Calcitonin Gene-related Peptide Research Articles

The Role of Purinergic Mechanisms in the Excitability of Trigeminal Afferents of Rats with Prenatal Hyperhomocysteinemia

Elevated levels of homocysteine in the blood plasma (hyperhomocysteinemia, HHCY) positively correlate with migraine symptoms in patients. Experimental studies show a higher sensitivity of rats with prenatal HHCY (pHHCY) to migraine symptoms like allodynia, photophobia, anxiety, and a higher excitability of meningeal trigeminal afferents. In the present study, the roles of purinergic mechanisms in the homocysteine-induced hyperexcitability of the trigeminal ganglion (TG) system using electrophysiological recordings from the trigeminal nerve, Ca2+ imaging of cells isolated from TG, and mast cell staining in meninges were investigated. Experiments were performed using rats with pHHCY born from females fed with a high-methionine-containing diet before and during pregnancy. Firstly, we found that lower concentrations of 4-aminopyridine, a K+-channel blocker, were able to induce an increase in the nociceptive activity of trigeminal afferents, supporting the hypothesis of the higher excitability of the trigeminal nerve of rats with pHHCY. Trigeminal afferents of rats with pHHCY were more sensitive to the exogenous application of the nonspecific agonist of purinergic ATP receptors. In neurons and satellite glial cells of TG of rats with pHHCY ATP, ADP (an agonist of metabotropic P2Y receptors) and BzATP (an agonist of ionotropic P2X with especially high potency for the P2X7 receptor) induced larger Ca2+ transients. The incubation of TG neurons in homocysteine for 24 h increased the ratio of neurons responding simultaneously to ATP and capsaicin. Moreover, rats with pHHCY exhibit a higher rate of degranulation of mast cells and increased response to the agonist of the P2X7 receptor BzATP application. In addition, higher levels of calcitonin gene-related peptide (CGRP) were found in rats with pHHCY. Our results suggest that chronic elevated levels of homocysteine induce the upregulation of ionotropic or metabotropic ATP receptors in neurons, satellite glial cells, and mast cells, which further provide inflammatory conditions and the sensitization of peripheral afferents underlying pain.

Ubrogepant, erenumab, and eptinezumab antagonize positive inotropic effects of the calcitonin gene-related peptide in the isolated human atrium.

The calcitonin gene-related peptide (CGRP) is an endogenous peptide that is known to be involved in the development of a migraine. CGRP is also present in the human heart, acts via CGRP receptors, and has been shown to increase the force of contraction (FOC) in isolated, electrically driven human atrial preparations (HAP) from adult patients obtained during open-heart surgery. Here, the hypothesis was tested that the positive inotropic effect (PIE) of CGRP could be attenuated by three anti-migraine drugs, namely ubrogepant, erenumab (both CGRP receptor antagonists), and eptinezumab (a CGRP antagonist). CGRP, cumulatively applied at concentrations ranging from 1 to 100 nM, increased the FOC. In the presence of cilostamide, an inhibitor of phosphodiesterase III, CGRP was more potent and effective than in the absence of cilostamide. Furthermore, when 100 nM CGRP was administered, subsequent application of ubrogepant (1 nM), erenumab (2 nM), and eptinezumab (6 nM) led to a reduction of FOC in HAP. In a more effective way, 1 µM carbachol and 1 µM (-)-N6-phenylisopropyladenosine (PIA) attenuated the PIE of CGRP in the presence of cilostamide. Conversely, when we applied first ubrogepant (1 nM), erenumab (2 nM), or eptinezumab (6 nM), then, this pre-incubation attenuated the PIE in HAP of cumulatively applied CGRP compared to CGRP given alone. We conclude that ubrogepant, erenumab, and eptinezumab are functional antagonists of CGRP in HAP at therapeutic concentrations of these anti-migraine drugs. Further investigation is necessary to determine whether this reduction in FOC is beneficial or detrimental for migraine patients.

A single blinded randomized controlled trial assessing the effect of photobiomodulation therapy on neuron specific biomarkers in type II diabetes mellitus patients with peripheral neuropathy.

A single blinded randomized controlled trial assessing the effect of photobiomodulation therapy on neuron specific biomarkers in type II diabetes mellitus patients with peripheral neuropathy.

