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Objective: The objective of this study was to characterize the utility of calcitonin gene–related peptide (CGRP) and nerve growth factor (NGF) as potential biomarkers for headache and pain disorders in the post–military deployment setting. Background: The need to improve recognition, assessment, and prognoses of individuals with posttraumatic headache or other pain has increased interest in the potential of CGRP and NGF as biomarkers. Methods: The Warrior Strong Study (NCT01847040) is an observational longitudinal study of United States–based soldiers who had recently returned from deployment to Afghanistan or Iraq from 2009 to 2014. The present nested cross‐sectional analysis uses baseline data collected from soldiers returning to Fort Bragg, North Carolina. Results: In total, 264 soldiers (mean (standard deviation [SD] age 28.1 [6.4] years, 230/264 [87.1%] men, 171/263 [65.0%] White) were analyzed. Mean (SD) plasma levels of CGRP were 1.3 (1.1) pg/mL and mean levels of NGF were 1.4 (0.4) pg/mL. Age was negatively correlated with NGF (−0.01 pg/mL per year, p = 0.007) but was not associated with CGRP. Men had higher mean (SD) CGRP plasma levels than women (1.4 95% confidence interval [CI; 1.2] vs. 0.9 95% CI [0.5] pg/mL, p < 0.002, Kruskal–Wallis test). CGRP levels were lower in participants who had a headache at the time of the blood draw (1.0 [0.6] pg/mL vs. 1.4 [1.2] pg/mL, p = 0.024). NGF was lower in participants with continuous pain (all types; 1.2 [0.4] vs. 1.4 [0.4] pg/mL, p = 0.027) and was lower in participants with traumatic brain injury (TBI) + posttraumatic headache (PTH) versus TBI without PTH (1.3 [0.3] vs. 1.4 [0.4] pg/mL, p = 0.021). Otherwise, CGRP and NGF were not associated with migraine‐like headache, TBI status, or headache burden as measured by the number of medical encounters in crude or adjusted models. Conclusion: In this exploratory study, plasma levels of NGF and CGRP showed promise as biomarkers for headache and other types of pain. These findings need to be replicated in other cohorts. [ABSTRACT FROM AUTHOR]

Purpose: The present study investigates the efficacy of Photobiomodulation (PBM) and Vitamin B Complex (VBC) to relieve pain, both in separately and combined (PBM and VBC). Methods: Rats with chronic constriction injury of the right infraorbital nerve (CCI-IoN) or Sham surgery were used. PBM was administered at a wavelength of 904 nm and energy density of 6.23 J/cm2 and VBC (containing B1, B6 and B12) subcutaneously, both separately and combined. Behavioral tests were performed to assess mechanical and thermal hypersensitivity before and after CCI and after PBM, VBC, or PBM + VBC. The expression of inflammatory proteins in the trigeminal ganglion and the immunohistochemical alterations of Periaqueductal Gray (PAG) astrocytes and microglia were examined following CCI and treatments. Results: All testeds treatments reversed the painful behavior. The decrease in pain was accompanied by a decrease of Glial Fibrillary Acidic Protein (GFAP), a specific astrocytic marker, and Ionized calcium-binding adaptor molecule 1 (Iba-1), a marker of microglia, and decreased expression of Transient Receptor Potential Vanilloid 1 (TRPV1), Substance P, and Calcitonin Gene-Related Peptide (CGRP) induced by CCI-IoN in PAG and Trigeminal ganglion. Furthermore, both treatments showed a higher expression of Cannabinoid-type 1 (CB1) receptor in the trigeminal ganglion compared to CCI-IoN rats. Our results show that no difference was observed between groups. Conclusion: We showed that PBM or VBC regulates neuroinflammation and reduces inflammatory protein expression. However, the combination of PBM and VBC did not enhance the effectiveness of both therapies alone. [ABSTRACT FROM AUTHOR]

Pain is a common non-motor symptom of Parkinson's disease (PD), which often occurs in the early disease stages. Despite the high prevalence, it remains inadequately treated. In a hemi-parkinsonian rat model, we aimed to investigate the neurochemical factors involved in orofacial pain development, with a specific focus on pain-related peptides and cannabinoid receptors. We also evaluated whether treadmill exercise could improve orofacial pain and modulate these mechanisms. Rats were unilaterally injected in the striatum with either 6-hydroxydopamine (6-OHDA) or saline. Fifteen days after stereotactic surgery, the animals were submitted to treadmill exercise (EX), or remained sedentary (SED). Pain assessment was performed before the surgical procedure and prior to each training session. Pain-related peptides, substance P (SP), calcitonin gene-related peptide (CGRP), and transient receptor potential vanilloid type 1 (TRPV1) activation and cannabinoid receptor type 1 (CB1) and type 2 (CB2) were evaluated in the trigeminal nucleus. In order to confirm the possible involvement of cannabinoid receptors, we also injected antagonists of CB1 and CB2 receptors. We confirmed the presence of orofacial pain after unilateral 6-OHDA-injection, which improved after aerobic exercise training. We also observed increased pain-related expression of SP, CGRP and TRPV1 and decreased CB1 and CB2 in the trigeminal ganglion and caudal spinal trigeminal nucleus in animals with PD, which was reversed after aerobic exercise training. In addition, we confirm the involvement of cannabinoid receptors since both antagonists decreased the nociceptive threshold of PD animals. These data suggest that aerobic exercise effectively improved the orofacial pain associated with the PD model, and may be mediated by pain-related neuropeptides and cannabinoid receptors in the trigeminal system. [ABSTRACT FROM AUTHOR]

Background: A myocardial ischemia/reperfusion (IR) injury activates the transient receptor potential vanilloid 1 (TRPV1) dorsal root ganglion (DRG) neurons. The activation of TRPV1 DRG neurons triggers the spinal dorsal horn and the sympathetic preganglionic neurons in the spinal intermediolateral column, which results in sympathoexcitation. In this study, we hypothesize that the selective epidural administration of resiniferatoxin (RTX) to DRGs may provide cardioprotection against ventricular arrhythmias by inhibiting afferent neurotransmission during IR injury. Methods: Yorkshire pigs (n = 21) were assigned to either the sham, IR, or IR + RTX group. A laminectomy and sternotomy were performed on the anesthetized animals to expose the left T2–T4 spinal dorsal root and the heart for IR intervention, respectively. RTX (50 μg) was administered to the DRGs in the IR + RTX group. The activation recovery interval (ARI) was measured as a surrogate for the action potential duration (APD). Arrhythmia risk was investigated by assessing the dispersion of repolarization (DOR), a marker of arrhythmogenicity, and measuring the arrhythmia score and the number of non-sustained ventricular tachycardias (VTs). TRPV1 and calcitonin gene-related peptide (CGRP) expressions in DRGs and CGRP expression in the spinal cord were assessed using immunohistochemistry. Results: The RTX mitigated IR-induced ARI shortening (−105 ms ± 13 ms in IR vs. −65 ms ± 11 ms in IR + RTX, p = 0.028) and DOR augmentation (7093 ms2 ± 701 ms2 in IR vs. 3788 ms2 ± 1161 ms2 in IR + RTX, p = 0.020). The arrhythmia score and VT episodes during an IR were decreased by RTX (arrhythmia score: 8.01 ± 1.44 in IR vs. 3.70 ± 0.81 in IR + RTX, p = 0.037. number of VT episodes: 12.00 ± 3.29 in IR vs. 0.57 ± 0.3 in IR + RTX, p = 0.002). The CGRP expression in the DRGs and spinal cord was decreased by RTX (DRGs: 6.8% ± 1.3% in IR vs. 0.6% ± 0.2% in IR + RTX, p < 0.001. Spinal cord: 12.0% ± 2.6% in IR vs. 4.5% ± 0.8% in IR + RTX, p = 0.047). Conclusions: The administration of RTX locally to thoracic DRGs reduces ventricular arrhythmia in a porcine model of IR, likely by inhibiting spinal afferent hyperactivity in the cardio–spinal sympathetic pathways. [ABSTRACT FROM AUTHOR]

