Shared and independent roles of CGRP and PACAP in migraine pathophysiology

The Journal of Headache and Pain, Journal Year: 2023, Volume and Issue: 24(1)

Published: April 3, 2023

The neuropeptides calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have emerged as mediators of migraine pathogenesis. Both are vasodilatory peptides that can cause migraine-like attacks when infused into people symptoms injected rodents. In this narrative review, we compare the similarities differences between in both their clinical preclinical actions. A notable difference is PACAP, but not CGRP, causes premonitory-like patients. found distinct, overlapping areas relevant to migraine, most notably with prevalence CGRP trigeminal ganglia PACAP sphenopalatine ganglia. rodents, two share activities, including vasodilation, neurogenic inflammation, nociception. Most strikingly, similar rodents manifested light aversion tactile allodynia. Yet, appear act by independent mechanisms possibly distinct intracellular signaling pathways. complexity these pathways magnified existence multiple receptors may contribute Based on differences, suggest its provide a rich set targets complement augment current CGRP-based therapeutics.

Language: Английский

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The Interplay Between Gut Microbiota, Adipose Tissue, and Migraine: A Narrative Review

Nutrients, Journal Year: 2025, Volume and Issue: 17(2), P. 337 - 337

Published: Jan. 18, 2025

Background: Migraine, a prevalent neurovascular disorder, affects millions globally and is associated with significant morbidity. Emerging evidence suggests crucial role of the gut microbiota adipose tissue in modulation migraine pathophysiology, particularly through mechanisms involving neuroinflammation metabolic regulation. Material Methods: A narrative review literature from 2000 to 2024 was conducted using PubMed database. Studies addressing relationships between microbiota, tissue, migraine—including dietary interventions their impact—were analyzed. Results: The findings highlight bidirectional gut–brain axis, influencing via metabolites such as short-chain fatty acids (SCFAs). Obesity exacerbates severity chronic inflammation dysregulation adipocytokines like leptin adiponectin. Dietary patterns, low glycemic index diets Mediterranean diets, use prebiotics, probiotics, postbiotics show potential management. Conclusions: This underscores need for integrative approaches targeting microbiota–gut–brain axis therapy. Future studies should explore longitudinal effects personalized optimize outcomes.

Language: Английский

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Mode and site of action of therapies targeting CGRP signaling

The Journal of Headache and Pain, Journal Year: 2023, Volume and Issue: 24(1)

Published: Sept. 10, 2023

Targeting CGRP has proved to be efficacious, tolerable, and safe treat migraine; however, many patients with migraine do not benefit from drugs that antagonize the CGRPergic system. Therefore, this review focuses on summarizing general pharmacology of different types treatments currently available, which target directly or indirectly receptor its ligand. Moreover, latest evidence regarding selectivity site action small molecule antagonists (gepants) monoclonal antibodies is critically discussed. Finally, reasons behind non-responders anti-CGRP rationale for combining and/or switching between these therapies are addressed.

Language: Английский

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Future targets for migraine treatment beyond CGRP

The Journal of Headache and Pain, Journal Year: 2023, Volume and Issue: 24(1)

Published: June 27, 2023

Abstract Background Migraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation release of calcitonin gene-related peptide (CGRP) play pivotal role in the pathogenesis migraine. This knowledge has led to development CGRP(-receptor) therapies. Yet, substantial proportion patients do not respond these treatments. Therefore, alternative targets for future therapies are warranted. The current narrative review provides comprehensive overview pathophysiological possible non-CGRP Findings We covered metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal (VIP), amylin, adrenomedullin), intracellular (nitric oxide (NO), phosphodiesterase-3 (PDE3) -5 (PDE5)), ion channels (potassium, calcium, transient receptor potential (TRP), acid-sensing (ASIC)). majority were able induce migraine-like attacks, except (i) calcium channels, as it yet directly target elucidate their precise involvement migraine; (ii) TRP which can non-migraine headache; (iii) ASICs, inducing migraine attacks been investigated thus far. Drugs that its exist PACAP, NO, potassium, TRP, ASIC channels. No selective drugs other targets, however, some existing (migraine) treatments appear indirectly antagonize responses adrenomedullin, against potassium only PAC 1 antibody have tested treatment, albeit with ambiguous results. Conclusion While research on drug efficacious therapies, human provocation studies using provided valuable insight into underlying mechanisms headaches auras. Further needed non-responders targeted ultimate aim pave way towards headache-free all patients.

Language: Английский

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Research Progress in Calcitonin Gene-Related Peptide and Bone Repair

Biomolecules, Journal Year: 2023, Volume and Issue: 13(5), P. 838 - 838

Published: May 15, 2023

Calcitonin gene-related peptide (CGRP) has 37 amino acids. Initially, CGRP had vasodilatory and nociceptive effects. As research progressed, evidence revealed that the peripheral nervous system is closely associated with bone metabolism, osteogenesis, remodeling. Thus, bridge between skeletal muscle system. can promote inhibit resorption, vascular growth, regulate immune microenvironment. The G protein-coupled pathway vital for its effects, while MAPK, Hippo, NF-κB, other pathways have signal crosstalk, affecting cell proliferation differentiation. current review provides a detailed description of repair effects CGRP, subjected to several therapeutic studies, such as drug injection, gene editing, novel materials.