Activation of central and peripheral transient receptor potential melastatin 8 increases susceptibility to spreading depolarization and facilitates trigeminal neuroinflammation

BackgroundTransient receptor potential melastatin 8 (TRPM8), a gene encoding a nonselective cation channel responsive to cold stimuli, has been implicated in migraine susceptibility. Despite this association, the role of TRPM8 to migraine pathogenesis remains elusive. This study aims to elucidate the potential role of TRPM8 in migraine pathophysiology.MethodsTRPM8 expression in the cortex and primary trigeminal ganglion (TG) cells was analyzed via immunostaining. The central role of TRPM8 was assessed using a spreading depolarization (SD) model, where intracerebroventricular injections or topical applications of TRPM8 agonists and antagonists were administered to rats to investigate their effects on KCl-evoked SD and SD-induced cortical inflammation. The peripheral role of TRPM8 in migraine was evaluated using primary cultures of rat TG cells by analyzing the effects of TRPM8 activation on calcitonin gene-related peptide (CGRP) expression, release, and trigeminal neuroinflammation.ResultsTRPM8 was homogeneously distributed in the cerebral cortex, predominantly co-localizing with cortical neurons. Activation of cortical TRPM8 increased the frequency of KCl-evoked SD and exacerbated SD-induced cortical inflammation. Interestingly. Interestingly, inhibition of cerebral TRPM8 had negligible effects. In TG primary cultures, TRPM8 activation upregulated CGRP expression and release and induced cyclooxygenase-2 (Cox2) upregulation via a calmodulin kinase II (CaMKII)-dependent mechanism.ConclusionsTRPM8 activation increased susceptibility to SD and facilitated the effects of CGRP and trigeminal neuroinflammation, implicating that TRPM8 may contribute to migraine pathophysiology through central and peripheral mechanisms.Graphical abstract

UPLC-Q-TOF-MS/MS and NMR studies for the structural characterization of degradation impurities of rimegepant.

Rimegepant is a type of medication classified as a calcitonin gene-related peptide (CGRP) receptor antagonist, used to treat migraines. The present research focused to identify and characterize its degradation products using the liquid chromatography-high-resolution mass spectrometry (Q-TOF-HRMS) and nuclear magnetic resonance spectroscopy (NMR). The degradation profile of rimegepant was evaluated using forced degradation studies, which included exposure to hydrolysis, oxidation, photolysis, and thermal conditions. The drug degraded under hydrolytic and oxidative conditions whereas it was found to be stable under photolytic and thermal conditions. An Acquity CSH C18 column (2.1 × 100mm; 1.7µm) was used to separate the analytes using a mobile phase of 0.1% formic acid in water and 0.1% formic acid in acetonitrile eluting in gradient mode at a flow rate of 0.3mL/min. The degradation products were separated and identified using the mass fragmentation and accurate mass information obtained from LC-MS. A preparative HPLC was used to isolate the major degradation products for structural identification through 1D and 2D NMR studies. According to ICH Q2 (R1) guidelines, the developed UHPLC-PDA method was validated for its accuracy, precision, linearity, and specificity.

Calcitonin Gene-Related Peptide Levels in Children and Adolescents With Primary Headache Disorder.

ObjectiveThis study aimed to investigate calcitonin gene-related peptide (CGRP) levels in children and adolescents with primary headache.MethodsAll patients underwent blood sampling regardless of their headache state (ictal or interictal) on the day of examination. The patients were grouped based on their headache diagnosis (migraine, tension-type headache, or mixed).ResultsNinety-two patients aged 5-18 years were included (29 diagnosed with migraine and 31 with tension-type headache). In the comparisons between the patients with migraine and the patients with tension-type headache, interictal CGRP levels in blood from the cubital vein showed no significant difference. Ictal samples were collected in the tension-type headache group only, and no significant difference was observed between the ictal and interictal phases. Variables such as headache diagnosis, sex, age, family history with primary headache, headache frequency, time since last headache, medication usage, and body mass index did not significantly influence CGRP levels.ConclusionNo significant difference in interictal CGRP levels between patients with migraine and patients with tension-type headache were found. In patients with tension-type headache, there were no significant differences between CGRP levels in the ictal and interictal state. We were not able to draw conclusions about differences in ictal levels of CGRP in patients with migraine compared with patients with tension-type headache, or in differences between ictal and interictal levels in patients with migraine. Future studies should aim to replicate these results in a larger study cohort.

Raised intracranial pressure alters cortical vascular function and cephalic allodynia.

