Calcitonin Gene-related Peptide Research Articles

Antimicrobial neuropeptides and their therapeutic potential in vertebrate brain infectious disease

The defense mechanisms of the vertebrate brain against infections are at the forefront of immunological studies. Unlike other body parts, the brain not only fends off pathogenic infections but also minimizes the risk of self-damage from immune cell induced inflammation. Some neuropeptides produced by either nerve or immune cells share remarkable similarities with antimicrobial peptides (AMPs) in terms of size, structure, amino acid composition, amphiphilicity, and net cationic charge. These similarities extend to a wide range of antibacterial activities demonstrated in vitro, effectively protecting nerve tissue from microbial threats. This review systematically examines 12 neuropeptides, pituitary adenylate cyclase-activating peptide (PACAP), vasoactive intestinal peptide (VIP), α-melanocyte stimulating hormone (α-MSH), orexin-B (ORXB), ghrelin, substance P (SP), adrenomedullin (AM), calcitonin-gene related peptide (CGRP), urocortin-II (UCN II), neuropeptide Y (NPY), NDA-1, and catestatin (CST), identified for their antimicrobial properties, summarizing their structural features, antimicrobial effectiveness, and action mechanisms. Importantly, the majority of these antimicrobial neuropeptides (9 out of 12) also possess significant anti-inflammatory properties, potentially playing a key role in preserving immune tolerance in various disorders. However, the connection between this anti-inflammatory property and the brain’s infection defense strategy has rarely been explored. Our review suggests that the combined antimicrobial and anti-inflammatory actions of neuropeptides could be integral to the brain’s defense strategy against pathogens, marking an exciting direction for future research.

MIGRAINE

Background Migraine is a prevalent neurological disorder characterized by chronic headaches, significantly impacting the global population. This comprehensive review aims to advance the understanding of migraine pathogenesis and treatment, focusing on molecular markers and novel therapeutic strategies. Material Molecular markers such as calcitonin gene-related peptide (CGRP) and their role in migraine development. Traditional medical treatments and emerging therapeutic strategies, including neuromodulation, are analyzed for their effectiveness and limitations. Clinical studies and imaging techniques are leveraged to identify key mechanisms and triggers in migraine pathology. Approximately 95% of people experience a headache at some point, with migraines being a significant contributor. Migraine is recognized by the World Health Organization as one of the top ten causes of disability globally, particularly affecting women. CGRP is identified as a crucial factor in migraine development. Inhibitors targeting CGRP have shown significant effectiveness in managing migraines. Other molecular markers, including proinflammatory cytokines and neurotransmitters, are discussed for their roles in pain transmission and migraine pathophysiology. Traditional treatments, such as triptans and NSAIDs, are evaluated alongside new therapies, including CGRP inhibitors and neuromodulation techniques. Neuromodulation, involving devices like external trigeminal nerve stimulators, shows promise in migraine management. Genetic markers associated with familial hemiplegic migraine (FHM) and common migraine forms are reviewed. Recent genome-wide association studies (GWAS) have identified several genetic variants linked to migraine susceptibility. Conclusion This presentation enhances the understanding of migraine pathogenesis and introduces novel therapeutic possibilities. By focusing on molecular markers like CGRP and exploring advanced treatment options, the study aims to improve migraine management and patient care. The findings underscore the need for continued research and innovation in migraine treatments to reduce the global burden of this debilitating condition.

Morphological aberration of corneal nerves in hyposecretory dry eye guinea pigs.

Dry eye, a common ocular surface disease associated with tear film instability and corneal impairment, is frequently accompanied by ocular discomfort and pain. Recent research has shown that corneal nerve dysfunction may play a role in certain pathologies of dry eye; however, the details remain unclear. To clarify the aberration in corneal nerves underlying sensory abnormalities, in addition to corneal impairment in dry eye, we examined the morphological alterations of nerve fibers in the corneas excised from guinea pigs with dry eye, where the lacrimal glands were surgically excised. Guinea pigs with dry eye exhibited reduced tear volume, increased spontaneous blink frequency, and corneal epithelial damage. Simultaneously, the subbasal nerve plexus in the cornea visualized using an anti-tubulin βIII antibody partially outgrew and became convoluted. The morphology of peptidergic nerves containing calcitonin gene-related peptide, which may function as a polymodal nociceptor, was also altered. These results indicate that guinea pigs with excised lacrimal glands can serve as useful tools for investigating the neuronal mechanisms underlying corneal pathology in dry eyes. Additionally, chronic tear deficiency may considerably alter nerve structure, including peptidergic nerves in the cornea, accompanied by epithelial damage and increased blink frequency.