Background: A growing body of evidence has demonstrated that a high-fat and high-protein diet (HFHPD) causes constipation. This study focuses on understanding how the use of Zhishi Daozhi decoction (ZDD) affects the intricate balance of intestinal microorganisms. The insights gained from this investigation hold the potential to offer practical clinical approaches to mitigate the constipation-related issues associated with HFHPD. Materials and methods: Mice were randomly divided into five groups: the normal (MN) group, the natural recovery (MR) group, the low-dose ZDD (MLD) group, the medium-dose ZDD (MMD) group, and the high-dose ZDD (MHD) group. After the constipation model was established by HFHPD combined with loperamide hydrochloride (LOP), different doses of ZDD were used for intervention. Subsequently, the contents of cholecystokinin (CCK) and calcitonin gene-related peptide (CGRP) in serum, superoxide dismutase (SOD), and malondialdehyde (MDA) in the liver were determined. The DNA of intestinal mucosa was extracted, and 16S rRNA amplicon sequencing was used to analyze the changes in intestinal mucosal microbiota. Results: After ZDD treatment, CCK content in MR group decreased and CGRP content increased, but the changes were not significant. In addition, the SOD content in MR group was significantly lower than in MLD, MMD, and MHD groups, and the MDA content in MR group was significantly higher than in MN, MLD, and MHD groups. Constipation modeling and the intervention of ZDD changed the structure of the intestinal mucosal microbiota. In the constipation induced by HFHPD, the relative abundance of pathogenic bacteria such as Aerococcus, Staphylococcus, Corynebacterium, Desulfovibrio, Clostridium, and Prevotella increased. After the intervention of ZDD, the relative abundance of these pathogenic bacteria decreased, and the relative abundance of Candidatus Arthromitus and the abundance of Tropane, piperidine, and pyridine alkaloid biosynthesis pathways increased in MHD group. Conclusion: Constipation induced by HFHPD can increase pathogenic bacteria in the intestinal mucosa, while ZDD can effectively relieve constipation, reduce the relative abundance of pathogenic bacteria, and alleviate oxidative stress injury. In addition, high-dose ZDD can increase the abundance of beneficial bacteria, which is more conducive to the treatment of constipation. [ABSTRACT FROM AUTHOR]

The acknowledged hypothesis of the cause of arterial hypertension is the emerging disbalance in sympathetic and parasympathetic regulations of the cardiovascular system. This disbalance manifests in a disorder of sustainability of endogenous autonomic and sensory neural substances including calcitonin gene‐related peptide (CGRP). This study aimed to examine neurochemical alterations of intrinsic cardiac ganglionated nerve plexus (GP) triggered by arterial hypertension during ageing in spontaneously hypertensive rats of juvenile (prehypertensive, 8–9 weeks), adult (early hypertensive, 12–18 weeks) and elderly (persistent hypertensive, 46–60 weeks) age in comparison with the age‐matched Wistar–Kyoto rats as controls. Parasympathetic, sympathetic and sensory neural structures of GP were analysed and evaluated morphometrically in tissue sections and whole‐mount cardiac preparations. Both the elevated blood pressure and the evident ultrasonic signs of heart failure were identified for spontaneously hypertensive rats and in part for the aged control rats. The amount of adrenergic and immunoreactive to CGRP neural structures was increased in the adult group of spontaneously hypertensive rats along with the significant alterations that occurred during ageing. In conclusion, the revealed chemical alterations of GP support the hypothesis about the possible disbalance of efferent and afferent heart innervation and may be considered as the basis for the emergence and progression of arterial hypertension and perhaps even as a consequence of hypertension in the aged spontaneously hypertensive rats. The determined anatomical changes in the ageing Wistar–Kyoto rats suggest this breed being as inappropriate for its use as control animals for hypertension studies in older animal age. [ABSTRACT FROM AUTHOR]

The new synthetic anti-inflammatory agent, 4-(5'-dimethylamino)-naphthalenesulfonyl-2(3H)-benzoxazolone (W3D), has demonstrated definite biological activity both in vitro and in vivo. In this study, we investigated the antinociceptive effects of W3D on various animal pain models. Our results showed that W3D, at doses of 12.5 and 25 mg/kg, significantly reduced acetic acidinduced mice writhing by 65.9% and inhibited the pain response in the second phase of formalin-induced pain from 167.75 ± 6.76 s to 97.25 ±9.63 s. Moreover, W3D prolonged the latent period on the tail-immersion test, which was stronger than the positive drug, aspirin (50 mg/kg). However, W3D did not show analgesic activity on the hot plate test, indicating no central pain response. Furthermore, the antinociceptive effects of W3D were not antagonized by naloxone, EGTA, CaCl2, and reserpine. However, LArginine was able to reverse the antinociceptive effect, indicating that W3D's antinociceptive effect does not depend on opioid receptors, Ca2+ concentration, or monoamine content. Instead, it is closely associated with nitric oxide (NO) content. In addition, W3D was found to alleviate nocifensive behavior and improve brain histopathology by inhibiting NO, inducible nitric oxide synthase (iNOS), and calcitonin gene-related peptide in nitroglycerin-induced migraine mice, with more than 50% inhibition ratio at only 12.5 mg/kg orally. However, noradrenaline, dopamine, and 5-hydroxytryptamine levels were not significantly altered after treatment with W3D. In conclusion, the presented data suggest that W3D can be considered a new non-steroidal anti-inflammatory and antinociceptive agent for the treatment of peripheral pain and migraine mediated by NO and iNOS. [ABSTRACT FROM AUTHOR]

Herein, a 3D bioprinted scaffold is proposed, containing a calcitonin gene‐related peptide (CGRP) and the β‐adrenergic receptor blocker propranolol (PRN) as a new method to achieve effective repair of bone defects. By leveraging the neuromodulation mechanism of bone regeneration, CGRP and PRN loaded mesoporous silica nanoparticles are added into a hybrid bio‐ink, which initially contains gelatin methacrylate, Poly (ethylene glycol) diacrylate and bone marrow mesenchymal stem cells (BMSCs). Subsequently, the optimized bio‐ink is used for 3D bioprinting to create a composite scaffold with a pre‐designed micro‐nano hierarchical structure. The migration and tube formation of human umbilical vein endothelial cells (HUVECs) can be promoted by the scaffold, which is beneficial to the formation of a new capillary network during the bone repair process. With the release of CGRP from the scaffold, the secretion of neuropeptides by sensory nerves is simulated. Meanwhile, the release of PRN can inhibit the binding process of catecholamine to β‐adrenergic receptor, co‐promoting the osteogenic differentiation of BMSCs with CGRP and silicon ions, which will effectively enhance bone repair of a critical‐sized cranial defect in a rat model. In conclusion, this study provides a promising strategy for bone defect repair by understanding the neuromodulatory mechanisms during bone regeneration. [ABSTRACT FROM AUTHOR]

