Spinal RAMP1-mediated neuropathic pain sensitisation in the aged mice through the modulation of CGRP-CRLR pain signalling.

Pain sensitivity varies depending on both the state and age of an individual. For example, chronic pain is more common in older individuals, but the underlying mechanisms remain unknown. This study revealed that 18-month-old mice (aged) experienced more severe and long-lasting allodynia and hyperalgesia in the chronic constriction injury (CCI)-induced pain state compared to 2-month-old mice. Interestingly, the aged mice had a higher baseline mechanical pain threshold than the adult mice. The expression of spinal receptor-active modification protein 1 (RAMP1), as a key component and regulator of the calcitonin gene-related peptide (CGRP) receptor for nociceptive transmission from the periphery to the spinal cord, was reduced in the physiological state but significantly increased after CCI in the aged mice compared to the adult mice. Moreover, when RAMP1 was knocked down using shRNA, the pain sensitivity of adult mice decreased significantly, and CCI-induced allodynia in aged mice was reduced. These findings suggest that spinal RAMP1 is involved in regulating pain sensitivity in a state- and age-dependent manner. Additionally, interfering with RAMP1 could be a promising strategy for alleviating chronic pain in older individuals.

Population pharmacokinetics of eptinezumab in paediatric patients with migraine and dose selection for phase 3 paediatric migraine studies.

This population pharmacokinetics (PopPK) analysis of eptinezumab used data from a paediatric study and a prior adult PopPK model to compare eptinezumab pharmacokinetics between adult and paediatric populations to determine dose recommendations for the phase 3 paediatric studies in migraine. The data consisted of 16 adolescents and 12 children with migraine, with corresponding demographics and 278 plasma concentrations in total. PopPK analysis was performed through nonlinear mixed effect modelling and with prior knowledge taken from a previous PopPK model in adults. A two-compartment model-adjusted for body weight impact on clearances and volumes of distributions and scaled to the power of 0.75 and 1.0, respectively-was found to adequately describe the paediatric pharmacokinetic data. The simulated population showed overlap in area under the plasma concentration-time curve and maximum plasma concentration between the paediatric and adult populations, with paediatric exposures within 10%-15% above adult levels on average. To provide comparable exposure to the approved adult doses, weight-based dosing adjustments are recommended for paediatric patients weighing ≤40 kg, while no adjustments are needed for patients weighing >40 kg. These results support the dosing strategy being used in the ongoing efficacy and safety studies with eptinezumab in children and adolescents with migraine.

Comparison of gepant effects at therapeutic plasma concentrations: connecting pharmacodynamics and pharmacokinetics.

BACKGROUND: Orally administered second-generation gepants are effective for the treatment of migraine. The intranasal administration of the third-generation gepant zavegepant might have additional benefits including a rapid onset of action, but it is not clear yet to which extent this has clinical relevance. METHODS: We examined the effect of zavegepant on the relaxations induced by calcitonin gene-related peptide (CGRP) in human isolated middle meningeal arteries. Furthermore, we connected the pharmacodynamics and pharmacokinetics of gepants by combining data from clinical and basic research. RESULTS: We showed that 10 nM zavegepant potently antagonized the functional response to CGRP. We also showed that all gepants are effective at inhibiting functional responses to CGRP at their therapeutic plasma concentrations. CONCLUSIONS: The relatively low predicted potency of zavegepant to inhibit CGRP-induced relaxation at therapeutic systemic plasma concentrations may point to the relevance of local delivery to the trigeminovascular system through intranasal administration. This approach may have additional benefits for various groups of patients, including overweight patients.

Unravelling the role of beta-CGRP in inflammatory bowel disease and its potential role in gastrointestinal homeostasis.

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.

Evidence-based review and frontiers of migraine therapy.