Raised intracranial pressure (ICP) is associated with altered cerebral hemodynamics and cephalic pain. The relationship between the algetic response and cortical neurovascular changes in raised ICP is unclear. This study aimed to evaluate this relationship and determine if lowering ICP (using a glucagon like peptide-1 receptor agonist) could ameliorate the algetic response. We also sought to explore the role of calcitonin gene-related peptide in cephalic pain driven by raised ICP by inhibiting calcitonin gene-related peptide signalling and quantifying changes in the algetic response. In a rat model of raised ICP, created by intracisternal kaolin injection, mechanical thresholds were measured alongside steady-state potential and cerebral blood flow responses to spreading depolarisation. Nuclear magnetic resonance spectroscopy evaluated energetic substrates in animals with raised ICP ex-vivo. Glucagon like peptide-1 receptor agonist exenatide and calcitonin gene-related peptide receptor antagonist olcegepant were injected daily and measurements were repeated. Kaolin increased ICP [median (range) 15.96mmHg (8.97) n = 8] versus controls [6.02mmHg (1.79) n = 6 p = 0.0007]. Animals with raised ICP exhibited reduced mechanical thresholds (mean (SD) hind paw baseline: 5.78g (2.81), day 7: 3.34g (2.22) p < 0.001, periorbital baseline: 6.13g (2.07), day 7: 2.35g (1.91) n = 12 p < 0.001). Depolarisation and repolarisation durations were increased [depolarisation raised ICP: 108.81s (222.12) n = 11, controls: 37.54s (108.38) n = 9 p = 0.038, repolarisation raised ICP: 1824.26s (3499.54) n = 12, controls: 86.96s (140.05) n = 9 p<0.0001]. CBF change was also reduced (85.55% (30.84) n = 9) compared to controls (217.64% (37.70) n = 8 p < 0.0001). Substrates for cellular energetics (ADP, ATP and NAD+) were depleted in rodent brains with raised ICP (p = 0.009, p = 0.018, p = 0.011 respectively). Exenatide significantly lowered ICP (exenatide: 9.74mmHg (6.09) n = 19, vehicle: 18.27mmHg (6.67) n = 16 p = 0.004) and rescued changes in mechanical withdrawal. Exenatide recovered characteristic spreading depolarisation responses (depolarisation duration exenatide: 56.46s (25.10) n = 7, vehicle: 115.98s (58.80) n = 6 p = 0.033) [repolarisation duration exenatide: 177.55s (562.88) n = 7, vehicle: 800.85s (1988.67) n = 6 p = 0.002]. In the setting of raised ICP olcegepant prevented changes in periorbital mechanical thresholds. We conclude that raised ICP disrupted the cortical neurovascular responses, reduced algetic thresholds and depleted crucial energetic substrates. Exenatide reduced ICP, improving algetic thresholds and cortical neurovascular changes. Importantly, olcegepant alleviated the cerebral algesia, suggesting calcitonin gene-related peptide's role in driving pain responses in elevated ICP. These studies support the rationale that reducing ICP improves cephalic pain in conditions of raised ICP. Furthermore, the data suggests that headache pain, in diseases associated with raised ICP, could be therapeutically ameliorated though blockade of the calcitonin gene-related peptide pathway.

NEUROCOSMETICS: AN EXTENSIVE OVERVIEW

The review on this fast-evolving field of neuro cosmetics, at the intersection of neuroscience and cosmetic science, has interestingly led to innovative skincare treatment approaches. The paper progresses from a basic discovery of neurogenic inflammation made by substance P in 1996 the more recent skin-brain axis of 2015 to its applications. The review focuses on neurotransmitters such as acetylcholine and serotonin, neuropeptides such as substance P and Calcitonin Gene-Related Peptide (CGRP), and the neuroendocrine cells, Merkel, and Langerhans cells, to achieve skin homeostasis, inflammation control, and aging. The article looks at neurocosmetic applications such as anti-aging, skin barrier enhancement, and pigmentation management to active ingredients such as acetyl hexapeptide-8, niacinamide, and cannabidiol. Also reviewed are delivery systems including nanoencapsulation, microneedle technology, and iontophoresis in enhancing bioavailability and penetration of neuroactive compounds. A meta-analysis of clinical trials is shown. One study, which lasted up to 24 w, registered a 27% decrease in wrinkles and an 18% increase in elasticity with the peptide complex; the second one described a 45% decrease in rosacea erythema with Alpha-Melanocyte Stimulating Hormone (α-MSH) and Transient Receptor Potential Vanilloid (TRPV1) antagonists. In this review, emerging areas for future research are AI-driven personalized neurocosmetics, interventions of the gut-brain-skin axis, chronocosmetics, epigenetic modulation, smart nanocarriers, and bioelectronic skin therapies. Safety and regulatory issues that arise are commented on, emphasizing long-term studies and standardized approaches. The review is apt for any researcher or dermatologist looking for a comprehensive overview of how neurocosmetics hold transformative promise in topical peptide formulations.