Microneedle patches incorporating zinc-doped mesoporous silica nanoparticles loaded with betamethasone dipropionate for psoriasis treatment.

Treating psoriasis presents a major clinical challenge because of the limitations associated with traditional topical glucocorticoid therapy. This study introduced a drug delivery system utilizing zinc-doped mesoporous silica nanoparticle (Zn-MSN) and microneedle (MN), designed to enhance drug utilization for prolonged anti-inflammatory and anti-itch effects. The MN system facilitated the transdermal delivery of betamethasone dipropionate (BD), allowing its slow release. The BD@Zn-MSN-MN system promoted the polarization of macrophages towards the anti-inflammatory M2 phenotype, achieving superior anti-inflammatory effects compared to the clinically used BD cream. Additionally, this study demonstrated that BD@Zn-MSN-MN could further alleviate itching in psoriasis-afflicted mice by decreasing the excitability of the transient receptor potential vanilloid V1 (TRPV1) ion channel positive neurons and reducing the release of calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG). These findings offer new insights and effective therapeutic options for the future design of transdermal drug delivery for psoriasis.

Regulatory T cells require peripheral CCL2-CCR2 signaling to facilitate the resolution of medication overuse headache-related behavioral sensitization.

Medication overuse headache (MOH) is the most common secondary headache disorder, resulting from chronic and excessive use of medication to treat headaches, for example, sumatriptan. In a recent study, we have shown that the peripheral C-C motif ligand 2 (CCL2), C-C motif chemokine receptor 2 (CCR2) and calcitonin-gene-related peptide (CGRP) signaling pathways interact with each other and play critical roles in the development of chronic migraine-related behavioral and cellular sensitization. In the present study, we investigated whether CCL2-CCR2 and CGRP signaling pathways play a role in the development of sumatriptan overuse-induced sensitization, and whether they are involved in its resolution by the low-dose interleukin-2 (LD-IL-2) treatment. Mice received daily sumatriptan administration for 12 days. MOH-related behavioral sensitization was assessed by measuring changes of periorbital mechanical thresholds for 3 weeks. CCL2-CCR2 and CGRP signaling pathways were inhibited by targeted gene deletion or with an anti-CCL2 antibody. Ca2+-imaging was used to examine whether repetitive sumatriptan treatment enhances CGRP and pituitary adenylate cyclase-activating polypeptide (PACAP) signaling in trigeminal ganglion (TG) neurons. LD-IL-2 treatment was initiated after the establishment of sumatriptan-induced sensitization. Immunohistochemistry and flow cytometry analyses were used to examine whether CCL2-CCR2 signaling controls regulatory T (Treg) cell proliferation and/or trafficking. CCL2, CCR2 and CGRPα global KO mice exhibited robust sumatriptan-induced behavioral sensitization comparable to wild-type controls. Antibody neutralization of peripheral CCL2 did not affect sumatriptan-induced behaviors either. Repeated sumatriptan administration did not enhance the strength of CGRP or PACAP signaling in TG neurons. Nevertheless, LD-IL-2 treatment, which facilitated the resolution of sumatriptan-induced sensitization in wild-type and CGRPα KO mice, was completely ineffective in mice with compromised CCL2-CCR2 signaling. In CCL2 KO mice, we observed normal LD-IL-2-induced Treg expansion in peripheral blood, but the increase of Treg cells in dura and TG tissues was significantly reduced in LD-IL-2-treated CCL2 KO mice relative to wild-type controls. These results indicate that the endogenous CCL2-CCR2 and CGRP signaling pathways are not involved in sumatriptan-induced behavioral sensitization, suggesting that distinct molecular mechanisms underlie chronic migraine and MOH. On the other hand, peripheral CCL2-CCR2 signaling is required for LD-IL-2 to reverse chronic headache-related sensitization.

Electroacupuncture alleviates neuropathic pain in a rat model of CCD via suppressing P2X3 expression in dorsal root ganglia.

