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.

A Risk-Difference Meta-Analysis for the Prophylactic Treatments of Chronic Migraine.

Chronic migraine (CM) imposes significant personal, societal, and financial burdens, historically lacking specific prophylactic treatments. Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) represent a novel, mechanism-based, and migraine-specific prophylactic approach. Four mAbs, namely, erenumab, fremanezumab, galcanezumab, and eptinezumab, have been marketed, although head-to-head trials with standard anti-migraine treatments are absent. This study aimed to compare the efficacy and safety of anti-CGRP mAbs with standard anti-migraine treatments using a cross-trial indirect model of the absolute risk difference (ARD) of a 50% responder rate, in order to express the final results in terms of the number needed to treat (NNT) and number needed to harm (NNH). Phase 3 and 2b randomized controlled trials (RCTs) for CM prophylaxis were searched in the MEDLINE and CENTRAL databases with specific inclusion and exclusion criteria. The ARD between groups for the percentage of trial participants who reported a 50% reduction in monthly migraine days and the differences in the number of adverse events (AEs), serious adverse events (SAEs), and participants who withdrew from each RCT were calculated, and subsequently, the NNT and NNH were calculated for each one of the outcome measures. In total, eight RCTs were considered eligible. A similar efficacy and safety have been demonstrated among CGRP mAbs and all standard CM treatments. The results of the ARD for the total number of studies concerning efficacy, total adverse events, serious adverse events, and dropout from the RCTs ranged from -0.688 (95% confidence interval (CI): -0.821-(-0.513)) to -0.018 (95% CI: -0.044-(0.007)), from 0.032 (95% CI: -0.041, 0.104) to -0.380 (95% CI: -0.589, -0.126), from -0.025 (95% CI: -0.046, -0.006) to 0.014 (95% CI: -0.015, 0.42), from 0.048 (95% CI: -0.112, 0.014) to 0.232 (95% CI: -0.016, 0.458) correspondingly. All anti-CGRP mAbs showed a roughly equal statistically significant ARD and similar NNTs, ranging from 5 to 8, while the ARD of onbotulinum toxin A (oBTA) was not significant with an NNT 56. The two studies of topiramate showed contradictory results, the one significant while the other not, with NNTs 2 and 22, respectively. All four anti-CGRP mAbs showed an invariably high efficacy among their studies, in terms of the ARD and its derivative measure of NNT, in contrast to oBTA, while in topiramate, the results are contradictory between the two studies.

A Vestibular Challenge Combined with Calcitonin Gene-Related Peptide (CGRP) Promotes Anxiety-Like Behaviors.

Motion-induced anxiety and agoraphobia are more frequent symptoms in patients with vestibular migraine (VM) than migraine without vertigo. The neuropeptide calcitonin gene-related peptide (CGRP) is a therapeutic target for migraine and VM, but the link between motion hypersensitivity, anxiety, and CGRP is relatively unexplored, especially in preclinical mouse models. To further examine this link, we tested the effects of systemic CGRP and off-vertical axis rotation (OVAR) on elevated plus maze (EPM) and rotarod performance in male and female C57BL/6J mice. Rotarod ability was assessed using two different dowel diameters: mouse dowel (r = 1.5 cm) versus rat dowel (r = 3.5 cm). EPM results indicate that CGRP alone or OVAR alone did not increase anxiety indices. However, the combination of CGRP and OVAR did elicit anxiety-like behavior. On the rotarod, CGRP reduced performance in both sexes on a mouse dowel but had no effect on a rat dowel, whereas OVAR had a significant effect on the rat dowel. These results suggest that only the combination of CGRP with vestibular stimulation induces anxiety-like behavior and that CGRP affects the dynamic balance function in mice depending on the type of challenge presented. These findings suggest that anxiety-like behaviors can be teased out from imbalance behaviors in a mouse model of "migraine." Future studies are aimed to determine if CGRP receptor antagonists that have been effective treating migraineurs and mouse "migraine" models may also reduce the anxiety observed in migraine.

Sensory neuron transient receptor potential vanilloid-1 channel regulates angiogenesis through CGRP in vivo.