Aim: Osteoarthritis (OA) is a disease in which degeneration occurs in various tissues such as cartilage and subchondral bone. Degeneration of ligaments also plays an important role in OA progression, resulting in an increase in chondrocytes and ossification, but the factor that causes this is still unclear. It is reported that the expression of calcitonin gene‐related peptide (CGRP) increases OA progression, and CGRP might play a role in ligament degeneration because CGRP has a function in endochondral ossification. The purpose of this study is to analyze the mechanism of ligament degeneration and the function of CGRP. Methods: To examine the relationship between ligament degeneration and CGRP expression, human posterior cruciate ligaments (PCL) from OA patients, and senescence‐accelerated mouse prone 8 (SAMP8) mice were histologically analyzed. The effect of CGRP on human ligament cells on chondrogenesis, osteogenesis, and adipogenesis was also examined. Results: In human PCL and SAMP8 mice, CGRP expression increased as degeneration progressed, and decreased in severe degeneration. CGRP was expressed in the chondrocyte‐like cells with SOX9. CGRP‐positive cells expressing type II collagen increased with OA progression. CGRP upregulated the gene expression of VEGF, SOX9, RUNX2, COL10a1, and MMP13 in the human ligament cells. CGRP also promoted chondrogenesis and osteogenesis from the human ligament cells. Conclusion: During OA progression, CGRP plays a role in the transdifferentiation from ligament cells to chondrocytes and promotes endochondral ossification in the ligament. CGRP would be the therapeutic target to prevent ligament degeneration. [ABSTRACT FROM AUTHOR]

Background: Migraine is a widespread headache disorder occurring in every age group. It is divided into two types: chronic and episodic migraine. Many medications have been used in its treatment over the years with different degrees of effectiveness. In recent years, more attention has been given to the role of CGRP monoclonal antibodies for treatment, which are CGRP ligand antibodies (fremanezumab, galcanezumab, eptinezumab) and a CGRP receptor antibody (erenumab). Aim of the study: This study aimed to analyze the efficacy and safety of using CGRP monoclonal antibodies in migraine treatment and discuss CGRP's role in migraine pathogenesis. Both chronic and episodic migraines were subjects of interest. Material and methods: The search was conducted using the PubMed database. We analyzed articles published in the years 2017-2022. The used keywords were "Migraine", "Monoclonal antibodies", "CGRP", and "Calcitonin gene-related peptide". Results: The number of articles found depended on the keyword used ("migraine" - 1875 results, "monoclonal antibodies" - 12173 results, "CGRP" - 352 results, and "calcitonin gene-related peptide" - 461 results). A total of 31 articles were quoted in this review. Positive results for treating migraines with CGRP ligand antibodies (fremanezumab, galcanezumab, eptinezumab) and CGRP receptor antibody (erenumab) were observed. Conclusions: The use of CGRP ligand and receptor antibodies seems promising for migraine therapy due to their relatively mild side effects and high efficiency. [ABSTRACT FROM AUTHOR]

Medication overuse headache (MOH) places both a physical and emotional burden on patients. MOH may occur as a consequence of a negative spiral of events comprising an increasing number of headache days while taking frequent or excessive amounts of medications for acute treatment of headaches or migraine. Despite acute and prophylactic treatment options, there remains a complex subset of patients who fail first-line oral prophylactic therapies due to insufficient response or failure to tolerate, and require access to new prophylactic treatment options, including calcitonin gene-related peptide (CGRP) inhibitors such as eptinezumab. In this article I present a series of clinical scenarios in which the use of eptinezumab may be beneficial, based on the extensive experience I have gained using the treatment, in more than 25 patients, (and over 40 infusions), over a 2-year period. Eptinezumab provides an additional therapeutic modality for patients who are refractory to other migraine medications, including other CGRP pathway monoclonal antibody (mAb) therapies. I discuss within this article the potential role for eptinezumab in various clinical scenarios such as refractory migraine, including MOH, in which the rapid bioavailability of the preparation may be of particular utility. It is important to tailor treatment plans to the individual patient needs and provide other lifestyle and non-drug-based recommendations when treating patients with MOH, who may be appropriate for treatment with eptinezumab. [ABSTRACT FROM AUTHOR]

Atogepant, an oral calcitonin gene‐related peptide receptor antagonist, and topiramate, a commonly used oral antiepileptic, are approved as preventive migraine treatments. Given the distinct mechanisms of action of these treatments, it is possible that they may be coprescribed for migraine. This open‐label, single‐center, 2‐cohort, phase 1 trial evaluated the potential pharmacokinetic (PK) 2‐way drug–drug interactions (DDIs), safety, and tolerability of atogepant and topiramate in healthy adults. Participants received atogepant 60 mg once daily and topiramate 100 mg twice daily. Cohort 1 (N = 28) evaluated the effect of topiramate on the PK of atogepant; cohort 2 (N = 25) evaluated the effect of atogepant on the PK of topiramate. Potential DDIs were assessed using geometric mean ratios and 90% confidence intervals calculated for maximum plasma drug concentration at steady state (Cmax,ss) and area under the plasma concentration–time curve during the dosing interval at steady state (AUC0−tau,ss). Additional PK parameters were assessed. Atogepant AUC0−tau,ss and Cmax,ss decreased by 25% and 24%, respectively, with topiramate coadministration. Topiramate AUC0−tau,ss and Cmax,ss decreased by 5% and 6%, respectively, with atogepant coadministration. The 25% reduction in atogepant exposure when coadministered with topiramate is not considered to be clinically relevant and would not require dose adjustments. [ABSTRACT FROM AUTHOR]

The mechanism of action of omalizumab in urticaria is still not literally known. This study examines the serum values of substance P (SP), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), and interleukin-31 (IL-31) in patients using omalizumab. In this study, 30 patients with chronic spontaneous urticaria (CSU) who were going to be treated with omalizumab and 20 healthy volunteers took part. Demographic data, clinical data, and disease activity scores were noted. For serum SP, CGRP, NPY, and IL-31 values, 10 mL of blood were taken from the patients before starting the treatment, 3 months after the treatment, at the end of the 6th month, and from healthy volunteers all at once. The change in values measured at baseline, 3rd month, and 6th month was analyzed by the Friedman Test. The Mann–Whitney U test was used to compare the parameters obtained from the patients and control groups. The significance level was set at p = 0.05. SP, CGRP, NPY, and IL-31 values were all statistically significantly lower in the CSU patient group compared to the control group. After treatment, the levels of SP and CGRP in the serum went up, and the levels of serum IL-31 went down. These changes were statistically significant. This study supports the view that omalizumab does not only affect IgE receptors but also affects mast cells through other mechanisms. According to our knowledge, this is the first study to show that omalizumab therapy and serum CGRP levels are related. [ABSTRACT FROM AUTHOR]

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 Gas. 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. [ABSTRACT FROM AUTHOR]

Introduction: Preeclampsia (PE) is a hypertensive disorder during pregnancy associated with elevated levels of soluble FMS-like tyrosine kinase (sFLT-1) and increased vascular sensitivity to angiotensin II (ATII). Calcitonin gene-related peptide (CALCA) is a potent vasodilator that inhibits the ATII-induced increase in blood pressure and protects against ATII-induced increases in oxidative stress through a mitochondrial-dependent pathway in male mice. In rodent pregnancy, CALCA facilitates pregnancy-induced vascular adaptation. Most of the vascular effects of CALCA are mediated by vascular smooth muscle cells (VSMCs). We recently reported that CALCA treatment inhibits sFLT-1-induced decreases in cAMP synthesis in omental artery smooth muscle cells (OASMCs) isolated from pregnant women and has relaxant effects in omental arteries (OAs) isolated from pregnant women with preeclamptic (PE) pregnancies. The current study was designed to assess the effects of sFLT-1 on mitochondrial bioenergetics in OASMCs isolated from pregnant women in the presence or absence of CALCA and assess the development of vascular dysfunction in sFLT-1 using a mouse model of PE pregnancy. Methods: OASMCs were isolated from pregnant women to assess the effects of sFLT-1 on mitochondrial bioenergetics and oxidative stress using the Seahorse assay and quantitative PCR. Pregnant mice overexpressing sFLT-1 via adenoviral delivery were used to assess the effects of CALCA infusion on the sFLT-1-induced increase in blood pressure, ATII hypersensitivity, fetal growth restriction, and the elevated albumin--creatinine ratio. Systemic blood pressure was recorded in conscious, freely moving mice using implantable radio telemetry devices. Results: CALCA inhibited the following sFLT-1-induced effects: 1) increased oxidative stress and the decreased oxygen consumption rate (OCR) in response to maximal respiration and ATP synthesis; 2) increases in the expression of mitochondrial enzyme complexes in OASMCs; 3) increased mitochondrial fragmentation in OASMCs; 4) decreased expression of mitophagy-associated PINK1 and DRAM1 mRNA expression in OASMCs; and 5) increased blood pressure, ATII hypersensitivity, fetal growth restriction, and the albumin--creatinine ratio in sFLT-1-overexpressing pregnant mice. Conclusion: CALCA inhibits sFLT-1-induced alterations in mitochondrial bioenergetics in vascular smooth muscle cells and development of maternal vascular dysfunction in a mouse model of PE. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