Sciatica and low back pain are prevalent clinical types of neuropathic pain that significantly impair patients' quality of life. Conventional therapies often lack effectiveness, making these conditions challenging to treat. Electroacupuncture (EA) is an effective physiotherapy for pain relief. Prior research has demonstrated a relationship between the frequency of neuropathic pain and the analgesic impact of EA stimulation. This work aimed to assess the analgesic effects of EA in a rat model of chronic compression of the dorsal root ganglion (CCD) and to understand the underlying processes. We established a rat CCD model to simulate sciatica and low back pain. EA was applied to rats with CCD at various frequencies (2Hz, 100Hz, and 2/100Hz). The paw withdrawal threshold (PWT) was measured to assess analgesic effects. Additionally, protein levels of the purinergic receptor P2X3 (P2X3) and the expression of nociceptive neuronal markers were analyzed using immunohistochemistry and western blot (WB) techniques. The study also measured levels of proinflammatory cytokines TNF-α and IL-1β in the dorsal root ganglion (DRG). The involvement of P2X3 receptors was further investigated using the P2X3 agonist, α,β-methylene ATP (α,β-meATP). CCD rats developed pronounced mechanical allodynia. EA stimulation at all tested frequencies produced analgesic effects, with 2/100Hz showing superior efficacy compared to 2Hz and 100Hz. The expression of P2X3 was increased in ipsilateral DRG of CCD model rats. P2X3 were co-labeled with isolectin B4 (IB4) and transient receptor potential vanilloid (TRPV1), indicating their role in nociception. 2/100Hz EA treatment significantly reduced mechanical allodynia and inhibited the overexpression of P2X3, TRPV1, substance P (SP), and calcitonin gene-related peptide (CGRP) in the ipsilateral DRG of CCD model rats. Additionally, EA reduced the levels of proinflammatory cytokines TNF-α and IL-1β in the ipsilateral DRG, indicating an anti-inflammatory effect. The P2X3 agonist α,β-me ATP attenuated the analgesic effect of 2/100Hz EA in CCD rats. The WB and immunofluorescence results consistently demonstrated P2X3 inhibition contributed to the analgesic effects of 2/100Hz EA on CCD-induced neuropathic pain. Our findings suggest that 2/100Hz EA alleviates neuropathic pain in rats by inhibiting the upregulation of P2X3 receptors in the ipsilateral DRG. This study backs up EA as a viable treatment option for sciatica and low back pain in clinical settings.

Dermal macrophages control tactile perception under physiological conditions via NGF signaling

We demonstrated previously that sorting nexin 25 (SNX25) in nerve-associated macrophages plays critical roles in pain sensation by regulating tissue NGF content under both physiological and neuropathic conditions. In the present study, we apply the SNX25–NGF paradigm to tactile perception by showing that Snx25+/- mice or macrophage-specific Snx25 conditional knock-out (mcKO) mice had weaker responses to tactile stimuli in normal conditions. Snx25 mcKO mice responded poorly to transcutaneous electrical stimuli at a frequency of 5 Hz (C fiber responses), but normally to stimuli at a frequency of 250 Hz (Aδ fiber responses) or of 2000 Hz (Aβ fiber responses). CX3CR1-positive dermal macrophages were frequently found near calcitonin gene–related peptide (CGRP)- positive nerves and, less frequently, tyrosine hydroxylase (TH)-positive nerves. We confirmed that the tissue content of NGF was lower in Snx25 mcKO mice than in wild-type mice, and in turn, dermal NGF injection restored tactile sensitivity in Snx25+/- mice and Snx25 mcKO mice to normal levels. These results indicate that CGRP-positive C-nociceptors (possibly also TH-positive C-LTMRs) associated dermal macrophages control tactile perception by producing NGF and secreting it into the dermis.

Comparative specialization of intrinsic cardiac neurons in humans, mice and pigs.