Angiogenesis plays a key role in bone regeneration. The role of neurons of peripheral nerves involved in angiogenesis of bone defects needs to be explored. The transient receptor potential vanilloid 1 (TRPV1), a nociceptor of noxious stimuli, is expressed on sensory neurons. Apart from nociception, little is known about the role of sensory innervation in angiogenesis. Calcitonin gene-related peptide (CGRP), a neuropeptide secreted by sensory nerve terminals, has been associated with vascular regeneration. We characterized the reinnervation of vessels in bone repair and assessed the impact of TRPV1-CGRP signaling on early vascularization. We investigated the pro-angiogenic effect of neuronal TRPV1 in the mouse model of femur defect. Micro-CT analysis with Microfil® reagent perfusion demonstrated neuronal TRPV1 activation enhanced angiogenesis by increasing vessel volume, number, and thickness. Meanwhile, TRPV1 activation upregulated the mRNA and protein expression of vascular endothelial growth factor A (VEGF-A), cell adhesion molecule-1 (CD31), and CGRP. Immunostaining revealed the co-localization of TRPV1 and CGRP in dorsal root ganglia (DRG) sensory neurons. By affecting neuronal TRPV1 channels, the release of neuronal and local CGRP was controlled. We demonstrated that TRPV1 influenced on blood vessel development by promoting CGRP release from sensory nerve terminals. Our results showed that neuronal TRPV1 played a crucial role in regulating angiogenesis during bone repair and provided important clinical implications for the development of novel therapeutic approaches for angiogenesis.

Parabrachial Calca neurons drive nociplasticity.

Pain that persists beyond the time required for tissue healing and pain that arises in the absence of tissue injury, collectively referred to as nociplastic pain, are poorly understood phenomena mediated by plasticity within the central nervous system. The parabrachial nucleus (PBN) is a hub that relays aversive sensory information and appears to play a role in nociplasticity. Here, by preventing PBN Calca neurons from releasing neurotransmitters, we demonstrate that activation of Calca neurons is necessary for the manifestation and maintenance of chronic pain. Additionally, by directly stimulating Calca neurons, we demonstrate that Calca neuron activity is sufficient to drive nociplasticity. Aversive stimuli of multiple sensory modalities, such as exposure to nitroglycerin, cisplatin, or lithium chloride, can drive nociplasticity in a Calca-neuron-dependent manner. Aversive events drive nociplasticity in Calca neurons in the form of increased activity and excitability; however, neuroplasticity also appears to occur in downstream circuitry.

Reporting Quality and Risk of Bias Analysis of Published RCTs Assessing Anti-CGRP Monoclonal Antibodies in Migraine Prophylaxis: A Systematic Review.

Objective: Phase II/III randomized clinical trials (RCTs) are vulnerable to many types of bias beyond randomization. Insights into the reporting quality of RCTs involving migraine patients treated with monoclonal antibodies targeting the calcitonin gene-related peptide system (anti-CGRP MAbs) are currently lacking. Our aim was to analyze the reporting quality of phase II/III RCTs involving migraine patients treated with anti-CGRP MAbs. Methods: A systematic search was performed on the PubMed and EMBASE databases, according to PRISMA guidelines, for relevant RCTs in either episodic or chronic migraine prevention. Additionally, an adapted version of the 2010 CONSORT statement checklist was utilized. The ROBvis online tool was used to document the risk of bias. Results: From the initially identified 179 articles, we finally found 31 RCTs that were eligible for evaluation. The average CONSORT compliance was 88.7% (69.7-100%), while 93.5% (N = 29) of the articles had a compliance greater than 75%. Twenty-eight CONSORT items were reported in more than 75% of the articles. The average compliance of the analyzed RCTs was 93.9% for Galcanezumab, 91.3% for Fremanezumab, followed by 85.4% for Erenumab and Eptinezumab studies. Implementation of the ROB2 tool showed some concerning "missing information" arising from the inadequate reporting. Specifically, 50% of the studies (N = 16) were categorized as having inadequate information regarding the randomization process. Conclusions: Adequate reporting quality was disclosed in the evaluated RCTs with anti-CGRP MAbs in migraine prevention. However, some methodological issues need to be highlighted to be addressed in future studies assessing the efficacy of new molecules targeting CGRP or other candidate pathways implicated in migraine pathophysiology.