Photoelectric activity of titania nanotube by dimensionality control for neural-stimulated osteoblast activation.

Photoelectric activity of titania nanotube by dimensionality control for neural-stimulated osteoblast activation.

Exploring vestibulocerebellum-vestibular nuclei-spinal trigeminal nucleus causals communication and TRPV2 ion channel in a mouse model of vestibular migraine

BackgroundVestibular migraine (VM) is a disorder characterized by recurrent episodes of dizziness or vertigo and is often accompanied by headache. The mechanisms underlying vestibular dysfunction and pain in VM remain unclear.MethodsChronic migraine (CM) and VM models were induced by NTG and kainic acid, respectively. Behavioral assessments were conducted to evaluate vestibular dysfunction and pain in the VM and CM models. Transmission electron microscopy (TEM) was used to examine peripheral receptor impairment. Immunofluorescence, including staining for Cellular Proto-oncogene (c-Fos), Neuronal Nuclei (NeuN), and calcitonin gene-related peptide (CGRP), identified activated brain regions such as the cortex, midbrain, and cerebellum. Multiplex immunohistochemistry and cholera toxin subunit B (CTB) tracing were performed to analyze nuclear heterogeneity and neural communication. Additionally, RNA sequencing (RNA-Seq) and Ionized calcium-binding adapter molecule 1 (IBA1) immunostaining were used to investigate ion channel expression in the spinal trigeminal nucleus caudalis (Sp5c).ResultsCM and VM-related behaviors, such as allodynia and balance disturbance, were successfully reproduced in mouse model. TEM revealed significant damage to peripheral sensory receptors, particularly in the trigeminal ganglion and cochlear cells. Distinct activation patterns of c-Fos and CGRP were observed in VMs and CMs. CTB tracing confirmed that signals are transmitted from the vestibulocerebellum (VbC) to the Sp5c via the vestibular nuclei (VN). Furthermore, RNA-Seq combined with coimmunostaining revealed an increased expression of transient receptor potential vanilloid 2 (TRPV2) ion channels in microglia within Sp5c, indicating their potential role in VM pathology.ConclusionsThis study preliminarily explored VbC-VN-Sp5c communication and identified TRPV2 ion channels in microglia as key players in neuron-glia crosstalk in VM. These findings provide new insights into the mechanisms underlying vestibular migraine and suggest potential therapeutic targets.Graphical abstract

Effects of intra-articular applied rat BMSCs expressing alpha-calcitonin gene-related peptide or substance P on osteoarthritis pathogenesis in a murine surgical osteoarthritis model

