11], \"Zusanli\" [ST 36], \"Taichong\" [LR 3] and \"Neiguan\" [PC 6]), with needles retained for 30 min, once daily. The duration of intervention was 28 days. Every week, using the the irritation scale, the sign of sympathetic irritation was evaluated dynamically. The arterial blood pressure of the rats tail was determined, using non-invasive blood pressure measurement system. ELISA was adopted to detect the levels of calcitonin gene-related peptide (CGRP), nitric oxide (NO), endothelin-1 (ET-1), neuropeptide Y (NPY) in the serum. DAB chromogenic in situ hybridization (CISH) was provided to detect the mRNA expression of endothelial nitric oxide synthase (eNOS) in the internal carotid artery and the arcuate nucleus (ARC), and that of CGRP in the paraventricular nucleus posterior (PVP) and the ventrolateral medulla (VLM). Liquid chromatography-mass spectrometry (LC-MS) was used to detect the levels of epinephrine (E) and norepinephrine (NE) in the paraventricular nucleus anterior (PVA).
RESULTS: Compared with the normal group, the irritation scores, systolic blood pressure and diastolic blood pressure were increased at each time point in the model group (P<0.05). When compared with the model group, the irritation scores after the intervention for 3 and 4 weeks, and systolic and diastolic blood pressure after intervention for 2, 3 and 4 weeks were reduced in the acupuncture group (P<0.05). In comparison with the normal group, the serum CGRP and NO levels of the rats were decreased (P<0.05), and the serum ET-1 and NPY levels, as well as E and EN levels in PVA were increased (P<0.05) in the model group. The levels of serum CGRP and NO were elevated (P<0.05), and the serum ET-1 and NPY levels, as well as E and EN levels of PVA were reduced (P<0.05) in the acupuncture group when compared with those of the model group. In the model group, the media of internal carotid artery exhibited thickening and remodeling, while the neuron volume in ARC was small. In the acupuncture group, every layer of internal carotid artery was acceptably arranged, and the parvicellular neuron of ARC was moderate in volume. For the in situ hybridization of eNOS mRNA for the rats of each group, the smooth muscle cells were predominantly expressed in each layer of the internal carotid artery, whereas the expression of parvicellular neurons was dominated in ARC. In the model group, the large and small neurosecretory cells were distributed sparsely in the nerves of PVP; in the acupuncture group, the cells of these two species were distributed regularly; and there were few species of glial cell in the VLM of either the model group or the acupuncture group. In each group, for the in situ hybridization of CGRP mRNA, the small neurosecretory cells were expressed predominately in the PVP, while, the expression of glial cell nuclei and the cell cytoplasm was dominated in the VLM. Compared with the normal group, the mRNA expression of eNOS in the internal carotid artery and ARC and that of CGRP mRNA in the PVP and VLM was decreased in the model group (P<0.05). In the acupuncture group, when compared with the model group, the mRNA expression of eNOS in the internal carotid artery and ARC and that of CGRP in the PVP and VLM was increased in the acupuncture group (P<0.05).
CONCLUSIONS: Acupuncture at \"antihypertensive acupoint prescription\" can upregulate the level of vascular relaxing factors, downregulate the level of contracting factors, enhance the response of relaxing factors in targeting blood vessels and regulating the center. The mechanism may be related to the modulation of the sympathetic-adrenergic autonomic neurotransmitters in the paraventricular nucleus in spontaneous hypertension rats.
目的：观察针刺“降压方”对自发性高血压大鼠（SHR）内皮活性因子及相关自主神经递质的影响，探讨针刺降压的血管调节和中枢调控机制。方法：将30只SPF级雄性SHR随机分为模型组（15只）、针刺组（15只），另以15只京都种Wistar大鼠（WKR）为空白对照组（正常组）。针刺组予“降压方”（双侧“人迎”“曲池”“足三里”“太冲”“内关”）针刺，留针30 min，每日1次，共干预28 d。每周采用激惹评分动态评价大鼠交感激惹表征；通过全自动无创血压测量系统检测大鼠尾动脉血压；ELISA法检测血清降钙素基因相关肽（CGRP）、一氧化氮（NO）、内皮素-1（ET-1）、神经肽Y（NPY）含量；DAB显色原位杂交（CISH）检测颈内动脉、弓状核内皮型一氧化氮合酶（eNOS）及室旁核后部、延髓腹外侧CGRP mRNA表达；液相色谱及质谱联用检测室旁核前部肾上腺素（E）、去甲肾上腺素（NE）含量。结果：与正常组比较，模型组大鼠观察期间各时间点激惹评分及收缩压、舒张压升高（P<0.05）；与模型组比较，针刺组大鼠干预第3、4周后激惹评分及干预第2、3、4周后收缩压、舒张压降低（P<0.05）。与正常组比较，模型组大鼠血清CGRP、NO含量降低（P<0.05），血清ET-1、NPY含量及室旁核前部E、NE含量升高（P<0.05）；与模型组比较，针刺组大鼠血清CGRP、NO含量升高（P<0.05），血清ET-1、NPY含量及室旁核前部E、NE含量降低（P<0.05）。模型组大鼠颈内动脉中膜增厚且有重构表现，弓状核神经元体积较小；针刺组大鼠颈内动脉各层排布尚可，弓状核小细胞神经元适中。各组大鼠eNOS mRNA在颈内动脉主要表达于各层中平滑肌细胞，而在弓状核主要表达于小细胞神经元。模型组大鼠室旁核后部神经分泌大细胞及小细胞分布较为稀疏，针刺组大鼠两类细胞排布尚可；模型组、针刺组大鼠延髓腹外侧区胶质细胞种类相对较少。各组大鼠CGRP mRNA在室旁核后部主要表达于神经分泌小细胞，而在延髓腹外侧主要表达于胶质细胞核及细胞质。与正常组比较，模型组大鼠颈内动脉及弓状核eNOS mRNA、室旁核后部及延髓腹外侧CGRP mRNA表达降低（P<0.05）；与模型组比较，针刺组大鼠颈内动脉及弓状核eNOS mRNA、室旁核后部及延髓腹外侧CGRP mRNA表达增加（P<0.05）。结论：针刺“降压方”可上调血管舒张因子水平，下调血管收缩因子水平，同时增强血管舒缩因子靶向血管及调控中枢的响应，其机制可能与调节SHR室旁核交感肾上腺素能自主神经递质有关。.