Advances in understanding migraine pathophysiology: a bench to bedside review of research insights and therapeutics.

The individual and global burden of migraine is of such significance that there are accelerated efforts to develop new therapies. New migraine therapeutics are needed to address the current deficiencies that exist in the efficacy and adherence rate of approved anti-migraine medications. The recent discovery of the calcitonin gene related peptide as an add-on to the role of serotonin has markedly increased the range of new treatment options for acute and chronic migraine. Despite this, tackling the complexity of migraine disorders requires a complete understanding of its pathophysiology. Preclinical animal models can shed light on disease-related pathophysiology, including migraine. Indeed, the use of animal models has been instrumental in developing many therapeutics. However, an animal model is limited by the predictive and face validity of that model, and this extends to preclinical migraine models. In this review, a summary of the current understanding of the pathophysiology of migraine is given from both a preclinical and clinical perspective, and an emphasis is placed on the animal models of migraine. We will discuss the strengths and pitfalls of common preclinical migraine models as well as experimental research areas to explore further.

Modification of Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles by Calcitonin Gene Related Peptide (CGRP) Antagonist: Potential Implications for Inflammation and Pain Reversal.

During the progression of knee osteoarthritis (OA), the synovium and infrapatellar fat pad (IFP) can serve as source for Substance P (SP) and calcitonin gene-related peptide (CGRP), two important pain-transmitting, immune, and inflammation modulating neuropeptides. Our previous studies showed that infrapatellar fat pad-derived mesenchymal stem/stromal cells (MSC) acquire a potent immunomodulatory phenotype and actively degrade Substance P via CD10 both in vitro and in vivo. On this basis, our hypothesis is that CD10-bound IFP-MSC sEVs can be engineered to target CGRP while retaining their anti-inflammatory phenotype. Herein, human IFP-MSC cultures were transduced with an adeno-associated virus (AAV) vector carrying a GFP-labelled gene for a CGRP antagonist peptide (aCGRP). The GFP positive aCGRP IFP-MSC were isolated and their sEVs' miRNA and protein cargos were assessed using multiplex methods. Our results showed that purified aCGRP IFP-MSC cultures yielded sEVs with cargo of 147 distinct MSC-related miRNAs. Reactome analysis of miRNAs detected in these sEVs revealed strong involvement in the regulation of target genes involved in pathways that control pain, inflammation and cartilage homeostasis. Protein array of the sEVs cargo demonstrated high presence of key immunomodulatory and reparative proteins. Stimulated macrophages exposed to aCGRP IFP-MSC sEVs demonstrated a switch towards an alternate M2 status. Also, stimulated cortical neurons exposed to aCGRP IFP-MSC sEVs modulate their molecular pain signaling profile. Collectively, our data suggest that yielded sEVs can putatively target CGRP in vivo, while containing potent anti-inflammatory and analgesic cargo, suggesting the promise for novel sEVs-based therapeutic approaches to diseases such as OA.

Anti-CGRP and Anti-CGRP Receptor Monoclonal Antibodies for Migraine Prophylaxis: Retrospective Observational Study on 209 Patients.

BACKGROUND: Migraine is a neurological disorder characterized by attacks of head pain with prevalent unilateral localization, moderate to high intensity and specifically associated accompanying symptoms. METHODS: In this retrospective observational study, we analyzed data regarding 209 patients who had previously been diagnosed with migraine and who were prescribed, between 2019 and 2022, subcutaneous injections of anti-CGRP monoclonal antibodies (mAbs) fremanezumab or galcanezumab or anti-CGRP receptors mAb erenumab regardless of the concomitant assumption of any other acute-phase or prophylactic migraine medication. RESULTS: Regarding efficacy, in the 205 analyzed patients, the change from baseline in terms of MIDAS, HIT-6, MMDs and MAD scores was statistically significant for erenumab and galcanezumab, while for fremanezumab a statistical significance was not achieved likely due to the small sample size. In the treated population, 36 patients (17.5%) reported AEs (pain during injection, transient injection site erythema, nausea, constipation and fatigue). Only 5 patients (2.4%) discontinued the treatment for AEs while 15 patients (7.3%) left for lack of efficacy. CONCLUSIONS: this retrospective study comes out in favor of both significant efficacy and safety of anti-CGRP and anti-CGRP receptors mAbs in migraine patients. Further methodologically stronger studies are necessary to validate our observation.