BackgroundAbout 655 million persons worldwide are affected by osteoarthritis (OA). As no therapy modifies disease progression long-term, there is an immense clinical need for novel therapies. The joints are innervated by alpha calcitonin gene-related peptide (αCGRP)- and substance P (SP)-positive sensory nerve fibers. Both neuropeptides have trophic effects on target cells within the joints. The aim of this study was to examine the effects of SP- and αCGRP-expressing intra-articular (i.a.) applied rat(r)BMSC on cartilage and subchondral bone structural changes after OA induction.MethodsMice were subjected to destabilization of the medial meniscus (DMM) surgery, followed by i.a. injections with rBMSC, transduced with lacZ, SP or αCGRP. 2, 8 and 16 weeks after DMM/Sham surgery, motion analysis and serum marker analysis were performed. Cartilage and subchondral bone properties were assessed by OA scoring, atomic force microscopy and nano-CT analysis.ResultsOARSI scores of the medial cartilage compartments indicated induction and progression of OA after DMM surgery in all groups. Differences between the treatment groups were mostly restricted to the lateral cartilage compartments, where αCGRP caused a decrease of structural changes. DMM-rBMSC-αCGRP or -SP mice displayed decreased cartilage stiffness in the cartilage middle zone. DMM-rBMSC-αCGRP mice revealed improved mobility, whereas Sham-rBMSC-SP mice revealed reduced mobility compared to rBMSC-lacZ. With respect to condyle length, subarticular bone and ephiphyseal bone morphology, DMM-rBMSC-SP mice had more alterations indicating either a more progressed OA stage or a more severe OA pathology compared to controls. In addition, DMM-rBMSC-SP mice developed osteophytes already 8 weeks after surgery. Adiponectin serum level was increased in DMM-rBMSC-αCGRP mice, and MIP1b level in DMM-rBMSC-SP mice. Notably, pain and inflammation markers increased over time in rBMSC-SP mice while rBMSC-αCGRP mice revealed a bell-shaped curve with a peak at 8 weeks.ConclusionsWe conclude that i.a. injection of rBMSC in general have a beneficial effect on cartilage matrix structure, subchondral bone microarchitecture and inflammation. rBMSC-αCGRP have anabolic and possible analgesic properties and may attenuate the progression or severity of OA. In contrast, rBMSC-SP exert a more catabolic influence on knee joints of both, Sham and DMM mice, making it a potential candidate for inhibition studies.

Serum levels of autotaxin reveal its role as a novel biomarker of migraine.

Migraine is the most common neurological disorder and the second most disabling human condition. Autotaxin (ATX) is a plasma enzyme that leads to the formation of lysophosphatidic acid (LPA), which is involved in different functions involved in migraine, such as vascular tone control, inflammation, neuronal excitation, endothelial dysfunction, and neuropathic pain, among others. Most patients with migraine are females and, interestingly, ATX is physiologically higher in the serum of females compared to males. As ATX may be a link between common mechanisms associated with migraine, we aimed to determine the potential role of ATX in migraine by studying its concentrations in serum between patients with episodic (EM) and chronic migraine (CM) compared to healthy controls, as well as the correlation of ATX with clinical outcomes, and other biomarkers described in migraine. In this cross-sectional study, healthy controls (n = 62), and patients with EM (n = 45), and CM (n = 38) were studied. Clinical outcomes, such as migraine intensity as assessed on a visual analog scale (VAS), frequency of headaches (days/month), evolution time (months), and the duration of attacks (h) were investigated together with the serum biomarkers for inflammation (interleukin 6 [IL-6] and IL-10), trigeminovascular system activation (calcitonin gene-related peptide [CGRP]), endothelial dysfunction (pentraxin 3 [PTX3], cellular fibrinogen [cFN], soluble tumor necrosis factor-like weak inducer of apoptosis [sTWEAK]), and ATX. Additionally, the serum lipidomic biomarkers profile was also analyzed. Serum ATX levels were found to be significantly elevated in both patients with EM (mean [standard deviation, SD] 310.7 [79.7] ng/mL) and CM (mean [SD] 336.7 [66.9] ng/mL) compared to controls (mean [SD] 212.3 [53.2] ng/mL) (p < 0.001). Elevated ATX levels were associated with migraine outcomes in CM, such as VAS score (Spearman's coefficient = 0.405, p < 0.05), frequency (Spearman's coefficient = 0.718, p < 0.001), and evolution time (Spearman's coefficient = 0.2257, p < 0.01). ATX was correlated with CGRP (Pearson's coefficient = 0.278, p < 0.001), PTX3 (Pearson's coefficient = 0.468, p < 0.001), sTWEAK (Pearson's coefficient = 0.242, p < 0.001), cFN (Pearson's coefficient = 0.252, p < 0.01), and IL-6 serum levels (Pearson's coefficient = 0.159, p < 0.001). A drastic decrease in serum lysophosphatidylcholine levels indicates high ATX activity in patients with migraine. Serum levels of ATX were significantly increased in patients with EM and CM. In addition, ATX correlates with clinical outcomes, as well as CGRP, endothelial dysfunction and inflammation biomarkers. Further studies are necessary to elucidate the potential role of ATX as a therapeutic target for migraine.

Botulinum toxin effects on biochemical biomarkers related to inflammation-associated head and neck chronic conditions: a systematic review of clinical research.