To assess factors associated with galcanezumab response in a real-world study of Korean patients with migraine. Predictors of the efficacy of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRP(-R) mAb) have been rarely investigated in Asians. We prospectively recruited and followed up patients with migraine who received monthly galcanezumab treatment in a single university hospital from June 2020 to October 2021. We defined the treatment response with ≥ 50% reduction in moderate/severe headache days in the 3rd month of treatment compared to baseline. Responders and non-responders were compared in terms of demographics, disease characteristics and severity, and previous response to migraine prophylactic treatments. Potential predictors of anti-CGRP(-R) mAb response were tested by using the univariable and multivariable logistic regression analyses. Among 104 patients (81.7% female; mean age 42.0 ± 13.02; 76.9% chronic migraine; and 45.5% medication overuse headache) included, 58 (55.7%) were responders. Non-responders had more chronic migraine, medication overuse headache, monthly headache days, days with acute medication, and daily headaches (i.e. chronic migraine persisting everyday without remission). The multivariable logistic analysis showed chronic migraine (OR 0.05 [95% CI 0.00–0.82], p = 0.036) and the number of previously failed preventive medication classes (OR 0.55 [95% CI 0.33–0.92], p = 0.024] were independently associated with treatment response. Chronic migraine and multiple failures from preventive medication are associated with poor galcanezumab response. Further studies are needed to investigate if earlier treatment before disease chronification or multiple failures may lead to a greater therapeutic gain from anti-CGRP(-R) mAb treatment. [ABSTRACT FROM AUTHOR]

Background: Migraine is a common neurovascular disorder with typical throbbing and unilateral headaches, causing a considerable healthcare burden on the global economy. This research aims to prepare chitosan-alginate (CS-AL) nanoparticles (NPs) containing Foshousan oil (FSSO) and investigate its potential therapeutic effects on the treatment of migraine. Methods: FSSO-loaded CS-AL NPs were prepared by using the single emulsion solvent evaporation method. Lipopolysaccharide (LPS)-stimulated BV-2 cells and nitroglycerin (NTG)-induced migraine mice were further used to explore antimigraine activities and potential mechanisms of this botanical drug. *Results: FSSO-loaded CS-AL NPs (212.1 ± 5.2 nm, 45.1 ± 6.2 mV) had a welldefined spherical shape with prolonged drug release and good storage within 4 weeks. FSSO and FSSO-loaded CS-AL NPs (5, 10, and 15 μg/mL) showed antiinflammatory activities in LPS-treated BV-2 cells via reducing the levels of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO), but elevating interleukin-10 (IL-10) expressions. Moreover, FSSO-loaded CS-AL NPs (52 and 104 mg/kg) raised pain thresholds against the hot stimulus and decreased acetic acid-induced writhing frequency and foot-licking duration in NTG-induced migraine mice. Compared with the model group, calcitonin gene-related peptide (CGRP) and NO levels were downregulated, but 5-hydroxytryptamine (5-HT) and endothelin (ET) levels were upregulated along with rebalanced ET/NO ratio, and vasomotor dysfunction was alleviated by promoting cerebral blood flow (CBF) in the FSSOloaded CS-AL NPs (104 mg/kg) group. Conclusion: FSSO-loaded CS-AL NPs could attenuate migraine via inhibiting neuroinflammation in LPS-stimulated BV-2 cells and regulating vasoactive substances in NTG-induced migraine mice. These findings suggest that the FSS formula may be exploited as new phytotherapy for treating migraine. [ABSTRACT FROM AUTHOR]

In migraine patients with a poor response to a calcitonin gene-related peptide monoclonal antibody against the receptor, switching to a calcitonin gene-related peptide monoclonal antibodies against the ligand may be beneficial. This was a long-term real-world prospective analysis conducted in treatment-refractory chronic migraine patients coming from two large tertiary referral headache centres, who did not achieve a meaningful response to erenumab and were switched to fremanezumab. Responders to fremanezumab were considered those who achieved at least 30% reduction in monthly migraine days by month 3, compared to the post-erenumab baseline. Secondary efficacy and disability outcomes were analysed. Thirty-nine patients (female n = 32, 82.1%; median age: 49 years old, IQR = 29.0–56.0) were included. After three months of treatment with fremanezumab, ten out of 39 patients (25.6%) were considered responders. Four of the 11 patients who continued fremanezumab became responders at month 6, increasing the number of responders to 14 patients (35.9%). Responders received a median of 12 injections (IQR = 9.0–18.0) at the time of the analysis. After the last treatment, 13 patients (33.3%) remained responders. The number of mean monthly migraine days significantly decreased from 21.4 at baseline (IQR = 10.7–30.0) to 8.6 (IQR = 3.8–13.9) at the last follow-up. Painkillers intake and HIT-6 score were significantly reduced at the last follow-up. About 1/3 of patients with treatment refractory chronic migraine who have a disappointing response to erenumab and switch to fremanezumab, obtained a meaningful and sustained improvement of their migraine load over time, supporting the appropriateness of this therapeutic approach in clinical practice. [ABSTRACT FROM AUTHOR]

Post-burn pruritus and neuropathic pain significantly affect the quality of life of affected individuals in several domains including psychosocial well-being, sleep and general impairment in activities of daily living. Whilst neural mediators involved in itch in the non-burns setting have been well investigated, there remains a lacuna of literature examining the pathophysiological and histological changes unique to burn-related pruritus and neuropathic pain. The aim of our study was to conduct a scoping review into the neural factors that contribute to burn-related pruritus and neuropathic pain. A scoping review was conducted to provide an overview of the available evidence. The PubMed, EMBASE and Medline databases were searched for publications. Data regarding neural mediators implicated, population demographics, total body surface area (TBSA) affected and sex was extracted. In total, 11 studies were included in this review with a total of 881 patients. The most frequently investigated neurotransmitter was the Substance P (SP) neuropeptide which appeared in 36% of studies (n = 4), followed by calcitonin gene-related peptide (CGRP) in 27% of studies (n = 3). Post-burn pruritus and neuropathic pain are symptomatic experiences that are predicated upon a heterogeneous group of underlying mechanisms. What is clear from the literature, however, is that itch and pain may occur secondary to the influence of both neuropeptides, such as SP, and other neural mediators including Transient receptor protein channels. Of the articles included for review, they were characterized by small sample sizes and large differences in statistical methodology and reporting. [ABSTRACT FROM AUTHOR]