Effect of anti-CGRP-targeted therapy on migraine aura: Results of an observational case series study.

INTRODUCTION: Limited clinical evidence is available regarding the potential effectiveness of anti-CGRP monoclonal antibodies for the preventive treatment of migraine with aura. AIM OF THE STUDY: This observational study involved a series of migraine patients affected by either migraine with or without aura, who were investigated for any changes in their frequencies and their migraine aura attack characteristics observed during treatment with anti-CGRP Mabs over a 1-year period. PATIENTS AND METHODS: Twelve migraine patients were included, seven of whom were treated with erenumab, 2 with fremanezumab, and 3 with galcanezumab. Clinical data were collected at baseline, which were defined as 3 months prior to the initiation of treatment, and thereafter at each trimester, over the 1-year treatment period. The parameters included the number of headache and migraine days/month, the frequency of aura episodes, the number of days with acute drug intakes/month, and the scores from the migraine disability status scale (MIDAS), and the Headache Impact Test 6 (HIT-6). RESULTS: Anti-CGRP Mbs antibodies induced significant decreases in mean headache and migraine without aura days per month, the number of days with medication intake, as well as MIDAS and HIT-6 scores (p < 0.0001). In contrast, the anti-CGRP Mab treatment did not appear to impact the frequency of migraine with aura attacks but seemed to reduce both the intensity and the duration of headache phases of migraine aura. Furthermore, some migraine patients referred to having aura attacks without headache over the course of the treatment period. CONCLUSIONS: Based on the above findings, we hypothesize that anti-CGRP Mabs did not influence neuronal and vascular events related to cortical spreading depression (CSD) which is considered the pathophysiological substrate of aura. Conversely, these antibodies are able to counteract, via their peripheral mechanisms of action, the sensitization of the trigemino-vascular pathway which is triggered by CSD. This aforementioned might explain why in our patients, migraine aura attacks remained unchanged in their frequencies, but the headache phases were either reduced or absent.

Role of tear size and tendon degeneration for development of pain in rat models of rotator cuff tear.

BACKGROUND: Rotator cuff tear (RCT) is a frequent etiology of shoulder pain and disability; however, the triggers for the onset and aggravation of pain remain obscure. In this study, we established novel rat RCT models to examine the impact of tear size and tendon degeneration on pain. METHODS: Fifty-five adult male Sprague-Dawley rats were allocated into 4 study groups: large tear (L group, n = 10), small tear (S group, n = 15), small tear with scratching (S+ group n = 15), and sham surgery (Sham group, n = 15). Pain-related behaviors were evaluated by weight distribution of forelimbs during a 5-minute free gait using a dynamic weight-bearing apparatus at 2, 4, 6, and 8 weeks. Calcitonin gene-related peptide (CGRP) expressions in ipsilateral dorsal root ganglion (DRG) neurons of C4, C5, and C6 were evaluated at 4 and 8 weeks. The area of scar tissues around the torn tendon, infiltration of inflammatory cells, and severity of tendon degeneration (modified Bonar score) were histologically assessed at 4 and 8 weeks. Additionally, enzyme-linked immunosorbent assay (ELISA) was conducted to evaluate the levels of cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) expression in torn tendons and surrounding tissues at 4 weeks. RESULTS: The weight distribution ratio (ipsilateral and contralateral side) was significantly decreased in the L and S+ group compared with its baseline and Sham group (P < .05), but the S group showed no significant difference compared with the Sham. The ratio of CGRP-immunoreactive neurons in the DRGs was significantly higher in the L and S+ groups than in the S and Sham groups. The histologic assessment indicated that scar tissue formation was more extensive in the L group than in the S and S+ groups. Still, there was no significant difference between the S and S+ groups. The modified Bonar score was considerably higher in the S+ group than in the S group. Furthermore, ELISA analysis demonstrated no significant disparity in COX-2 levels between the groups; however, NGF levels were substantially higher in the S+ group than in the S and Sham groups. CONCLUSION: The present study provides compelling evidence that large RCT is strongly associated with heightened pain severity in a rat model. Nevertheless, even a small tear can significantly aggravate pain when the torn tendon is degenerated. CGRP upregulation driven by peripheral NGF possibly played a pivotal role in the genesis and exacerbation of pain in small RCT.