Botulinum toxin type A (BoNT) has emerged as a potential alternative to conventional therapies to many debilitating chronic diseases characterised by inflammatory states. However, the biological rationale remains ambiguous. Our review aimed to systematically assessed which biochemical biomarkers have been reported in clinical research to evaluate BoNT analgesic and mood-lifting effects in head and neck chronic conditions related to inflammation. We searched databases and registries between inception and September 29, 2023. Of the nine included studies, there were concerns about risk of bias for six studies. The leading biomarker with five studies was the calcitonin gene-related peptide (CGRP), followed by serotonin with two studies. Oxidative stress biomarkers were only reported in one study. Several important players in inflammatory processes and different immune cell classes have been evaluated in four studies. There was only one trial measuring changes in beta Tubulin and SNAP-25, and another study evaluating cutaneous neuropeptide substance-P. After BoNT, a significant effect was reported in six studies, including decrease in plasma levels of CGRP in chronic migraine and trigeminal neuralgia; serotonin decrease when collected from human tears in refractory intractable dry eye disease and increase in peripheral blood platelets in painful cervical dystonia associated to depression and anxiety; decrease in plasma concentration of markers of oxidative damage to proteins and increase in biomarkers for antioxidant power; decrease in expression of gene sets involved in inflammatory pathways and immune cells classes in the periosteum and metalloproteinase-9 molecule in the tears. BoNT seems to affect some biomarkers present in chronic inflammatory conditions. However, the certainty evidence found was very low to moderate. This study is registered on PROSPERO (CRD42023432131).

Effect of erenumab versus other migraine preventive medications on cardiovascular and cerebrovascular outcomes: A United States claims database-based observational cohort study.

To estimate the real-world risk of cardiovascular events among patients with migraine treated with erenumab and other migraine preventive medications. Migraine preventive treatment with calcitonin gene-related peptide (CGRP) pathway inhibitors, such as erenumab and others, may theoretically result in cardiovascular effects due to a lack of compensatory vasodilation with CGRP pathway inhibition. In this retrospective observational cohort study, we estimated the unadjusted cumulative risk (CR) of new-onset hypertension, acute myocardial infarction (MI), or stroke among patients with migraine newly treated with erenumab, other anti-CGRP pathway monoclonal antibodies (mAbs), standard oral preventive medications, and onabotulinumtoxinA using data from the MarketScan® Commercial and Medicare Supplemental medical claims database. Comparative analyses to assess the relative risk (RR) of vascular events were gated on the comparability of treatment groups with respect to baseline demographics and clinical characteristics. Potential bias due to unmeasured confounding was evaluated via negative control outcome (NCO) analyses. Confounding based on measured covariates and differential informative censoring were addressed with inverse probability weights. A total of 108,019 new users of migraine preventive medications were included. Unadjusted CR (95% confidence interval [CI]) of hypertension at 12 months of treatment was: erenumab, 9.34% (8.79-9.89%); other anti-CGRP pathway mAbs, 9.42% (8.92-9.92%); standard oral preventive medications, 9.09% (8.77-9.41%); and onabotulinumtoxinA, 9.10% (8.39-9.81%). NCO analyses identified minimal concerns related to unmeasured confounding in erenumab versus other mAbs and erenumab versus onabotulinumtoxinA comparisons. Adjusted RRs (95% CIs) of acute MI and stroke, respectively, at 36 months of treatment were 1.02 (0.45-1.59) and 0.90 (0.56-1.25) for erenumab versus other mAbs and 0.87 (0.19-1.55) and 0.97 (0.42-1.52) for erenumab versus onabotulinumtoxinA. In this analysis of the MarketScan medical claims database, we found no difference in the risk of vascular events in patients treated with erenumab versus other anti-CGRP pathway mAbs or onabotulinumtoxinA.

Real-world adherence to erenumab, rescue medication utilization, and work absenteeism for patients with migraine: Results from an outcomes-based agreement.