Background: In real-world studies, it is unclear whether galcanezumab has a significant effect in the first week after administration. Methods: We retrospectively assessed 55 high-frequency episodic migraine (HFEM) and chronic migraine patients who received three galcanezumab doses. Mean changes in the numbers of weekly migraine days (WMDs) during month 1 and migraine days per month (MMDs) after 1–3 months of treatment were obtained. Clinical factors related to a ≥ 50% response rate (RR) at month 3 were analyzed. The prediction of ≥ 50% responders at month 3 using different weekly RRs at week 1 (W1) was evaluated. The RR at W1 was calculated with the following formula: RR (%) = 100 − [(WMDs at W1/baseline WMD) × 100]. Results: The number of MMDs significantly improved from baseline to 1, 2 and 3 months. The ≥ 50% RR was 50.9% at 3 months. The number of WMDs decreased significantly from baseline to week 1 (− 1.6 ± 1.7 days), week 2 (− 1.2 ± 1.6 days), week 3 (− 1.0 ± 1.3 days), and week 4 (− 1.1 ± 1.6 days) during month 1. The RR at W1 was largest (44.6 ± 42.2%). The ≥ 30%, ≥ 50% and ≥ 75% RRs at W1 were significantly predictive of a ≥ 50% RR at 3 months. Logistic regression analysis predicting a ≥ 50% RR at month 3 showed that the RR at W1 was the sole contributing factor. Conclusion: In our study, galcanezumab showed a significant effect in the first week after administration, and the RR at W1 could predict the RR at 3 months. [ABSTRACT FROM AUTHOR]

A "brain-skin" connection has been long been observed between chronic stress and chronic inflammatory skin disease including urticaria, psoriasis, atopic dermatitis, and prurigo nodularis. The relationship appears to be bidirectional. Chronic psychological stress has been shown to sustain hyperactivity of the sympathetic branch of the autonomic nervous system. Chronic stress is proinflammatory and in the context of several dermatologic disorders may be associated with an increase in dermal nerve fiber density, mast cells, nerve growth factor and calcitonin-gene-related peptide (CGRP). Furthermore, CGRP elicits a TH2-polarized T-cell response that is a hallmark of chronic pruritic conditions such as atopic dermatitis and prurigo nodularis. This TH2 response contributes directly to acute pruritus as well as the sensitization of cutaneous sensory neurons that are critical for chronic pruritus. Prurigo nodularis is a debilitating skin disorder featuring prominent nerve structural, neuropeptide, and TH2 cytokine aberrations that is a model deserving of future study. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of ubrogepant for the acute treatment of perimenstrual migraine (pmM) attacks. Background: Ubrogepant is an oral calcitonin gene‐related peptide receptor antagonist approved for the acute treatment of migraine in adults. Methods: After completing one of two phase 3 trials, participants could enroll in a phase 3, 52‐week, open‐label, long‐term safety extension trial and were re‐randomized 1:1:1 to usual care, ubrogepant 50 mg, or ubrogepant 100 mg. This post hoc analysis evaluated the efficacy of ubrogepant in a subset of women who treated ≥1 pmM or non‐pmM attack with ubrogepant. A pmM attack started on or between 2 days before and the first 3 days of menstrual bleeding. Mean (standard deviation [SD]) percentages of ubrogepant‐treated attacks achieving 2‐h pain freedom and pain relief were reported, with outcomes weighted equally by participant. Results: Of 734 women in the modified intent‐to‐treat population, 354 reported ≥1 menstrual cycle start date and a ubrogepant‐treated headache day in the same month. A qualifying pmM and non‐pmM attack was reported by 278 and 716 women, respectively. Pain freedom at 2 h was achieved in a mean (SD) of 28.7% (37.4) of pmM attacks and 22.1% (26.9) of non‐pmM attacks treated with ubrogepant 50 mg (p = 0.054) and 29.7% (35.2) versus 25.3% (26.3) of attacks treated with ubrogepant 100 mg (p = 0.757). No difference was found in the mean percentage of ubrogepant‐treated pmM and non‐pmM attacks that achieved 2‐h pain relief with ubrogepant 50 mg (64.8% [39.9] vs. 65.2% [32.4]; p = 0.683) and with 100 mg (67.1% [37.4] vs. 68.4% [30.2]; p = 0.273). Treatment‐related treatment‐emergent adverse events were reported by 8.8% (12/137) and 12.8% (18/141) in the ubrogepant 50 and 100 mg pmM subgroups, respectively. Conclusions: Ubrogepant demonstrated similar efficacy for the treatment of pmM and non‐pmM attacks. No new safety signals were identified. [ABSTRACT FROM AUTHOR]

Background. Monoclonal antibodies (mAbs) directed against the calcitonin gene-related peptide (CGRP) or its receptor represented the first targeted and specialized approach to migraine prophylaxis. Nevertheless, they have been rarely considered in the treatment of vestibular migraine (VM). Our aim was to evaluate the effectiveness of anti-CGRP mAbs in VM patients who did not respond to conventional migraine treatments. Methods. Consecutive VM patients treated with erenumab were considered. As a comparison, we considered the same VM patients during conventional migraine treatments (i.e., propranolol, flunarizine, or valproic acid), which were tried before mAbs therapy. Videonystagmography, the Italian version of the Dizziness Handicap Inventory (DHI) questionnaire, and migraine days over the last 3 months were evaluated in all patients before and after treatments. Results. In the present retrospective study, we included 21 female and 2 male VM patients, mean age 45.2 years. All patients underwent contrast-enhanced magnetic resonance imaging that ruled out other causes of vertigo. The DHI questionnaire significantly improved after mAb therapy (p < 0.0001). Mean migraine days over the last 3 months were significantly reduced after treatment (p = 0.001). Videonystagmography was altered in 11 (48%) patients prior to monoclonal antibodies. We found vertical positional nystagmus in 9 patients and horizontal positional nystagmus in 2 patients. After the treatment, we found vertical positional nystagmus only in 1 patient (p = 0.002). When patients were treated with conventional therapies, there was no significant reduction in DHI, and instrumental vestibular examinations remained altered. Conclusions. VM patients using anti-CGRP mAbs experienced a reduction in the dizziness-derived handicap, as reported in the DHI questionnaire. Furthermore, these treatments were significantly associated with a normalization of vestibular instrumental analysis. These findings were not seen with conventional treatments. Treatment with anti-CGRP mAbs may be effective in VM patients who did not respond to conventional migraine treatments. These findings should be tested in large, randomized clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: Mechanical overloading can trigger a degenerative‐like cascade in an organ culture of intervertebral disc (IVD). Whether the overloaded IVD can influence the activation of nociceptors (i.e., the damage sensing neurons) remains unknown. The study aims to investigate the influence of overloaded IVD conditioned medium (CM) on the activation of nociceptors. Methods: In the static loading regime, force‐controlled loading of 0.2 MPa for 20 h/day representing "long‐term sitting and standing" was compared with a displacement‐controlled loading maintaining original IVD height. In the dynamic loading regime, high‐frequency‐intensity loading representing degenerative "wear and tear" was compared with a lower‐frequency‐intensity loading. CM of differently loaded IVDs were collected to stimulate the primary bovine dorsal root ganglion (DRG) cultures. Calcium imaging (Fluo‐4) and calcitonin gene‐related peptide (CGRP) immunofluorescent labeling were jointly used to record the calcium flickering in CGRP(+) nociceptors. Results: Force‐controlled loading led to a higher IVD cell death compared to displacement‐controlled loading. Both static and dynamic overloading (force‐controlled and high‐frequency‐intensity loadings) elevated the frequency of calcium flickering in the subsurface space of CGRP(+) nociceptors compared to their mild loading counterparts. Conclusion: In the organ culture system, IVD overloading mediated an altered IVD‐nociceptor communication suggesting a biological mechanism associated with discogenic pain. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) is an effective curative cancer treatment. However, RT can seriously damage kidney tissues resulting in radiotherapy nephropathy (RN) where oxidative stress, inflammation, and apoptosis are among the common pathomechanisms. Carvacrol and thymol are known for their antioxidative, anti-inflammatory, and radioprotective activities. Therefore, this study investigated the nephroprotective potentials of carvacrol and/or thymol against gamma (γ) irradiation-induced nephrotoxicity in rats along with the nephroprotection mechanisms, particularly the involvement of insulin-like growth factor-1 (IGF-1) and calcitonin gene-related peptide (CGRP). Methods: Male rats were injected with carvacrol and/or thymol (80 and 50 mg/kg BW in the vehicle, respectively) for five days and exposed to a single dose of irradiation (6 Gy). Then, nephrotoxicity indices, oxidative stress, inflammatory, apoptotic biomarkers, and the histopathological examination were assessed. Also, IGF-1 and CGRP renal expressions were measured. Results: Carvacrol and/or thymol protected kidneys against γ-irradiation-induced acute RN which might be attributed to their antioxidative, anti-inflammatory, and antiapoptotic activities. Moreover, both reserved the γ -irradiation-induced downregulation of CGRP- TNF-α loop in acute RN that might be involved in the pathomechanisms of acute RN. Additionally, in Silico molecular docking simulation of carvacrol and thymol demonstrated promising fitting and binding with CGRP, IGF-1, TNF-α and NF-κB through the formation of hydrogen, hydrophobic and alkyl bonds with binding sites of target proteins which supports the reno-protective properties of carvacrol and thymol. Collectively, our findings open a new avenue for using carvacrol and/or thymol to improve the therapeutic index of γ-irradiation. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors in trigeminal ganglion (TG) neurons are often associated with sensory mechanisms, including nociception. We have previously reported the expression of P2Y12 receptors, which are Gi protein-coupled receptors, in TG cells. Activating P2Y12 receptors decreased the intracellular free Ca2+ concentration ([Ca2+]i). This indicated that intracellular adenosine 3′,5′-cyclic monophosphate (cAMP) levels can mediate Ca2+ signaling in TG cells. Here, we report more extensive-expression patterns of Gs protein-coupled receptors in primary cultured TG neurons isolated from 7-day-old newborn Wistar rats and further examine the roles of these receptors in cAMP signaling using the BacMam sensor in these neurons. To identify TG neurons, we also measured [Ca2+]i using fura-2 in TG cells and measured intracellular cAMP levels. TG neurons were positive for Gαs protein-coupled receptors, beta-2 adrenergic (β2), calcitonin gene-related peptide (CGRP), adenosine A2A (A2A), dopamine 1 (D1), prostaglandin I2 (IP), and 5-hydroxytriptamine 4 (5-HT4) receptor. Application of forskolin (FSK), an activator of adenylyl cyclase, transiently increased intracellular cAMP levels in TG neurons. The application of a phosphodiesterase inhibitor augmented the FSK-elicited intracellular cAMP level increase. These increases were significantly suppressed by the application of SQ22536, an adenylyl cyclase inhibitor, in TG neurons. Application of agonists for β2, CGRP, A2A, D1-like, IP, and 5-HT4 receptors increased intracellular cAMP levels. These increases were SQ22536-sensitive. These results suggested that TG neurons express β2, CGRP, A2A, D1, IP, and 5-HT4 receptors, and the activations of these Gαs protein-coupled receptors increase intracellular cAMP levels by activating adenylyl cyclase. [ABSTRACT FROM AUTHOR]