Intrinsic cardiac neurons (ICNs) play a crucial role in the proper functioning of the heart; yet a paucity of data pertaining to human ICNs exist. We took a multidisciplinary approach to complete a detailed cellular comparison of the structure and function of ICNs from mice, pigs and humans. Immunohistochemistry of whole and sectioned ganglia, transmission electron microscopy, intracellular microelectrode recording and dye filling for quantitative morphometry were used to define the neurophysiology, histochemistry and ultrastructure of these neurons across species. The densely packed, smaller ICNs of mouse lacked dendrites, formed axosomatic connections and had high synaptic efficacy constituting an obligatory synapse. At pig ICNs, a convergence of subthreshold cholinergic inputs onto extensive dendritic arbors supported greater summation and integration of synaptic input. Human ICNs were tonically firing, with synaptic stimulation evoking large suprathreshold EPSPs like mouse, and subthreshold potentials like pig. Ultrastructural examination of synaptic terminals revealed conserved architecture, yet small clear vesicles were larger in pigs and humans. The presence and localization of ganglionic neuropeptides was distinct, with abundant vasoactive intestinal polypeptide observed in human but not pig or mouse ganglia, and little substance P or calcitonin gene-related peptide in pig ganglia. Action potential waveforms were similar, but human ICNs had larger after-hyperpolarizations. Intrinsic excitability differed; 95% of human neurons were tonic, all pig neurons were phasic, and both phasic and tonic phenotypes were observed in mouse. In combination, this publicly accessible, multimodal atlas of ICNs from mice, pigs and humans identifies similarities and differences in the evolution of ICNs. KEY POINTS: Intrinsic cardiac neurons (ICNs) are essential to the regulation of cardiac function. We investigated the neurochemistry, morphology, ultrastructure, membrane physiology and synaptic transmission of ICNs from donated human hearts in parallel with identical studies of ICNs from mice and pigs to create a publicly accessible cellular atlas detailing the structure and function of these neurons across species. In addition to presenting foundational data on human ICNs, this comparative study identifies both conserved and derived attributes of these neurons within mammals. The findings have significant implications for understanding the regulation of cardiac autonomic function in humans and may greatly influence strategies for neuromodulation in conditions such as atrial fibrillation and heart failure.

Safety and Efficacy of Atogepant for the Preventive Treatment of Migraines in Adults: A Systematic Review and Meta-Analysis

Background: Migraine is a common neurological condition marked by unilateral recurrent pulsating headaches, often associated with systemic signs and symptoms. Recently, calcitonin gene-related peptide (CGRP) antagonists, including atogepant, an oral CGRP receptor antagonist, have emerged as effective and safe treatments. The current study sought to assess the efficacy and safety of atogepant for preventing episodic migraines in adults. Methods: A comprehensive search, following PRISMA guidelines, was conducted using PubMed, Web of Science, and Cochrane Library to identify randomized, double-blind, placebo-controlled trials published up to June 2024. Results: The studies included adult participants with episodic migraine treated with atogepant. The primary outcomes assessed were changes in mean monthly migraine days (MMDs) and monthly headache days (MHDs) over 12 weeks. Secondary outcomes included reduction in acute medication use, 50% responder rates, and adverse events. A meta-analysis using a random-effects model was performed to evaluate efficacy and safety. Six trials with 4569 participants were included. Atogepant significantly reduced mean monthly migraine days (MMDs) and monthly headache days (MHDs) compared to placebo at all doses (10 mg, 30 mg, 60 mg), with the 60 mg dose showing the greatest reduction (mean difference: −1.48 days, p < 0.001). Significant reductions in acute medication use and improved 50% responder rates were also observed for all doses. The safety profile of atogepant was favorable, with common adverse events being mild to moderate, such as constipation and nausea. There were no significant differences in serious adverse events between the atogepant and placebo groups. Conclusions: Atogepant is an effective and well-tolerated option for preventing episodic migraines, showing significant reductions in migraine frequency and acute medication use. However, further studies are necessary to assess its long-term safety and efficacy, especially at higher doses, and to investigate its potential role in personalized treatment strategies for migraine prevention.

Crowdsourcing Adverse Events Associated With Monoclonal Antibodies Targeting Calcitonin Gene-Related Peptide Signaling for Migraine Prevention: Natural Language Processing Analysis of Social Media.