Language: Английский

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Navigating the Neurobiology of Migraine: From Pathways to Potential Therapies

Cells, Journal Year: 2024, Volume and Issue: 13(13), P. 1098 - 1098

Published: June 25, 2024

Migraine is a debilitating neurological disorder characterized by recurring episodes of throbbing headaches that are frequently accompanied sensory disturbances, nausea, and sensitivity to light sound [...]

Language: Английский

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The neuroimmune CGRP–RAMP1 axis tunes cutaneous adaptive immunity to the microbiota

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(11)

Published: March 7, 2024

The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. roles of sensory neurons in controlling the adaptive system, more specifically immunity to microbiota, however, remain elusive. Here, we identified a mechanism for direct neuroimmune communication between commensal-specific T lymphocytes mediated by neuropeptide calcitonin gene–related peptide (CGRP) skin. Intravital imaging revealed that are close proximity cutaneous nerve fibers vivo. Correspondingly, observed upregulation receptor CGRP, RAMP1, CD8 + induced skin commensal colonization. CGRP–RAMP1 signaling axis functions constrain Type 17 responses moderate activation status microbiota-reactive homeostasis. As such, modulation shapes overall epithelium, thereby impacting outcome insults such as wounding. ability control microbiota via underscores various layers regulation multisystem coordination required optimal cell steady state pathology.

Language: Английский

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Involvement of neuronal factors in tumor angiogenesis and the shaping of the cancer microenvironment

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 5, 2024

Emerging evidence suggests that nerves within the tumor microenvironment play a crucial role in regulating angiogenesis. Neurotransmitters and neuropeptides released by can interact with nearby blood vessels cells, influencing their behavior modulating angiogenic response. Moreover, nerve-derived signals may activate signaling pathways enhance production of pro-angiogenic factors microenvironment, further supporting vessel growth around tumors. The intricate network communication between neural constituents vascular system accentuates potential therapeutically targeting neural-mediated as an innovative strategy to modulate angiogenesis and, consequently, neoplastic proliferation. Hereby, we review studies evaluate precise molecular interplay clinical ramifications manipulating elements for purpose anti-angiogenic therapeutics scope cancer treatment.

Language: Английский

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Untangling the mess of CGRP levels as a migraine biomarker: an in-depth literature review and analysis of our experimental experience

The Journal of Headache and Pain, Journal Year: 2024, Volume and Issue: 25(1)

Published: April 29, 2024

Abstract Background Calcitonin gene-related peptide (CGRP) is the most promising candidate to become first migraine biomarker. However, literature shows clashing results and suggests a methodological source for such discrepancies. We aimed investigate some of these factors evaluate actual role CGRP as Methods Previous experimental part, we performed review articles measuring in patients. Using our 399 bio-bank sera samples, series experiments test validity different ELISA kits employed, time sample processing, long-term storage, sampling rest or after moderate exercise. Analysis in-house data was analyse average levels effect sex age. Results Literature high variability terms study design, determination methods, conclusions obtained by studies including determinations measurements depends on method specific kit also isoform detected, showing completely ranges concentrations. Alpha-CGRP beta-CGRP had median with IQR 37.5 (28.2–54.4) 4.6 (2.4–6.4)pg/mL, respectively. content preserved serum within 24 hours when samples are stored at 4°C clotting immediate centrifugation. Storages -80°C more than 6 months result decrease levels. Moderate exercise prior blood extraction does not modulate concentration peptide. Age positively correlates men have higher alpha-CGRP women. Conclusions present valuable information serum. suitability should be tested experiments. Alpha analysed separately they can show behaviours even same condition. Samples processed 24-h window if been kept before assayed. Patients do need unless high-endurance For comparative studies, age accounted parameters impact Graphical

Language: Английский

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Understanding the Biological Relationship between Migraine and Depression

Biomolecules, Journal Year: 2024, Volume and Issue: 14(2), P. 163 - 163

Published: Jan. 30, 2024

Migraine is a highly prevalent neurological disorder. Among the risk factors identified, psychiatric comorbidities, such as depression, seem to play an important role in its onset and clinical course. Patients with migraine are 2.5 times more likely develop depressive disorder; this becomes even higher patients suffering from chronic or aura. This relationship bidirectional, since depression also predicts earlier/worse of migraine, increasing chronicity and, consequently, requiring healthcare expenditure compared alone. All these data suggest that may share overlapping biological mechanisms. Herein, review explores topic further detail: firstly, by introducing common epidemiological for comorbidity; secondly, focusing on providing cumulative evidence aspects, particular emphasis serotoninergic system, neuropeptides calcitonin-gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), substance P, neuropeptide Y orexins, sexual hormones, immune system; lastly, remarking future challenges required elucidate etiopathological mechanisms updated information regarding new key targets pharmacological treatment entities.

Language: Английский

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