The nervus conarii provides sympathetic nerve innervation to the pineal gland, which is thought to be the primary type of stimulus to this gland. This underreported nerve has been mostly studied in animals. One function of the nervus conarii may be to activate pinealocytes to produce melatonin. Others have also found substance P and calcitonin gene-related peptide from the nervus conarii ending in the pineal gland. The following paper reviews the extant medical literature on the nervus conarii including its anatomy and potential function. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Treatment with the anti-CGRP antibody fremanezumab is successful in the prevention of chronic and frequent episodic migraine. In preclinical rat experiments, fremanezumab has been shown to reduce calcitonin gene-related peptide (CGRP) release from trigeminal tissues and aversive behaviour to noxious facial stimuli, which are characteristic pathophysiological changes accompanying severe primary headaches. To further decipher the effects of fremanezumab that underlie these antinociceptive effects in rats, immunohistochemistry and ELISA techniques were used to analyse the content and concentration of CGRP in the trigeminal ganglion, as well as the ratio of trigeminal ganglion neurons which are immunoreactive to CGRP and CGRP receptor components, 1–10 days after subcutaneous injection of fremanezumab (30 mg/kg) compared to an isotype control antibody. After fremanezumab treatment, the fraction of trigeminal ganglion neurons which were immunoreactive to CGRP and the CGRP receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) was significantly lowered compared to the control. The content and concentration of CGRP in trigeminal ganglia were not significantly changed. A long-lasting reduction in CGRP receptors expressed in trigeminal afferents may contribute to the attenuation of CGRP signalling and antinociceptive effects of monoclonal anti-CGRP antibodies in rats. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) contribute to skin inflammation. In psoriasis, the activation of cutaneous neuroimmune networks commonly leads to itch. To dissect the unique contribution of MCs to the cutaneous neuroinflammatory response in psoriasis, we examined their density, distribution, relation to nerve fibres and disease severity, and molecular signature by comparing RNA-seq analysis of MCs isolated from the skin of psoriasis patients and healthy volunteers. In involved psoriasis skin, MCs and Calcitonin Gene-Related Peptide (CGRP)-positive nerve fibres were spatially associated, and the increase of both MC and nerve fibre density correlated with disease severity. Gene set enrichment analysis of differentially expressed genes in involved psoriasis skin showed significant representation of neuron-related pathways (i.e., regulation of neuron projection along with dendrite and dendritic spine morphogenesis), indicating MC engagement in neuronal development and supporting the evidence of close MC–nerve fibre interaction. Furthermore, the analysis of 208 identified itch-associated genes revealed that CTSB, TLR4, and TACR1 were upregulated in MCs in involved skin. In both whole-skin published datasets and isolated MCs, CTSB was found to be a reliable indicator of the psoriasis condition. Furthermore, cathepsin B+ cells were increased in psoriasis skin and cathepsin B+ MC density correlated with disease severity. Therefore, our study provides evidence that cathepsin B could serve as a common indicator of the MC-dependent itch signature in psoriasis. [ABSTRACT FROM AUTHOR]

Background and Objective: Migraine is a neurological disorder characterized by episodes of moderate-to-severe headache. The emergence of drugs derived from monoclonal antibodies specific for the calcitonin gene has brought forth a therapeutic option for patients in whom the traditional treatments have failed. This study aimed to evaluate the clinical effectiveness of calcitonin gene-related peptide antibodies in the prevention of migraine through a systematic review and meta-analysis of observational cohort studies. Methods: A literature search for evidence was performed in electronic databases for observational studies that evaluated adult patients with migraine receiving calcitonin gene-related peptide receptor antagonists (e.g. erenumab, fremanezumab, galcanezumab and eptinezumab) and reported effectiveness outcomes (mean reduction in monthly migraine/headache days, and proportion of patients with 50% or greater reduction in migraine/headache days). Results: During the screening process, 47 records were included for data extraction and qualitative and quantitative analyses. The overall rate of patients with a reduction of at least 50% of mean monthly migraine days was 54% (95% CI 49–59%), and overall mean monthly migraine reduction was about 7.7 days (95% CI 8.4–7.0 days). Regarding the outcome ≥ 50% reduction in mean monthly headache reduction, the overall rate of patients with a reduction of at least 50% was 57% (95% CI 48–64%), and the overall mean monthly headache reduction was approximately 8.8 days (95% CI 10.1–7.5 days). Subgroup analyses considering the drug treatment used and type of migraine were consistent with previous results. Conclusions: The use of calcitonin gene-related peptide antibodies in real-world studies to prevent migraine demonstrates promising effectiveness outcomes, in agreement with those reported in previously published randomized clinical trial reports. [ABSTRACT FROM AUTHOR]