Clinical trials demonstrate the efficacy and tolerability of medications targeting calcitonin gene-related peptide (CGRP) signaling for migraine prevention. However, these trials may not accurately reflect the real-world experiences of more diverse and heterogeneous patient populations, who often have higher disease burden and more comorbidities. Therefore, postmarketing safety surveillance is warranted. Regulatory organizations encourage marketing authorization holders to screen digital media for suspected adverse reactions, applying the same requirements as for spontaneous reports. Real-world data from social media platforms constitute a potential venue to capture diverse patient experiences and help detect treatment-related adverse events. However, while social media holds promise for this purpose, its use in pharmacovigilance is still in its early stages. Computational linguistics, which involves the automatic manipulation and quantitative analysis of oral or written language, offers a potential method for exploring this content. This study aims to characterize adverse events related to monoclonal antibodies targeting CGRP signaling on Reddit, a large online social media forum, by using computational linguistics. We examined differences in word frequencies from medication-related posts on the Reddit subforum r/Migraine over a 10-year period (2010-2020) using computational linguistics. The study had 2 phases: a validation phase and an application phase. In the validation phase, we compared posts about propranolol and topiramate, as well as posts about each medication against randomly selected posts, to identify known and expected adverse events. In the application phase, we analyzed posts discussing 2 monoclonal antibodies targeting CGRP signaling-erenumab and fremanezumab-to identify potential adverse events for these medications. From 22,467 Reddit r/Migraine posts, we extracted 402 (2%) propranolol posts, 1423 (6.33%) topiramate posts, 468 (2.08%) erenumab posts, and 73 (0.32%) fremanezumab posts. Comparing topiramate against propranolol identified several expected adverse events, for example, "appetite," "weight," "taste," "foggy," "forgetful," and "dizziness." Comparing erenumab against a random selection of terms identified "constipation" as a recurring keyword. Comparing erenumab against fremanezumab identified "constipation," "depression," "vomiting," and "muscle" as keywords. No adverse events were identified for fremanezumab. The validation phase of our study accurately identified common adverse events for oral migraine preventive medications. For example, typical adverse events such as "appetite" and "dizziness" were mentioned in posts about topiramate. When we applied this methodology to monoclonal antibodies targeting CGRP or its receptor-fremanezumab and erenumab, respectively-we found no definite adverse events for fremanezumab. However, notable flagged words for erenumab included "constipation," "depression," and "vomiting." In conclusion, computational linguistics applied to social media may help identify potential adverse events for novel therapeutics. While social media data show promise for pharmacovigilance, further work is needed to improve its reliability and usability.

The potential role of CGRP in synuclein-associated neurodegenerative disorders

In this hypothesis article, the potential clinicopathological associations of Calcitonin Gene Related Peptide (CGRP) with the development of synuclein-associated neurodegenerative disorders (SAND) are discussed. The presence of α-syn and CGRP in the CNS and the ENS and the intricate role of CGRP and its related pathways in inflammation, apoptosis, metabolism, neuromodulation, and brain-gut communication are analyzed. Since this hypothesis is confirmed, modulating CGRP-potential related pathways may lead to novel disease-modifying therapies.

Nociceptor-to-macrophage communication through CGRP/RAMP1 signaling drives endometriosis-associated pain and lesion growth in mice.

Endometriosis is a debilitating and painful gynecological inflammatory disease affecting up to 15% of women and transgender men. Current treatments are ineffective for a substantial proportion of patients, underscoring the need for additional therapies with long-term benefits. Nociceptors release neuropeptides, such as calcitonin gene-related peptide (CGRP), which are known to shape immunity through neuroimmune communication. Given the comorbidity between endometriosis and migraine and the integral role of immune cells and inflammation in endometriosis, we investigated the role of CGRP-mediated neuroimmune communication in endometriosis. Using samples from eight patients with endometriosis and a nonsurgical mouse model of the disease, we found that mouse and human endometriosis lesions contain both CGRP and its coreceptor, receptor activity modifying protein 1 (RAMP1). In mice, nociceptor ablation reduced pain, monocyte recruitment, and lesion size, suggesting that nociceptor activation and neuropeptide release contribute to endometriosis lesion growth and pain. Mechanistically, CGRP changed the phenotype of macrophages to a pro-endometriosis phenotype. CGRP-stimulated macrophages demonstrated impaired efferocytosis and supported increased endometrial cell growth in a RAMP1-dependent manner. Treatment of lesion-bearing mice with US Food and Drug Administration-approved drugs that block CGRP-RAMP1 signaling reduced mechanical hyperalgesia, spontaneous pain, and lesion size. Together, our data demonstrated the effectiveness and underlying cellular mechanisms of nonhormonal and nonopioid CGRP/RAMP1 blockade in a mouse model of endometriosis, suggesting that targeting this axis may lead to clinical benefit for patients with endometriosis.