BACKGROUND: Cyclic vomiting syndrome (CVS) is identified as one of the "episodic syndromes that may be associated with migraine," along with benign paroxysmal torticollis, benign paroxysmal vertigo, and abdominal migraine. It has been proposed that CVS and migraine may share pathophysiologic mechanisms of hypothalamic activation and altered dopaminergic signaling, and impaired sensorimotor intrinsic connectivity. The past decade has brought groundbreaking advances in the treatment of migraine and other headache disorders. While many of these therapies have yet to be studied in episodic syndromes associated with migraine including CVS and abdominal migraine, the potential shared pathophysiology among these conditions suggests that use of migraine-specific treatments may have a beneficial role even in those for whom headache is not the primary symptom. PURPOSE: This manuscript highlights newer therapies in migraine. Calcitonin gene-related peptide (CGRP) and its relation to migraine pathophysiology and the therapies that target the CGRP pathway, as well as a 5HT1F receptor agonist and neuromodulation devices used to treat migraine are briefly discussed as they may potentially prove to be useful in the future treatment of CVS.

CGRP inhibits SARS-CoV-2 infection of bronchial epithelial cells, and its pulmonary levels correlate with viral clearance in critical COVID-19 patients.

Upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with critical coronavirus disease 2019 (COVID-19) present with life-threatening respiratory distress, pulmonary damage, and cytokine storm. One unexplored component in COVID-19 is the neuropeptide calcitonin gene-related peptide (CGRP), which is highly abundant in the airways and could converge in multiple aspects of COVID-19-related pulmonary pathophysiology. Whether CGRP affects SARS-CoV-2 infection directly remains elusive. We show that in critical COVID-19 patients, CGRP is increased in both plasma and lungs. Importantly, CGRP pulmonary levels are elevated in early SARS-CoV-2-positive patients and restored to baseline upon subsequent viral clearance in SARS-CoV-2-negative patients. We further show that CGRP and its stable analog SAX directly inhibit infection of bronchial Calu-3 epithelial cells with SARS-CoV-2 Omicron and Alpha variants in a dose-dependent manner. Both pre- and post-infection treatments with CGRP and/or SAX are enough to block SARS-CoV-2 productive infection of Calu-3 cells. CGRP-mediated inhibition occurs via activation of the CGRP receptor and involves down-regulation of both SARS-CoV-2 entry receptors at the surface of Calu-3 cells. Together, we propose that increased pulmonary CGRP mediates beneficial viral clearance in critical COVID-19 patients by directly inhibiting SARS-CoV-2 propagation. Hence, CGRP-based interventions could be harnessed for management of COVID-19.IMPORTANCEThe neuropeptide CGRP is highly abundant in the airways. Due to its immunomodulatory, vasodilatory, and anti-viral functions, CGRP could affect multiple aspects of COVID-19-related pulmonary pathophysiology. Yet, the interplay between CGRP and SARS-CoV-2 during COVID-19 remains elusive. Herein, we show that pulmonary levels of CGRP are increased in critical COVID-19 patients, at an early stage of their disease when patients are SARS-CoV-2-positive. Upon subsequent viral clearance, CGRP levels are restored to baseline in SARS-CoV-2-negative patients. We further show that pre- and post-infection treatments with CGRP directly inhibit infection of Calu-3 bronchial epithelial cells with SARS -CoV-2, via activation of the CGRP receptor leading to decreased expression of both SARS-CoV-2 entry receptors. Together, we propose that increased pulmonary CGRP is beneficial in COVID-19, as CGRP-mediated inhibition of SARS-CoV-2 infection could contribute to viral clearance in critical COVID-19 patients. Accordingly, CGRP-based formulations could be useful for COVID-19 management.

Impact of Erenumab on Migraine Disability: A Three-Month MIDAS (Migraine Disability Assessment Scale) Score Analysis at Dubai Health Facilities.