Our aim was to explore possible relationships between serum levels of biomarkers in patients with hand-arm vibration injury in relation to the severity of the vascular, i.e., Raynaud\'s phenomenon (RP), and neurosensory manifestations, the current exposure level, and the duration of exposure. This study was of case series design and involved 92 patients diagnosed with hand-arm vibration injury. Jonckheere\'s trend test was used to assess any association between serum levels of biomarkers and RP as well as neurosensory manifestations, graded by the International Consensus Criteria. Generalized linear models with adjustment for possible confounders were also used for associations between serum levels of biomarkers and; (1) severity of RP recorded as the extent of finger blanching calculated with Griffin score, (2) vibration perception thresholds, (3) magnitude of current exposure as [A(8); (m/s2)] value, and (4) the duration of exposure in years. Serum levels of thrombomodulin, von Willebrand factor, calcitonin gene related peptide (CGRP), heat shock protein 27, and caspase-3 were positively associated with severity of RP. Serum levels of CGRP were positively associated with the neurosensory component. No associations with exposure were shown for these biomarkers. For Intercellular adhesion molecule 1 and monocyte chemoattractant protein 1, no associations were found with neither severity nor exposure. Levels of serum biomarkers associated with endothelial injury or dysfunction, inflammation, vasodilation, neuroprotection, and apoptosis were positively associated with the severity of hand-arm vibration injury.

Physical activity can worsen migraine, leading to reduced activity levels in adults with chronic migraine. This study investigated the change in average steps per day, as a surrogate marker of physical activity, in adults with chronic migraine successfully treated with monoclonal antibodies against calcitonin gene-related peptide or its receptor. Data were obtained from adults with chronic migraine, who were classified as responders to preventive treatment with monoclonal antibodies. The primary endpoint was the difference in a mean number of steps per day between the 3 months prior to treatment initiation and the first 3 months after treatment initiation. The secondary endpoint was the correlation between the change in steps per day and the change in monthly migraine days. Twenty-two (20 females) participants with a median age of 48.5 years were enrolled. The median number of steps per day increased from 4421 at baseline to 5241 after treatment (P = 0.039). We found a positive correlation between the increase in steps per day and the treatment response (P = 0.013). In conclusion, an increase in physical activity, based on steps per day, positively correlated with treatment response to monoclonal antibodies. Automatically registered daily step count data might be used to monitor physical activity as a response to preventive treatment in adults with chronic migraine.

暂无摘要。

Neuroimmune cross-talk participates in intestinal tissue homeostasis and host defense. However, the matrix of interactions between arrays of molecularly defined neuron subsets and of immunocyte lineages remains unclear. We used a chemogenetic approach to activate eight distinct neuronal subsets, assessing effects by deep immunophenotyping, microbiome profiling, and immunocyte transcriptomics in intestinal organs. Distinct immune perturbations followed neuronal activation: Nitrergic neurons regulated T helper 17 (TH17)-like cells, and cholinergic neurons regulated neutrophils. Nociceptor neurons, expressing Trpv1, elicited the broadest immunomodulation, inducing changes in innate lymphocytes, macrophages, and RORγ+ regulatory T (Treg) cells. Neuroanatomical, genetic, and pharmacological follow-up showed that Trpv1+ neurons in dorsal root ganglia decreased Treg cell numbers via the neuropeptide calcitonin gene-related peptide (CGRP). Given the role of these neurons in nociception, these data potentially link pain signaling with gut Treg cell function.

Migraines are a type of headache that occur with other neurological symptoms, but the pathophysiology remains unclear. In this issue of the JCI, Nelson-Maney and authors used constitutive and inducible knockouts of the CGRP receptor components, elegantly demonstrating an essential function of CGRP in modulating meningeal lymphatic vessels (MLVs) in migraine. CGRP was shown to induce rearrangement of membrane-bound gap junction proteins in MLVs, resulting in a reduced CSF flux into cervical lymph nodes. The authors also provided evidence of a primary role for CGRP in modulating neuro-immune function. Finally, by showing that blocking CGRP signaling in MLVs attenuated pain behavior associated with acute migraine in rodents, the authors provided a target for pharmacological blockade of CGRP in relation to primary headache disorders.