Effects of multiple-dose administration of zavegepant nasal spray on the single-dose pharmacokinetics of ethinyl estradiol-levonorgestrel.

The potential for drug-drug interaction of multiple-dose intranasal zavegepant on the single-dose oral contraceptive ethinyl estradiol and levonorgestrel (EE-LNG) was evaluated. Zavegepant (as a nasal spray) is a calcitonin gene-related peptide receptor antagonist approved in the United States for treatment of acute migraine in adults. This single-center, Phase 1, open-label, fixed-sequence study included healthy, nonsmoking females (18-45 years old). In treatment Period 1, a single oral dose of EE-LNG 0.02-0.10 mg was administered on Day 1. In treatment Period 2, intranasal zavegepant (20 mg daily; 10 mg per nostril separated by 1 h) was administered on Days 1-5; 1 oral dose of EE-LNG 0.02-0.10 mg was administered immediately after first 10 mg intranasal zavegepant dose on Day 2. Blood samples for EE-LNG concentrations were collected on Day 1, treatment Period 1, and Day 2, treatment Period 2, and zavegepant concentrations on Day 2, treatment Period 2. Noncompartmental pharmacokinetic parameters included maximum observed concentration (Cmax), area under the concentration-time curve (AUC) from Time 0 to last non-zero concentration (AUC0-t), and AUC from Time 0 to infinity (AUC0-inf). The safety and pharmacokinetic sample sizes were 26 and 23, respectively. Statistical comparisons of pharmacokinetic exposure parameters after co-administration of zavegepant and EE-LNG versus EE-LNG alone showed small, but statistically insignificant, changes in either EE or LNG exposure. EE comparison ratios (90% confidence intervals [CIs]) were 109.9% (105.3%, 114.8%) for AUC0-inf and 110.2% (104.6%, 116.1%) for Cmax. LNG comparison ratios (90% CIs) were 107.0% (100.2%, 114.3%) for AUC0-inf and 108.8% (99.9%, 118.4%) for Cmax. Frequently reported treatment-emergent adverse events included dysgeusia (n = 25, 96%), throat irritation (n = 11, 42%), headache (n = 10, 39%), nasal discomfort (n = 7, 27%), pharyngeal paresthesia (n = 5, 19%), and nausea (n = 4, 15%). Co-administration of zavegepant nasal spray with a single dose of an oral contraceptive resulted in no clinically meaningful changes (<12% increase) in EE-LNG exposure.

The significant relief of Ayurvedic management for Severe Migraine Episodes: A Case Study

Migraine is a common and debilitating neurological disorder marked by recurrent, severe headaches that are frequently accompanied by nausea, sensitivity to light, and sensitivity to sound. These migraine attacks can profoundly disrupt daily life and overall well-being. The development of migraines is influenced by a complex interaction of genetic, environmental, and neurovascular factors. Recent studies have enhanced our understanding of migraine mechanisms, highlighting the role of cortical spreading depression and neuropeptides such as calcitonin gene-related peptide (CGRP). Managing migraines effectively often involves a combination of lifestyle changes, medications, and, in some cases, alternative treatments. In Ayurveda, migraine is compared with Ardhavbhedaka (half-headache) which belongs to the Shiroroga. Ardhavbhedaka is primarily associated with imbalances in the Pitta and Vata Doshas due to etiological factors such as eating dry food, eating immediately after a meal, exposure to air from the east, dew, excessive sexual activity, preventing the natural urge of bodily waste, excessive physical labor, develop Ardhavbhedaka.

Current and Novel Therapies for Cluster Headache: A Narrative Review.

Cluster headache (CH) is an excruciating and debilitating primary headache disorder. The prevalence is up to 1.3%, and the typical onset is around age 30. Often misdiagnosed as migraine, particularly in children, the diagnosis rate of CH has been increasing among women. CH is characterized by intense unilateral pain and autonomic symptoms, significantly impacting patients' quality of life, mental health, and productivity.Genetic associations suggest a familial risk for developing CH, with lifestyle factors also potentially playing a role. The pathophysiology involves alterations in both central and peripheral nervous system, with the hypothalamus, trigeminocervical complex, and neuropeptides such as calcitonin gene-related peptide (CGRP) being implicated.Nonpharmacological treatments focus on patient education and lifestyle modifications, while pharmacological treatments include acute therapies such as oxygen and subcutaneous or nasal sumatriptan, as well as preventive therapies like verapamil, lithium, and CGRP monoclonal antibodies. Transitional options include oral corticosteroids and greater occipital nerve injections. Emerging interventional procedures offer new avenues for managing refractory cases. Noninvasive vagal nerve stimulation and occipital nerve stimulation show promise for both acute and preventive treatment. Careful consideration of safety profiles is crucial in specific populations such as pregnant patients and children.Current treatments still leave patients highly burdened by limited efficacy and side effects. Future research continues to explore novel pharmacological targets, interventional procedures, and the potential role of psychedelics in CH management. Comprehensive, multifaceted treatment strategies are essential to improve the daily functioning and quality of life for individuals with CH.