Real-world experience with calcitonin gene-related peptide-targeted antibodies for migraine prevention: a retrospective observational cohort study at two Japanese headache centers.

BACKGROUND: Although randomized controlled trials (RCTs) have shown that calcitonin gene-related peptide (CGRP)-targeted monoclonal antibodies (CGRP mAbs) are an efficacious and safe therapeutic modality for migraine prevention, their clinical benefits have not been well validated in Japanese patients in the real-world setting. The present study aimed to evaluate the real-world efficacy and safety of galcanezumab, fremanezumab, and erenumab in Japanese patients with migraine. METHODS: This observational retrospective cohort study was conducted at two headache centers in Japan. Patients with migraine who had experienced treatment failure with at least one traditional oral migraine preventive agent were treated with a CGRP mAb de novo. The primary efficacy endpoints were the changes from baseline in monthly migraine days (MMDs) and Headache Impact Test-6 (HIT-6) score after 3 dosing intervals (V3). We explored whether demographic and clinical characteristics predicted therapeutic outcomes at V3. RESULTS: Sixty-eight patients who completed three doses of a CGRP mAb (85.3% female [58/68], mean age: 46.2 ± 13.1 years) were included in the analysis. There were 19 patients with chronic migraine. The baseline MMDs were 13.4 ± 6.0. After 3 doses, the MMDs significantly decreased to 7.4 ± 5.5 (p < 0.0001), and the 50% response rate was 50.0%. HIT-6 score was significantly reduced from 66.7 ± 5.4 to 56.2 ± 8.7 after 3 doses (P = 0.0001). There was a positive correlation between the changes in MMDs and HIT-6 score from baseline after 2 doses (p = 0.0189). Those who achieved a ≥ 50% therapeutic response after the first and second doses were significantly more likely to do so at V3 (crude odds ratio: 3.474 [95% CI: 1.037 to 10.4], p = 0.0467). The most frequent adverse event was constipation (7.4%). None of the adverse events were serious, and there was no need for treatment discontinuation. CONCLUSIONS: This real-world study demonstrated that CGRP mAbs conferred Japanese patients with efficacious and safe migraine prevention, and an initial positive therapeutic response was predictive of subsequent favorable outcomes. Concomitant measurement of MMDs and HIT-6 score was useful in evaluating the efficacy of CGRP mAbs in migraine prevention.

Comparing the Efficacy and Safety of Galcanezumab Versus Rimegepant for Prevention of Episodic Migraine: Results from a Randomized, Controlled Clinical Trial.