BACKGROUND AND AIM: Migraine is a prevalent neurological disorder causing recurrent headaches that significantly impact daily life. Erenumab, a calcitonin gene-related peptide (CGRP) receptor antagonist, has emerged as a promising treatment for migraine. CGRP is thought to play a role in migraine pathophysiology, and erenumab works by blocking CGRP binding to its receptors. Erenumab has been found to be effective in reducing migraine frequency, with potential benefits for improving patient outcomes. This study investigated the impact of erenumab on migraine disability in patients treated at Dubai Health facilities. We specifically assessed changes in Migraine Disability Assessment Scale (MIDAS) scores before and after a three-month treatment period. METHODS: This retrospective analysis examined data from 26 patients diagnosed with migraine according to the established criteria. All patients received erenumab treatment for three months. MIDAS, a validated tool, was used to quantify migraine-related disability at baseline and after treatment completion. Due to potential skewness in the data distribution, the statistical analysis focused on the median change in MIDAS scores across groups based on gender and erenumab dosage. Non-parametric tests were employed to assess group differences. RESULTS: Erenumab treatment resulted in a median decrease of 13 points in MIDAS scores, suggesting a potential improvement in migraine disability at three months. Statistical analysis revealed no statistically significant group differences regarding MIDAS score changes between genders or erenumab dosage groups. However, trends toward improvement were observed in all subgroups. CONCLUSION: While not statistically significant due to the limited sample size and the absence of a control group, these findings suggest a potential benefit of erenumab in reducing migraine disability. Future research with more extensive, controlled trials is warranted to definitively assess erenumab's effectiveness and explore potential treatment regimen variations for optimal patient outcomes.

Situational prevention in migraine: are we doing the right thing?

This commentary addresses the use of rimegepant for situational prevention in migraine management. While the approach of using prophylactic treatments during high-risk periods is not new, its application with rimegepant described by Lipton et al. raises ethical and clinical concerns. These include the challenge of defining high-risk periods, the potential for overmedication, and the risk of medication overuse headache (MOH). The current evidence on MOH with gepants is inconclusive, and recommendations on dosing may be insufficient. Additionally, the long-term safety of calcitonin gene-related peptide (CGRP) antagonists remains uncertain, especially regarding cardiovascular and other systemic effects. The commentary emphasizes the need for caution and thorough investigation into the long-term risks and benefits of situational prevention with rimegepant before widespread adoption.

Linking severe traumatic brain injury to pulmonary Infections: Translocation of intestinal bacteria mediated by nociceptor neurons.

The prevalence of bacterial infections significantly increases among patients with severe traumatic brain injury (STBI), leading to a notable rise in mortality rates. While immune dysfunctions are linked to the incidence of pneumonia, our observations indicate that endogenous pathogens manifest in the lungs post-STBI due to the migration of gut commensal bacteria. This translocation involves gut-innervating nociceptor sensory neurons, which are crucial for host defense. Following STBI, the expression of transient receptor potential vanilloid 1 (TRPV1) in dorsal root ganglion (DRG) neurons significantly decreases, despite an initial brief increase. The timing of TRPV1 defects coincides with the occurrence of pulmonary infections post-STBI. This alteration in TRPV1+ neurons diminishes their ability to signal bacterial injuries, weakens defense mechanisms against intestinal bacteria, and increases susceptibility to pulmonary infections via bacterial translocation. Experimental evidence demonstrates that pulmonary infections can be successfully replicated through the chemical ablation and gene interference of TRPV1+ nociceptors, and that these infections can be mitigated by TRPV1 activation, thereby confirming the crucial role of nociceptor neurons in controlling intestinal bacterial migration. Furthermore, TRPV1+ nociceptors regulate the immune response of microfold cells by releasing calcitonin gene-related peptide (CGRP), thereby influencing the translocation of gut bacteria to the lungs. Our study elucidates how changes in nociceptive neurons post-STBI impact intestinal pathogen defense. This new understanding of endogenous risk factors within STBI pathology offers novel insights for preventing and treating pulmonary infections.

Long-term safety of zavegepant nasal spray for the acute treatment of migraine: A phase 2/3 open-label study.