Migraine prevalence is estimated to be 15% (approximately 50 million people) in the United States, posing a significant burden on the health care system and a top cause of years lived with disability. Consequently, migraine leads to increased work-related disability, including presenteeism and absenteeism. Novel prophylactic treatments for migraine that target the calcitonin gene-related peptide pathway, including monoclonal antibodies to the calcitonin gene-related peptide ligand or the calcitonin gene-related peptide receptor (calcitonin gene-related peptide monoclonal antibodies) and gepants, offer new options for migraine prevention. The advent of new medications presents an opportunity for development of outcomes-based agreements, particularly because these agents are more costly than traditional, nonspecific treatment alternatives. Outcomes-based agreements are pricing agreements between pharmaceutical manufacturers and payers, centered around predefined performance metrics to better align incentives and create shared risk between them. To report results of an outcomes-based agreement that was executed in a large integrated delivery and finance health system for patients with migraine who were prescribed erenumab, an anti-calcitonin gene-related peptide pathway monoclonal antibody. This is a prospective real-world analysis of commercial or health insurance exchange data from a large regional health system, based on parameters of an outcomes-based agreement. Eligible patients were new to calcitonin gene-related peptide monoclonal antibodies. Outcomes of interest included an erenumab adherence metric and changes in work absenteeism and rescue medication use. Proportion adherent and rescue medication use were assessed for the entire eligible patient cohort, whereas work absenteeism was only evaluated for a subset of eligible patients for whom work outcomes data were available. There were 5,507 patients who filled erenumab during the contract period, and 1,281 patients were new to calcitonin gene-related peptide monoclonal antibodies medications. Of those, 865 constituted the eligible patient cohort and 224 constituted the work outcomes cohort. Patient adherence to erenumab was 80.5% and 81.7% for the entire patient cohort and work outcomes cohort, respectively. Absenteeism was reduced by 5.5% (21.64 vs 20.44 hours; P = 0.664) and rescue medication use was decreased by 3.6% (0.362 vs 0.349 doses; P = 0.589). Absenteeism could have been impacted by the onset of the COVID-19 pandemic. As measured, adherence to erenumab was high within the cohort. The inclusion of a work outcomes cohort provided valuable insights about the clinical benefits of erenumab for migraine prevention. Our findings provide additional insights on the real-world use of erenumab within the context of an outcomes-based agreement.

Genetic tools that target mechanoreceptors produce reliable labeling of bladder afferents and altered mechanosensation.

Mechanosensitive neurons are important sensors of bladder distention, but their role in urologic disease remains unclear. Our current knowledge about how disease alters bladder sensation comes from studies that focus primarily on peptidergic nociceptors, leaving our understanding of neuropeptide-negative mechanoreceptors incomplete. In this study, we found that a substantial proportion of neurofilament heavy (NFH)-positive A-fibers innervating the bladder was calcitonin gene-related peptide (CGRP)-negative, potentially representing uncharacterized mechanoreceptors. We then identified two genetic strategies that label mechanoreceptors in mouse skin and confirmed that they likewise label bladder afferents. Cre-mediated tdTomato reporter expression driven by tropomyosin receptor kinase B (TrkB), which labels Aδ mechanoreceptors in the skin, successfully labeled bladder nerve terminals. The majority of TrkB bladder afferents were CGRP-negative and NFH-positive, with more characteristic staining patterns seen at the level of the cell body. The Ret proto-oncogene (Ret) also produced robust labeling of bladder afferents, where colocalization with CGRP and NFH was consistent with multiple afferent subtypes. Because TrkB labeling was more specific for putative mechanoreceptors, we directly tested the role of TrkB neurons in bladder mechanosensation in vivo. Using an intersectional genetic strategy, we selectively ablated TrkB afferents and measured bladder responses to mechanical distention using anesthetized cystometry. Compared with controls, mice with ablated TrkB afferents required higher distention pressure to elicit voids. Interestingly, after ablation, distention also increased the frequency of nonvoiding contractions, a poorly understood phenotype of several urologic diseases. These genetic strategies comprise critical new tools to advance the study of mechanoreceptors in bladder function and urologic disease pathophysiology.NEW & NOTEWORTHY Most mechanosensitive afferents do not express markers of peptidergic nociceptors and therefore remain largely overlooked in studies of bladder dysfunction and disease. TrkB-mediated labeling of putative Aδ mechanoreceptors emerged as a valuable tool for the study of neuropeptide-negative bladder afferents with a confirmed role in bladder mechanosensation. Targeted neuronal ablation likewise validated an intersectional genetic strategy that can now directly test the role of TrkB mechanoreceptors in bladder physiology and disease.

Neuroimmunology of psoriasis: Possible roles for calcitonin gene-related peptide in its pathogenesis.

Neuroimmunology of psoriasis: Possible roles for calcitonin gene-related peptide in its pathogenesis.