INTRODUCTION: There have been no prior trials directly comparing the efficacy of different calcitonin gene-related peptide (CGRP) antagonists for migraine prevention. Reported are the results from the first head-to-head study of two CGRP antagonists, galcanezumab (monoclonal antibody) versus rimegepant (gepant), for the prevention of episodic migraine. METHODS: In this 3-month, double-blind, double-dummy study, participants were randomized (1:1) to subcutaneous (SC) galcanezumab 120 mg per month (after a 240 mg loading dose) and a placebo oral disintegrating tablet (ODT) every other day (q.o.d.) or to rimegepant 75 mg ODT q.o.d. and a monthly SC placebo. The primary endpoint was the proportion of participants with a ≥ 50% reduction in migraine headache days per month from baseline across the 3-month double-blind treatment period. Key secondary endpoints were overall mean change from baseline in: migraine headache days per month across 3 months and at month 3, 2, and 1; migraine headache days per month with acute migraine medication use; Migraine-Specific Quality of Life Questionnaire Role Function-Restrictive domain score at month 3; and a ≥ 75% and 100% reduction from baseline in migraine headache days per month across 3 months. RESULTS: Of 580 randomized participants (galcanezumab: 287, rimegepant: 293; mean age: 42 years), 83% were female and 81% Caucasian. Galcanezumab was not superior to rimegepant in achieving a ≥ 50% reduction from baseline in migraine headache days per month (62% versus 61% respectively; P = 0.70). Given the pre-specified multiple testing procedure, key secondary endpoints cannot be considered statistically significant. Overall, treatment-emergent adverse events were reported by 21% of participants, with no significant differences between study intervention groups. CONCLUSIONS: Galcanezumab was not superior to rimegepant for the primary endpoint; however, both interventions demonstrated efficacy as preventive treatments in participants with episodic migraine. The efficacy and safety profiles observed in galcanezumab-treated participants were consistent with previous studies. TRIAL REGISTRATION: ClinTrials.gov-NCT05127486 (I5Q-MC-CGBD).

Galcanezumab and rimegepant are preventive treatments for episodic migraine. The goal of this study was to compare the efficacy of galcanezumab and rimegepant in reducing the number of monthly migraine headaches and to determine if galcanezumab was better than rimegepant. The study provides important information to doctors and their patients when making treatment decisions.People with episodic migraine were assigned to the galcanezumab (given as an injection under the skin) or rimegepant (given as a tablet that dissolves in the mouth) group and treated for 3 months. The doctor and the patient did not know which group they were assigned to, and to keep it unknown to both, people in the galcanezumab group got an injection with real medicine and a fake tablet, and people in the rimegepant group got a tablet with real medicine and a fake injection. The researchers wanted to know how many people in each group had at least a 50% reduction in their monthly migraine headaches.Of the 580 people in the study, 287 were assigned to galcanezumab and 293 to rimegepant. In both groups, most were female and white. After 3 months of treatment, 62% of the people in the galcanezumab group and 61% of people in the rimegepant group had at least a 50% reduction in monthly migraine headaches. Both treatments were effective, but galcanezumab was not better than rimegepant. About 20% of the people in each treatment group had a side effect from the medication, and most were mild or moderate in severity.

Mediation of the JNC/ILC2 pathway in DBP-exacerbated allergic asthma: A molecular toxicological study on neuroimmune positive feedback mechanism.

BACKGROUND: Dibutyl phthalate (DBP), a commonly used plasticizer, has been found to be strongly linked to a consistently high prevalence of allergic diseases, particularly allergic asthma. Previous animal experiments have demonstrated that exposure to DBP can worsen asthma by triggering the production of calcitonin gene-related peptide (CGRP), a neuropeptide in the lung tissue. However, the precise neuroimmune mechanism and pathophysiology of DBP-exacerbated allergic asthma with the assistance of CGRP remain unclear. OBJECTIVE: The present study was to investigate the potential pathophysiological mechanism in DBP-exacerbated asthma from the perspective of neural-immune interactions. METHODS AND RESULTS: C57BL/6 mice were orally exposed to different concentrations (0.4, 4, 40 mg/kg) of DBP for 28 days. They were then sensitized with OVA and nebulized with OVA for 7 consecutive excitations. To investigate whether DBP exacerbates allergic asthma in OVA induced mice, we analyzed airway hyperresponsiveness and lung histopathology. To investigate the activation of JNC and TRPV1 neurons and the release of CGRP by JNC cells, we measured the levels of TRPV1 channels, calcium inward flow, and downstream neuropeptide CGRP. Results showed that TRPV1 expression, inward calcium flux, and CGRP levels were significantly elevated in the lung tissues of the 40DBP + OVA group, suggesting the release of CGRP by JNC cells. To counteract the detrimental effects of DBP mediated by CGRP, we employed olcegepant (also known as BIBN-4096), a CGRP receptor specific antagonist. Results revealed that 40DBP + OVA + olcegepant led to notable decreases in TRPV1, calcium inward flow, and CGRP expression in lung tissues compare with 40DBP + OVA, further supporting the efficacy of olcegepant. Additionally, we also conducted ILC2 flow sorting and observed that neuropeptide CGRP-activated ILC2 cells have a crucial role as key effector cells in DBP-induced neuroimmune positive feedback regulation. Finally, we examined the protein expression of CGRP, GATA3 and P-GATA3, and found that significant upregulations of CGRP and P-GATA3 in the 40DBP + OVA group, suggest that GATA3 acted as a key regulator of CGRP-activated ILC2. CONCLUSION: The aforementioned studies indicate that exposure to DBP can exacerbate allergic asthma, leading to airway inflammation. This exacerbation occurs through the activation of TRPV1 in JNC, resulting in the release of CGRP. The excessive release of CGRP further promotes the release of Th2 cytokines by inducing the activation of ILC2 through GATA phosphorylation. Consequently, this process contributes to the development of airway inflammation and allergic asthma. The increased production of Th2 cytokines also triggers the production of IgE, which interacts with FcεRI on JNC neurons, thereby mediating neuro-immune positive feedback regulation.