BACKGROUND: Zavegepant is the first small molecule calcitonin gene-related peptide receptor antagonist for intranasal administration for the acute treatment of migraine. The objective of this study was to evaluate the safety and tolerability of zavegepant in the acute treatment of migraine under repeated, as-needed dosing for up to one year. METHODS: This phase 2/3, one-year open-label safety study of zavegepant 10 mg nasal spray for the acute treatment of migraine enrolled adults aged ≥18 years with a history of two to eight moderate to severe monthly migraine attacks. Participants used one dose of zavegepant as needed to self-treat migraine attacks of any severity, up to eight times per month, for 52 weeks. RESULTS: Participants were enrolled between 29 June and 4 December 2020. Of the 608 participants entering long-term treatment, 603 were treated with study drug. Participants administered a mean (SD) of 3.1 (1.55) zavegepant doses per month. There were no deaths. Of the seven serious adverse events reported, none was considered related to treatment. Altogether, 6.8% (41/603) of treated participants had an adverse event leading to study drug discontinuation. The most frequent adverse event leading to discontinuation was dysgeusia (1.5% [9/603]). The most common treatment-emergent adverse events (≥5% of participants) were dysgeusia (39.1% [236/603]); nasal discomfort (10.3% [62/603]); COVID-19 (7.5% [45/603]); nausea (6.1% [37/603]); nasal congestion and throat irritation (5.5% [33/603] each); and back pain (5.3% [32/603]). Aminotransferases >3x the upper limit of normal occurred in 2.6% [16/603] of participants; none had concurrent elevations in bilirubin >2x upper limit of normal. CONCLUSIONS: One year of zavegepant 10 mg nasal spray up to eight times per month was safe and well tolerated.Trial registration: Clinicaltrials.gov: NCT04408794.

Fentanyl induces analgesic effect through miR-381-3p/TRPM7 when combined with bupivacaine in subarachnoid injection.

Fentanyl combined with bupivacaine in subarachnoid anesthesia exerts a strong synergistic analgesic effect, extending the duration of analgesia. However, the mechanism of enhanced analgesic effect of fentanyl remains elusive. The present study investigated the potential mechanism of the analgesic effect of fentanyl when combined with bupivacaine. The subarachnoid injection (SI) rat model was employed, and SI of fentanyl or/and bupivacaine was used to investigate their analgesic effect. Dorsal root ganglion (DRG)' RNA sequencing (RNA-Seq) and bioinformatics analysis were performed to evaluate the downstream mechanisms of MicroRNAs (miRNAs). Further validation tests included RT-PCR, Western blot, and immunofluorescence. A single SI of fentanyl or bupivacaine decreased the positive responses to stimulation when used alone or in combination. RNA-seq results revealed that miR-381-3p played a role in the fentanyl-driven promotion of analgesia. Bioinformatics analysis and dual-luciferase reporter identified TRPM7 as a direct downstream target gene of miR-381-3p. In vitro, overexpression of miR-381-3p could further block fentanyl-induced expression of TRPM7, p-ERK1/2, CGRP, and SP. In addition, antagomir-381-3p reversed the inhibitory effect of fentanyl on the expression of TRPM7, p-ERK1/2, CGRP, and SP, in vivo; however, TRPM7 siRNA rescued the effect of antagomir-381-3p. In conclusion, fentanyl inhibits p-ERK by targeting TRPM7 via miR-381-3p, lowering the production of CGRP and SP, and ultimately inducing analgesic effects.

Monoclonal Antibodies Targeting CGRP to Treat Vestibular Migraine: A Rapid Systematic Review and Meta-Analysis.