Population pharmacokinetic modeling of zavegepant, a calcitonin gene-related peptide receptor antagonist, in healthy adults and patients with migraine.

Zavegepant (ZAVZPRET™) is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist available for acute treatment of migraine in adults. A population pharmacokinetic analysis was performed to describe zavegepant plasma concentration-time course, characterize bioavailability, and identify covariates affecting zavegepant exposure. The model was developed and validated using data from 10 phase I clinical studies, wherein zavegepant was administered intravenously, intranasally, or orally to healthy adults and patients with migraine. Plasma concentration-time data were analyzed using nonlinear mixed-effects modeling. A three-compartment model with first-order elimination from the central compartment, and sequential zero- and first-order absorption best described the observed plasma concentration-time course of zavegepant. Bioavailability was 5.1% and 0.65% for intranasal and oral treatment, respectively; absorption rate constants were 5.8 and 0.8 h-1, respectively. Body weight-based empirical allometric scaling was applied using standard exponents (0.75 for clearance and 1 for volume of distribution). Age (range 18-71 years), race, ethnicity, sex, renal function, and co-administration of oral contraceptives or sumatriptan did not significantly change zavegepant pharmacokinetics. Moderate hepatic impairment (Child-Pugh score 7-9) or co-administration of rifampin decreased elimination clearance of oral zavegepant by ~40%. The zavegepant population pharmacokinetic model adequately characterized zavegepant concentration-time profiles, the bioavailability of intranasal and oral zavegepant, as well as the effect of intrinsic and extrinsic factors on zavegepant pharmacokinetics.

Transcriptomics changes of calcitonin gene-related peptide in mitigating lipopolysaccharide-induced septic cardiomyopathy

Septic cardiomyopathy (SCM), a complication initiated by sepsis, presents a significant clinical challenge, leading to increased mortality rates. However, the mechanisms of SCM have not been fully uncovered. Our study involved analyzing RNA sequencing (RNA-seq) data from rat heart tissue, along with utilizing molecular docking and molecular dynamics (MD) simulations, to discover key targets and potential pharmacological actions of the calcitonin gene-related peptide (CGRP) against SCM. A lipopolysaccharide-induced SCM model was established in rats (LPS 10 mg/kg, intraperitoneal (i.p.)). Thereafter, the myocardial tissues from the three groups of rats (Ctrl group, LPS group, and CGRP group) (n = 5) were extracted and underwent RNA-seq, followed by bioinformatics analyses. The qPCR-validated hub targets potentially interacting with CGRP were identified. Following this, homology modeling was utilized to obtain the 3D structure of hub targets, and molecular docking was conducted to evaluate the interaction between CGRP and hub targets. MD simulations (300 ns) were performed to confirm the findings further. Our findings demonstrated that CGRP significantly lowered mortality in SCM rats. 633 DEGs were affected by LPS, contrasted with the Ctrl group. 96 DEGs were affected by CGRP compared to the LPS group. In total, ten fully annotated CGRP-triggered hub genes were obtained. The molecular docking and MD simulations indicate that the relationship between CGRP and eight hub genes is extremely strong. This research offers a thorough examination of the possible objectives and fundamental molecular processes of CGRP in combating SCM, laying the groundwork for investigating the potential protective mechanisms of CGRP against SCM.

Serum biomarkers in neuroendocrine cell hyperplasia of infancy.