Efficacy and Safety of Anti-calcitonin Gene-Related Peptide (CGRP) Monoclonal Antibodies in Preventing Migraines: A Systematic Review.

The neuropeptide calcitonin gene-related peptide (CGRP) is an essential pathophysiological treatment for migraines. A unique class of medications called CGRP monoclonal antibodies target CGRP and its receptor and have demonstrated promising benefits in the treatment and prevention of migraines. This study sought to identify and assess the quality of existing systematic reviews about the effectiveness of CGRP antibodies for preventing migraines, as well as systematically review and synthesize the evidence on these topics. This included the four Food and Drug Administration (FDA)-approved medications erenumab, galcanezumab, fremanezumab, and eptinezumab. The effectiveness and safety of these monoclonal antibodies in preventing migraines should also be examined in light of patient characteristics, and any gaps in the body of knowledge should be noted in order to suggest new lines of investigation. Data gathering included a thorough search of internet databases (PubMed, Cochrane Library, Web of Science, and Scopus) for relevant research released between 2018 and 2023. The findings imply that CGRP monoclonal antibodies are efficient and secure for preventing migraines and may be considered a first-line alternative for treating migraines and drug misuse. The results further imply that combination treatment with CGRP antibodies and onabotulinumtoxinA may enhance the prevention of migraine in adults. With suggestions for more studies to find and address these variables, the significance of genetic and epigenetic factors in the progression of pediatric patients' acute postoperative pain to chronic postsurgical pain is underlined. All four anti-CGRP monoclonal antibodies, erenumab, fremanezumab, galcanezumab, and eptinezumab, were shown to be safe and effective for the prevention of migraine when the research additionally looked at their individual effectiveness and safety. Additionally, the study discovered considerable variances in effectiveness amongst various groups. However, further investigation is required to establish the best time and dosage and the effect of patient characteristics on the effectiveness and safety of these medications.

Update of Gepants in the Treatment of Chronic Migraine.

PURPOSE OF REVIEW: Despite the unmet therapeutic needs of patients with chronic migraine (CM) and/or medication overuse, available treatment options are limited. Recently, four calcitonin gene-related peptide receptor antagonists, known as gepants, have been approved for the treatment of migraine. This review focuses on the preventive treatment of CM with gepants and highlights recent findings. RECENT FINDINGS: Two randomized controlled trials (RCTs) have shown promising results for rimegepant and atogepant as preventive treatments for CM. In an RCT targeting patients with CM, atogepant demonstrated a significant reduction in the mean monthly migraine days, irrespective of acute medication overuse. Moreover, the patients reported no significant safety concerns and exhibited good tolerance to treatment. These findings highlight the potential of gepants as a new and effective therapeutic option for patients with CM and/or medication overuse. Gepant use will help improve the management and quality of life of individuals with this debilitating condition.

Multi-biological functions of intermedin in diseases.