No change in interictal plasma and salivary CGRP levels in individuals with vestibular migraine corresponding to episodic migraine

Background Few studies have examined plasma calcitonin gene-related peptide (CGRP) levels in individuals with vestibular migraine (VM), with inconsistent findings. Additionally, salivary CGRP levels in VM have not been reported. Methods Interictal plasma and salivary CGRP levels were measured using an enzyme-linked immunosorbent assay in participants with VM corresponding to episodic migraine (VM, n = 81), chronic migraine without vestibular symptoms (CM, n = 73) and healthy controls (HC, n = 59). Results Plasma CGRP levels in VM with episodic migraine participants were significantly lower than those in participants with CM (median = 37.1 pg/mL, interquartile range (IQR) = 22.4–60.4 pg/mL vs. median = 74.6 pg/mL, IQR = 49.6–101.6 pg/mL; p &lt; 0.001) but did not significantly differ from levels in HC. Similarly, salivary CGRP levels were also significantly lower in VM compared to CM (median = 54.5 pg/mL, IQR = 37.0–83.4 pg/mL vs. median = 72.0 pg/mL, IQR = 56.5–96.2 pg/mL; p = 0.036), with no significant difference observed between VM and HC. Receiver operating characteristic analysis showed that plasma CGRP levels effectively differentiated CM from VM corresponding to episodic migraine, achieving an area under the curve of 0.88. No significant correlations were found between plasma or salivary CGRP levels and clinical features of CM and VM. Conclusions Interictal plasma and salivary CGRP levels are unlikely to serve a biomarkers for VM.

Neuropeptides as regulators of bone metabolism: from molecular mechanisms to traditional Chinese medicine intervention strategies

Osteoporosis (OP) is a complex bone metabolism disorder disease that affects the skeleton, nervous system, muscles, and multiple tissues. Neuropeptides, which are endogenous substances derived from both bone and brain, play a critical role in maintaining the balance of bone metabolism. This review summarizes research conducted from 1986 to 2024 on the pathological mechanisms of neuropeptides and their receptors in the context of OP. Specifically, the roles of Neuropeptide Y, Vasoactive Intestinal Peptide, Calcitonin Gene-Related Peptide, and Substance P and their receptors in key processes of OP were examined, including their function of bone formation and resorption, osteoblast differentiation, and osteoclast differentiation. Our study showed that these neuropeptides could promote bone formation and inhibit bone resorption, while their receptors in osteocytes exhibit distinct functions, indicating complex regulatory mechanisms that require further investigation. Additionally, we summarize the progress of Traditional Chinese Medicine (TCM) formulae, single TCM herbs, and bioactive compounds derived from TCM in exerting anti-OP effects through neuropeptide modulation. These studies highlight the multi-targeted and multi-mechanistic pharmacological actions of TCM in treating OP. By integrating these findings, we aim to enhance the understanding of neuropeptides’ roles in bone metabolism and to explore the development of neuropeptide-targeted TCM therapies for OP management. This comprehensive perspective highlights the potential of neuropeptides as therapeutic targets, paving the way for innovative approaches to treating OP.

CGRPβ suppresses the pathogenesis of ulcerative colitis via the immunoproteasome

Various factors have been implicated in the pathogenesis of ulcerative colitis (UC), with immune system failure being the most important one. Calcitonin gene-related peptide (CGRP), a neuropeptide with two isoforms, CGRPα and CGRPβ, has been reported to regulate the immune system. In this study, we investigated the role of CGRP isoforms in UC pathogenesis. We induced UC-like symptoms in CGRPα and CGRPβ knockout (KO) mice using dextran sulphate sodium. Compared to wild-type and CGRPα KO mice, CGRPβ-deficient mice exhibited severe symptoms with increased blood in the stool and diarrhoea. Proteome analysis revealed significant up-regulation of immune-related proteins and immunoproteasome components in CGRPβ-deficient mice, suggesting that an enhanced immune response contributes to the severity of this disease. Treatment with ONX-0914, an immunoproteasome inhibitor, markedly improved these symptoms, highlighting the role of the immunoproteasome in exacerbating UC. This study provides the first evidence that CGRPβ protects against UC by modulating immune responses, particularly those mediated by the immunoproteasome. Our findings suggest that functional differences in CGRP isoforms may influence the severity and management of UC. This insight into the neuro-immune mechanism of UC opens avenues for novel therapies that address both the neural and immune aspects of this disease.