Neuroendocrine cell hyperplasia of infancy (NEHI) is a form of childhood interstitial lung disease of unknown origin associated with hyperplasia of pulmonary neuroendocrine cells (PNECs). Diagnosis is based on the characteristic clinical picture and typical radiological imaging, and, in some cases, on lung biopsies. To date, no biochemical indicators of the disease have been identified. We aimed to determine biomarkers that could be useful in the management of children diagnosed with NEHI. Patients with NEHI and healthy children were enrolled. Concentrations of serum biomarkers secreted by PNECs (calcitonin gene-related peptide and gastrin-releasing peptide) and biomarkers of the destruction of alveolar capillary membrane (surfactant proteins A and D [SP-A and SP-D]; glycoprotein Krebs von den Lungen-6 [KL-6]; metalloproteinases 7 and 9 [MMP-7 and MMP-9]; tissue inhibitor of metalloprotease 1) were measured. Fifty-two children with NEHI and 23 healthy children were included in the study. The median age of children with NEHI was 3.9 years. There were no differences in serum levels of biomarkers secreted by PNECs between groups. KL-6 levels were significantly higher in children with NEHI than in healthy ones (median 119.6 vs. 92.1 U/mL, p = 0.003); however, concentrations of KL-6 were low in both groups. No significant differences existed between groups for the remaining biomarkers associated with the destruction of the alveolar-capillary membrane. Measurement of serum biomarkers released by PNECs and those associated with the destruction of the alveolar-capillary membrane does not appear to be useful in the management of children with NEHI.

Neuroplasticity and neuroimmune interactions in fatal asthma.

Alteration of airway neuronal function and density and bidirectional interaction between immune cells and sensory peripheral nerves have been proposed to trigger and perpetuate inflammation that contribute to asthma severity. To date, few studies analysed neuroplasticity and neuroinflammation in tissue of asthmatic individuals. We hypothesized that the presence of these phenomena would be a pathological feature in fatal asthma. We have quantified the expression of the pan-neuronal marker PGP9.5 and the neuronal sensory-derived neuropeptide calcitonin gene-related peptide (CGRP) in the large airways of 12 individuals deceased due to an asthma attack and compared to 10 control lung samples. The proximity between nerve bundles to eosinophils, mast cells and CADM1+ cells was also quantified. We have additionally developed a hPSC-derived sensory neuron/mast cell co-culture model, from where mast cells were purified and differences in gene expression profile assessed. Fatal asthma patients presented a higher PGP9.5 and CGRP positive area in the airways, indicating sensory neuroplasticity. Eosinophils, mast cells and CADM1+ cells were observed in close contact or touching the airway nerve bundles, and this was found to be statistically higher in fatal asthma samples. Invitro co-culture model showed that human mast cells adhere to sensory neurons and develop a distinct gene expression profile characterized by upregulated expression of genes related to heterophilic adhesion, activation and differentiation markers, such as CADM4, PTGS2, C-KIT, GATA2, HDC, CPA3, ATXN1 and VCAM1. Our results support a significant role for neuroplasticity and neuroimmune interactions in fatal asthma, that could be implicated in the severity of the fatal attack. Accordingly, the presence of physical neuron and mast cell interaction leads to differential gene expression profile in the later cell type.

Novel Calcitonin Gene-Related Peptide (CGRP) Interfering Migraine Therapies and Stroke-A Review.

Migraine and stroke are neurological disorders with significant global prevalence and impact. Recent advances in migraine therapy have focused on the calcitonin gene-related peptide (CGRP) pathway. This review examines the shared pathomechanisms between migraine and stroke, with emphasis on the role of CGRP. We analyze the current literature on CGRP's functions in cerebrovascular regulation, edema formation, neuroinflammation, and neuroprotection. CGRP acts as a potent vasodilator and plays a crucial role in trigeminovascular activation during migraine attacks. In stroke, CGRP has demonstrated neuroprotective effects by improving collateral circulation and reducing ischemia-reperfusion injury. Concerns have been raised about the potential impact of CGRP inhibitors on stroke risk and outcomes. Studies in animals suggest that CGRP receptor antagonists may worsen cerebral ischemia by impairing collateral flow. We discuss the implications of these findings for the use of CGRP-targeting therapies in migraine patients, especially those at increased risk of stroke. Additionally, we explore the complex interplay between CGRP, endothelial function, and platelet activity in both conditions. This review highlights the need for further research to elucidate the long-term cerebrovascular safety of CGRP pathway inhibitors and to identify potential subgroups of migraine patients who may be at higher risk of adverse cerebrovascular events with these novel therapies.