Intermedin (IMD) is a member of the calcitonin gene-related peptide (CGRP)/calcitonin (CT) superfamily, and it is expressed extensively throughout the body. The typical receptors for IMD are complexes composed of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein (RAMP), which leads to a biased activation towards Gαs. As a diagnostic and prognostic biomarker, IMD regulates the initiation and metastasis of multiple tumors. Additionally, IMD functions as a proangiogenic factor that can restrain excessive vascular budding and facilitate the expansion of blood vessel lumen, ultimately resulting in the fusion of blood vessels. IMD has protective roles in various diseases, including ischemia-reperfusion injury, metabolic disease, cardiovascular diseases and inflammatory diseases. This review systematically elucidates IMD's expression, structure, related receptors and signal pathway, as well as its comprehensive functions in the context of acute kidney injury, obesity, diabetes, heart failure and sepsis. However, the precise formation process of IMD short peptides in vivo and their downstream signaling pathway have not been fully elucidated yet. Further in-depth studies are need to translate IMD research into clinical applications.

Migraine: Advances in the Pathogenesis and Treatment.

This article presents a comprehensive review on migraine, a prevalent neurological disorder characterized by chronic headaches, by focusing on their pathogenesis and treatment advances. By examining molecular markers and leveraging imaging techniques, the research identifies key mechanisms and triggers in migraine pathology, thereby improving our understanding of its pathophysiology. Special emphasis is given to the role of calcitonin gene-related peptide (CGRP) in migraine development. CGRP not only contributes to symptoms but also represents a promising therapeutic target, with inhibitors showing effectiveness in migraine management. The article further explores traditional medical treatments, scrutinizing the mechanisms, benefits, and limitations of commonly prescribed medications. This provides a segue into an analysis of emerging therapeutic strategies and their potential to enhance migraine management. Finally, the paper delves into neuromodulation as an innovative treatment modality. Clinical studies indicating its effectiveness in migraine management are reviewed, and the advantages and limitations of this technique are discussed. In summary, the article aims to enhance the understanding of migraine pathogenesis and present novel therapeutic possibilities that could revolutionize patient care.

Calcitonin Gene-Related Peptide Systemic Effects: Embracing the Complexity of Its Biological Roles-A Narrative Review.

The calcitonin gene-related peptide (CGRP) is a neuropeptide widely distributed throughout the human body. While primarily recognized as a nociceptive mediator, CGRP antagonists are currently utilized for migraine treatment. However, its role extends far beyond this, acting as a regulator of numerous biological processes. Indeed, CGRP plays a crucial role in vasodilation, inflammation, intestinal motility, and apoptosis. In this review, we explore the non-nociceptive effects of CGRP in various body systems, revealing actions that can be contradictory at times. In the cardiovascular system, it functions as a potent vasodilator, yet its antagonists do not induce arterial hypertension, suggesting concurrent modulation by other molecules. As an immunomodulator, CGRP exhibits intriguing complexity, displaying both anti-inflammatory and pro-inflammatory effects. Furthermore, CGRP appears to be involved in obesity development while paradoxically reducing appetite. A thorough investigation of CGRP's biological effects is crucial for anticipating potential side effects associated with its antagonists' use and for developing novel therapies in other medical fields. In summary, CGRP represents a neuropeptide with a complex systemic impact, extending well beyond nociception, thus offering new perspectives in medical research and therapeutics.

Association Between Helicobacter pylori Infection and Migraine: A Systematic Review.

Migraine is a highly debilitating disease affecting humans worldwide. Despite having known this disease for a long time, not many studies have been done to search for a chronic infectious cause of migraine. The goal of this study was to look for an association between migraine and Helicobacter pylori infection. Following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) standards, we conducted the analysis and literature search using PubMed, Google Scholar and Cochrane databases. After applying the inclusion and exclusion criteria, the search technique produced a total of 10 articles including one cross-sectional study, two randomized controlled trials (RCTs), one cohort study, five case-control studies and one meta-analysis. Analysis of these studies revealed that there could be an association between Helicobacter pylori infection and migraine, especially in the Asian population. However, the mechanism by which the infection could possibly cause this extra-gastric disorder needs further research and analysis.