Vestibular migraine (VM), a subtype of migraine characterized by vestibular symptoms, poses a significant diagnostic and therapeutic challenge. This study aimed to evaluate the effectiveness of monoclonal antibodies targeting Calcitonin Gene Related Peptide (CGRP) in the treatment of VM. Therefore, we conducted a rapid systematic review and meta-analysis following PRISMA and Cochrane guidelines. A search of databases (PubMed, Scopus, Cochrane and Google Scholar) was performed in October 2023. Inclusion criteria required original research articles focusing on patients diagnosed with VM and utilizing CGRP-targeting monoclonal antibodies. We performed qualitative assessments of study design, patient characteristics, and outcomes and, for studies with comparable outcome measures, a meta-analysis was conducted. Our search yielded four relevant studies, including cohort studies and a case report, totaling 99 patients. Proper vestibular instrumental tests were employed in half of the studies. Overall, the included studies reported significant improvements in VM symptoms. Our quantitative analysis, focused on migraine symptoms, demonstrated a substantial reduction in Monthly Days with Migraine at 6 months following treatment. No severe adverse drug reactions were reported. In conclusion, this rapid systematic review and meta-analysis provide preliminary evidence for the efficacy of CGRP-targeting monoclonal antibodies in treating Vestibular Migraine. However, the absence of randomized controlled trials and variations in study designs and diagnostic criteria introduce some limitations. Further research is needed, including controlled trials, to establish a more robust evidence base. Nonetheless, this treatment approach offers hope for the effective management of VM, potentially enhancing the well-being of affected individuals and reducing their associated disability.

Exploring Erenumab's Efficacy and Safety for Migraine Prevention in Real-World Settings: A Systematic Review.

Migraine causes debilitating headaches and significantly impacts quality of life. Effective migraine-specific treatments have been lacking until the advent of monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) receptors, which have expanded therapy options for migraine treatment. This study explores the short- and long-term efficacy and safety of erenumab in migraine treatment. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 criteria guided this systematic review. Five databases - PubMed, PubMed Central, Google Scholar, ScienceDirect, and Sage Journal - were searched for published, freely accessible, full-text articles in English from the past five years. Eligible patients included those with episodic or chronic migraines who received erenumab intervention. From an initial search yielding 680 relevant studies, 12 prospective observational cohort studies were selected after assessing the risk of bias through the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. All included studies demonstrated a significant reduction in monthly migraine days (MMDs) by the end of the treatment period, with mild adverse effects observed. No significant short-term or long-term safety concerns were identified.

The role of depth of general anesthesia in serum CGRP and SP level in diabetes patients.

BACKGROUND: Diabetes, which is associated with cardiovascular disease and related microvascular complications, affects life expectancy and decrease quality of life. A trial reports that the risk of patients with diabetes having cardiovascular disease is 2-4 times compared with that in patients without diabetes. OBJECTIVE: This study aims to investigate the relationship between depth of general anesthesia in patients with diabetes mellitus. METHODS: This clinical study totally includes 40 patients with diabetes mellitus, and these patients are divided into following two groups: diabetes mellitus deep anesthesia group and diabetes mellitus light anesthesia group, and then these patients receive general anesthesia combined with laparoscopic surgery. Preoperative patient general data and intraoperative patient general data are collected and analyzed. Calcitonin gene-related peptide (CGRP) and substance P (SP) level are determined by Enzyme-linked immunosorbent assay (ELISA). RESULTS: This study included a total of 40 patients. There were no significant differences in demographic and preoperative patient general data between the two groups. Measurements were taken for operative time, anesthesia time, recovery time after drug withdrawal, dwell time in the recovery room, intraoperative fluid volume, intraoperative blood loss, and intraoperative urine output between the two groups. Significant differences were observed in the recovery time after drug withdrawal between the two groups. CGRP and SP level in diabetes mellitus deep anesthesia group are evidently more than those in diabetes mellitus light anesthesia group. CONCLUSIONS: CGRP and SP level are involved in the diabetes mellitus and up-regulated CGRP and SP can prevent the development of diabetes mellitus. Our study extends the existing literature by addressing a gap in knowledge regarding the impact of anesthesia depth on neuropeptide levels in diabetes mellitus patients. By delineating this relationship, we aim to contribute to the advancement of perioperative care practices and ultimately improve outcomes for individuals with diabetes undergoing surgical procedures. Our study's findings provide valuable insights into the complex interactions between anesthesia, neuropeptides, and diabetes mellitus, offering the potential for personalized perioperative care, enhanced pain management, and improved surgical outcomes. These implications highlight the clinical relevance of our research and its potential to inform future advancements in perioperative care for diabetic patients undergoing surgery.