Background: Migraine is a debilitating disorder that undoubtedly has a significant impact both clinically and socially. New treatment options are necessary in Iran due to issues with tolerance, interactions, contraindications, and the lack of effectiveness of current medications. Main text and a short conclusion: Gepants are small compounds that target calcitonin gene-related peptide and are currently in further clinical development as preventive treatment alternatives for migraine. However, their development was halted due to hepatotoxicity, so this process still needs to be completed. Recent clinical trials have demonstrated the effectiveness, safety, and general patient tolerability of the latest generation of gepants. In light of this information, we aim to provide readers with a concise and helpful overview of the two types of gepants and their potential side effects. [ABSTRACT FROM AUTHOR]

Bone resorption occurs after bone grafting, however, contemporaneous reconstruction of the innervation of the bone graft is a potential treatment to maintain the bone mass of the graft. The innervation of bone is an emerging research topic. To understand the potential molecular mechanisms of bone innervation after bone grafting, we collected normal iliac bone tissue as well as bone grafts with or without innervation from nine patients 1 year after surgery and performed RNA sequencing. We identified differentially expressed genes) from these samples and used the gene ontology and Kyoto Encyclopedia of Genes and Genomes databases for functional enrichment and signaling pathway analysis. In parallel, we established protein–protein interaction networks to screen functional modules. Based on bioinformatic results, we validated in vitro the osteogenic differentiation potential of rat bone marrow mesenchymal stem cells (BMMSCs) after calcitonin gene-related peptide (CGRP) stimulation and the expression of p38 MAPK and Wnt6/β-catenin pathways during osteogenesis. Our transcriptome analysis of bone grafts reveals functional modules and signaling pathways of innervation which play a vital role in the structural and functional integration of the bone graft. Simultaneously, we demonstrate that CGRP regulates the differentiation of BMMSCs through p38 MAPK and Wnt6/β-catenin. [ABSTRACT FROM AUTHOR]

Migraine is a complex and debilitating neurological disease that affects 15% of the population worldwide. It is defined by the presence of recurrent severe attacks of disabling headache accompanied by other debilitating neurological symptoms. Important advancements have linked the trigeminovascular system and the neuropeptide calcitonin gene-related peptide to migraine pathophysiology, but the mechanisms underlying its pathogenesis and chronification remain unknown. Glial cells are essential for the correct development and functioning of the nervous system and, due to its implication in neurological diseases, have been hypothesised to have a role in migraine. Here we provide a narrative review of the role of glia in different phases of migraine through the analysis of preclinical studies. Current evidence shows that astrocytes and microglia are involved in the initiation and propagation of cortical spreading depolarization, the neurophysiological correlate of migraine aura. Furthermore, satellite glial cells within the trigeminal ganglia are implicated in the initiation and maintenance of orofacial pain, suggesting a role in the headache phase of migraine. Moreover, microglia in the trigeminocervical complex are involved in central sensitization, suggesting a role in chronic migraine. Taken altogether, glial cells have emerged as key players in migraine pathogenesis and chronification and future therapeutic strategies could be focused on targeting them to reduce the burden of migraine. [ABSTRACT FROM AUTHOR]

Objective: To explore the curative effect of nano-Kuiyangye on radiation esophagitis in Wistar rats, and to explore its possible mechanism. Methods: Wistar rats were irradiated locally with 30Gy rays to establish an animal model of radiation esophagitis in rats. After irradiation, nano-Kuiyangye, traditional Chinese medicine ulcer solution, Kangfuxin solution, nano-hydrotalcite matrix, and distilled water were used to intervene continuously for 7 d, during which the body weight and food intake of the rats were recorded. On day 7, blood was collected from the abdominal aorta under anesthesia, and the serum was obtained by centrifugation. The expression levels of pain-related factors prostaglandin-2 (PGE-2), substance P (SP), and calcitonin gene-related peptide (CGRP) were detected by ELISA. Rats were sacrificed after blood collection, and full-length esophageal tissues were taken. Hematoxylin-eosin (HE) staining was performed to analyze the pathological changes of the rat esophagus, and Western Blotting was used to detect the expression of nuclear factor-κB (NF-κB) inflammatory protein. Results: Compared with the control group, the total food intake and body weight of the rats within 7 d after modeling were significantly decreased (P<0.05), and the expressions of pain-related factors PGE-2, SP, and CGRP were higher than those of the control group (P<0.05)., the esophageal pathological damage score increased (P<0.05), and the expression of NF-κB inflammatory protein increased (P<0.05); after treatment, the total food intake of the rats in the nano-Kuiyangye intervention group within 7 days after modeling was higher than that in other groups (P<0.05), the expressions of pain-related factors PGE-2, SP, and CGRP were lower than those in the model group (P<0.05), the esophageal pathological damage score was lower (P<0.05), and the expression of NF-κB inflammatory proteins was lower (P<0.05). Conclusion: Nano-Kuiyangye increases the food intake of rats with radiation esophagitis, reduces esophageal tissue damage, and reduces the concentration of serum pain factors; the anti-inflammatory effect of nano-Kuiyangye may be related to the reduction of NF-κB inflammatory factor levels. [ABSTRACT FROM AUTHOR]

Migraine is a chronic neurovascular disease with a complex, not fully understood pathophysiology with multiple causes. People with migraine suffer from recurrent moderate to severe headache attacks varying from 4 to 72 h. The prevalence of migraine is two to three times higher in women compared with men. Importantly, it is the most disabling disease in women <50 years of age due to a high number of years lived with disability, resulting in a very high global socioeconomic burden. Robust evidence exists on the association between migraine with aura and increased incidence of cardiovascular disease (CVD), in particular ischaemic stroke. People with migraine with aura have an increased risk of atrial fibrillation, myocardial infarction, and cardiovascular death compared with those without migraine. Ongoing studies investigate the relation between migraine and angina with non-obstructive coronary arteries and migraine patients with patent foramen ovale. Medication for the treatment of migraine can be preventative medication, such as beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, antiepileptics, antidepressants, some of the long-acting calcitonin gene-related peptide receptor antagonists, or monoclonal antibodies against calcitonin gene-related peptide or its receptor, or acute medication, such as triptans and calcitonin gene-related peptide receptor antagonists. However, these medications might raise concerns when migraine patients also have CVD due to possible (coronary) side effects. Specifically, knowledge gaps remain for the contraindication to newer treatments for migraine. All cardiologists will encounter patients with CVD and migraine. This state-of-the-art review will outline the basic pathophysiology of migraine and the associations between migraine and CVD, discuss current therapies, and propose future directions for research. [ABSTRACT FROM AUTHOR]

Background: Intradetrusor injection of botulinum toxin A (BTX-A) is an effective treatment for overactive bladder (OAB). However, the occurrence of adverse events associated with BTX-A injection therapy hinders its acceptance among patients and its clinical promotion. Intravesical instillation of BTX-A offers a promising alternative to injection therapy for treating OAB. Nevertheless, due to the presence of the bladder permeability barrier (BPB) and the high molecular weight of BTX-A, direct instillation is unable to penetrate the bladder urothelium.Purpose: This study aims to investigate the safety and feasibility of ultrasound-assisted intravesical delivery of BTX-A and its potential benefits in a rat model of bladder hyperactivity induced by acetic acid instillation.Methods: Hengli BTX-A and microbubbles (MB) were mixed and prepared as a novel complex. The size distribution and zeta potentials of the complex were measured. On day 1, rats’ bladders were instilled with 1 mL of saline, BTX-A (20 U in 1 mL), MB, or MB-BTX-A (20 U in 1 mL) complex with or without ultrasound (US) exposure (1 MHz, 1.5 W/cm², 50% duty cycle, sonication for 10 s with a 10-s pause for a total of 10 min). The instillations were maintained for 30 min. After 7 days, cystometry was performed by filling the bladder with saline and 0.3% acetic acid (AA). Bladders were collected, weighed, and processed for immunoblotting, enzyme-linked immunosorbent assay (ELISA), histologic, and immunofluorescence analyses. Expression and distribution of SNAP-25 and SNAP-23 were assessed using Western blot and immunofluorescence. Calcitonin gene-related peptide (CGRP) in the bladder was detected using ELISA.Results: Intercontraction intervals (ICI) decreased by 72.99%, 76.16%, and 73.96% in rats pretreated with saline, BTX-A, and US + MB, respectively. However, rats treated with US + MB + BTX-A showed a significantly reduced response to AA instillation (57.31% decrease in ICI) without affecting amplitude, baseline pressure, or threshold pressure. Rats treated with US + MB + BTX-A exhibited increased cleavage of SNAP-25 and CGRP expression compared to the control group.Conclusion: Ultrasound-assisted intravesical delivery of BTX-A, with the assistance of MB cavitation, led to cleavage of SNAP-25, inhibition of calcitonin gene-related peptide release from afferent nerve terminals, and amelioration of acetic acid-induced bladder hyperactivity. These results support ultrasound-assisted intravesical delivery as an efficient non-injection method for administering BTX-A. [ABSTRACT FROM AUTHOR]