An overview of S100 proteins and their functions in skin homeostasis, interface dermatitis conditions and other skin pathologies.

S100 proteins comprise a family of structurally related proteins that are calcium-sensitive. S100 proteins have been found to play various roles in regulation of cell apoptosis, cell proliferation and differentiation, cell migration and invasion, energy metabolism, calcium homeostasis, protein phosphorylation, anti-microbial activity and inflammation in a variety of cell types. While the specific function of many S100 proteins remains unknown, some of the S100 proteins serve as disease biomarkers as well as possible therapeutic targets in skin diseases. Interface dermatitis (ID) is a histopathological term that covers many different skin conditions including cutaneous lupus erythematosus, lichen planus, and dermatomyositis. These pathologies share similar histological features, which include basal cell vacuolization and lymphocytic infiltration at the dermal-epidermal junction. In this review, we summarize how the S100 protein family contributes to both homeostatic and inflammatory processes in the skin. We also highlight the role of S100 proteins in neuronal signalling, describing how this might contribute to neuroimmune interactions in ID and other skin pathologies. Last, we discuss what is known about the S100 family proteins as both biomarkers and potential treatment targets in specific pathologies.

Lasmiditan ameliorates serotonergic itch in mice: Possible involvement of 5-HT1F receptors.

Previously, some allergic conditions involving pruritus have been linked to migraine, raising the possibility that migraine and itching may be governed by similar underlying mechanisms. We aimed to investigate the efficacy of Lasmiditan, a highly selective agonist of the 5-hydroxytryptamine 1F (5-HT1F) receptor and a recently approved medication for the treatment of migraine headaches, in ameliorating serotonergic itching. Forty animals were employed in the present study (n = 40). Eight animals were randomly assigned to each of the following study groups (n = 8, in each group): (1) "Normal Saline": This group was given intradermal injections of normal saline (2) "5-HT": The animals were injected with intradermal 5-HT, which was used to induce itching. (3) "Lasmiditan 0.3", "Lasmiditan 1", and "Lasmiditan 3" groups: injected with 5-HT as well as intraperitoneal Lasmiditan at different dose levels (0.3, 1, and 3 mg/kg, respectively). Scratching behavior was recorded for 60 min, and the skin tissue of three mice was sampled at the end of the behavioral experiment to assess the levels of TLR-4, IL-31, 5-HT1F receptor, CGRP & TRPV4. In the present study, we found that Lasmiditan when administered at 1 mg/kg effectively reduced serotonin-induced itching compared to the "5-HT" group (P < 0.0001). Following the administration of Lasmiditan (1 mg/kg), the expression levels of the 5-HT1F receptor significantly increased (P < 0.01). Further, the levels of TLR-4, IL-31, CGRP & TRPV4 were substantially reduced upon the administration of Lasmiditan (1 mg/kg). We found that Lasmiditan is effective in reducing serotonergic itch in mice through its interaction with the 5-HT1F receptor in the skin tissue of mice.

Signalling of the neuropeptide calcitonin gene-related peptide (CGRP) through RAMP1 promotes liver fibrosis via TGFß1/Smad2 and YAP pathways.

The liver is innervated by primary sensory nerve fibres releasing the neuropeptide calcitonin gene-related peptide (CGRP). Elevated plasma levels of CGRP have been found in patients with liver fibrosis or cirrhosis. We hypothesised that signalling of CGRP and its receptors might regulate liver fibrosis and propose a novel potential target for the treatment. In this study, hepatic expression of CGRP and its receptor component, the receptor activity-modifying protein 1 (RAMP1), was dramatically increased in diseased livers of patients. In a murine liver fibrosis model, deficiency of RAMP1 resulted in attenuated fibrogenesis characterized by less collagen deposition and decreased activity of hepatic stellate cells (HSC). Mechanistically, activity of the TGFß1 signalling core component Smad2 was severely impaired in the absence of RAMP1, and Yes-associated protein (YAP) activity was found to be diminished in RAMP1-deficient liver parenchyma. In vitro, stimulation of the HSC line LX-2 cells with CGRP induces TGFß1 production and downstream signalling as well as HSC activation documented by increased α-SMA expression and collagen synthesis. We further demonstrate in LX-2 cells that CGRP promotes YAP activation and its nuclear translocation subsequent to TGFß1/Smad2 signals. These data support a promotive effect of CGRP signalling in liver fibrosis via stimulation of TGFß1/Smad2 and YAP activity.

Natural history of non-polyglutamine CACNA1A disease in Austria.

BACKGROUND AND OBJECTIVES: Non-polyglutamine CACNA1A variants underlie an extremely variable phenotypic spectrum encompassing developmental delay, hemiplegic migraine, epilepsy, psychiatric symptoms, episodic and chronic cerebellar signs. We provide our experience with the long-term follow-up of CACNA1A patients and their response to interval therapy. METHODS: Patients with genetically confirmed non-polyglutamine CACNA1A disease were prospectively followed at the Center for Rare Movement Disorders of the Medical University of Innsbruck from 2004 to 2024. RESULTS: We recruited 41 subjects with non-polyglutamine CACNA1A disease, of which 38 (93%) familial cases. The mean age at the first examination was 35 ± 22 years. Disease onset was in the childhood/adolescence in 31/41 patients (76%). Developmental delay and episodic symptoms were the first disease manifestation in 9/41 (22%) and 32/41 (78%) patients respectively. Chronic neurological signs encompassed a cerebellar syndrome in 35/41 (85%), which showed almost no progression during the observation period, as well as cognitive deficits in 9/20 (45%, MOCA test score < 26), psychiatric and behavioral symptoms in 11/41(27%). Seizures occurred in two patients concomitant to severe hemiplegic migraine. At the last visit, 27/41 patients (66%) required an interval prophylaxis (including acetazolamide, flunarizine, 4-aminopyridine, topiramate), which was efficacious in reducing the frequency and severity of episodic symptoms in all cases. In one patient in his 70ies with progressively therapy resistant hemiplegic migraine, treatment with the anti-CGRP antibody galcanezumab successfully reduced the frequency of migraine days from 4 to 1/month. CONCLUSIONS: Non-polyglutamine CACNA1A disease show an evolving age-dependent presentation. Interval prophylaxis is effective in reducing the burden of episodic symptoms.

Average steps per day as marker of treatment response with anti-CGRP mAbs in adults with chronic migraine: a pilot study.

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.

CGRP promotes osteogenic differentiation by regulating macrophage M2 polarization through HDAC6/AKAP12 signaling pathway.

Aim: To determine the mechanism of Calcitonin gene-related peptide (CGRP) in bone healing.Materials & methods: Alkaline phosphatase (ALP) activity and inflammatory-factor levels were detected using ELISA. Osteogenic differentiation was assessed using Alizarin red staining technique. The interaction between histone deacetylase 6 (HDAC6) and A-kinase anchoring protein 12 (AKAP12) was investigated through Co- immunoprecipitation.Results: CGRP treatment promoted rat bone marrow-derived macrophages (BMDMs) M2 polarization. CGRP facilitated osteogenic differentiation by enhancing M2 polarization of BMDMs. Mechanistically, CGRP promoted AKAP12 acetylation to activate the extracellular regulated protein kinases pathway by HDAC6 inhibition.Conclusion: CGRP promoted M2 polarization of rat BMDMs and facilitated osteogenic differentiation through the HDAC6/AKAP12/extracellular regulated protein kinases signaling pathway, thereby promoting bone healing.

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