Background: The phase 3 randomized PERSIST study demonstrated the efficacy and tolerability of galcanezumab, a humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody for prevention of episodic migraines. We present findings from the open-label extension (OLE) of PERSIST, which evaluated the long-term efficacy and safety of galcanezumab in patients from China, India, and Russia. Methods: Patients completing the 3-month double-blind period of PERSIST were eligible for the 3-month OLE. Patients previously randomized to galcanezumab (GMB/GMB group) continued to receive galcanezumab 120 mg at all three visits during the OLE whereas patients randomized to placebo received a 240 mg loading dose of galcanezumab and then two 120 mg doses (PBO/GMB group). The primary outcome was the mean change (from double-blind baseline) in the number of monthly migraine headache days (MHDs) to month 6. Other endpoints included percent reduction in monthly MHDs from double-blind baseline to month 6, functional outcomes, safety and tolerability. Results: Overall, 99% of patients completing the double-blind period entered the OLE, and 96% completed through month 6. Patients in the GMB/GMB group achieved continued improvements in efficacy, with the reduction from baseline in the mean number of monthly MHDs, and slightly increasing from 4.01 days at the end of the double-blind period to 4.62 at the end of the OLE. Of patients who were ≥ 50% responders to galcanezumab at month 3, 66% maintained this response through to month 6. Patients in the PBO/GMB group experienced a rapid reduction in the number of monthly MHDs after initiation of galcanezumab, with a mean reduction from baseline of 4.56 days by month 6. The long-term benefits of galcanezumab were also supported by improvements in other efficacy and functional endpoints. All safety findings were consistent with the known long-term safety profile of galcanezumab; no patients experienced a treatment-related serious adverse event. Conclusions: Galcanezumab was efficacious and well-tolerated in patients with episodic migraine from China, India and Russia, for up to 6 months. Trial registration: ClinicalTrisABSTRACT_pals.gov NCT03963232, registered May 24, 2019. [ABSTRACT FROM AUTHOR]

Periradicular tissues have a rich supply of peripheral afferent neurons, also known as nociceptive neurons, originating from the trigeminal nerve. While their primary function is to relay pain signals to the brain, these are known to be involved in modulating innate and adaptive immunity by initiating neurogenic inflammation (NI). Studies have investigated neuroanatomy and measured the levels of biomolecules such as cytokines and neuropeptides in human saliva, gingival crevicular fluid, or blood/serum samples in apical periodontitis (AP) to validate the possible role of trigeminal nociceptors in inflammation and tissue regeneration. However, the contributions of nociceptors and the mechanisms involved in the neuro-immune interactions in AP are not fully understood. This narrative review addresses the complex biomolecular interactions of trigeminal nociceptors with macrophages, the effector cells of the innate immune system, in the clinical manifestations of AP. [ABSTRACT FROM AUTHOR]

Multiple drugs targeting the calcitonin gene-related peptide (CGRP) receptor have been developed for the treatment of migraine. Here, the effect of the small-molecule CGRP receptor antagonist zavegepant (0.1 nM–1 µM) on CGRP-induced relaxation in isolated human coronary arteries (HCAs) was investigated. A Schild plot was constructed and a pA2 value was calculated to determine the potency of zavegepant. The potency and Schild plot slopes of atogepant, olcegepant, rimegepant, telcagepant, ubrogepant and zavegepant in HCAs and human middle meningeal arteries (HMMAs), obtained from our earlier studies, were compared. Zavegepant shifted the concentration–response curve to CGRP in HCAs. The corresponding Schild plot slope was not different from unity, resulting in a pA2 value of 9.92 ± 0.24. No potency difference between HCAs and HMMAs was observed. Interestingly, olcegepant, atogepant and rimegepant, with a Schild plot slope < 1 in HCAs, were all >1 log unit more potent in HMMAs than in HCAs, while telcagepant, ubrogepant and zavegepant, with a Schild plot slope not different from unity, showed similar (<1 log difference) potency across both tissues. As a Schild plot slope < 1 may point to the involvement of multiple receptors, it is important to further identify the receptors involved in the relaxation to CGRP in HCAs, which may be used to improve the cardiovascular safety of future antimigraine drugs. [ABSTRACT FROM AUTHOR]

The optimal dose of galcanezumab for patients with migraine remains uncertain. Therefore, we conducted a network meta-analysis to assess the comparative effectiveness of various doses of galcanezumab for this group of patients. A systematically search was implemented in several databases including the PubMed, Ovid MEDILNE, Ovid EMBASE and Cochrane Library from inception of the databases until 31 August 2020. Only randomized clinical trials of adults with migraine that assessed galcanezumab therapy and reported clinical outcomes were included. The primary efficacy outcome was monthly change in migraine headache days (MHDs). The primary safety outcome was treatment-emergent adverse events (TEAEs). Overall, eight randomized clinical trials included 4,720 patients, were assessed in our systematic review. In terms of efficacy, galcanezumab 120 and 240 mg significantly reduced monthly MHDs (MD −2.02, 95% CrI −2.62 to −1.42; MD −2.06, 95% CrI −2.74 to −1.36, respectively) compared to the placebo. In terms of safety, galcanezumab 120, 150 mg and 240 mg significantly increased incidences of adverse events (RR 1.11, 95% CrI 1.03–1.20; RR 1.85, 95% CrI 1.27–2.81; RR 1.15, 95% CrI 1.06–1.24, respectively). Galcanezumab 240 mg offers the first level in terms of efficacy outcomes and galcanezumab 150 mg ranks the first level in terms of increasing treatment-emergent adverse events among adult patients with migraine. Attention should be devoted to the potential risk of adverse events, especially for injection site pain when the drug is administered subcutaneously. [ABSTRACT FROM AUTHOR]

Objective: To characterize migraine pathophysiology, presentation, and current treatment strategies, specifically in regard to vestibulocochlear manifestations of migraine. Methods: Narrative review of available literature. Results: Migraine disorder can be described as a spectrum of otologic manifestations, with vestibular migraine now recognized with fully‐fledged diagnostic criteria. Otologic manifestations are theorized to be due, in part, to trigeminal innervation of the inner ear structures and calcitonin gene‐related peptide (CGRP) expression within the labyrinth. Patients can experience vertigo, aural fullness, enhanced tinnitus, and hearing loss without the characteristic migraine headache, leading to under recognition of these symptoms as migraine‐related. Meniere's disease, mal de débarquement syndrome, persistent postural perceptual dizziness, and recurrent benign paroxysmal positional vertigo have close associations to migraine and may exist on the migraine spectrum. Migraine treatment consists of two goals: halting acute attacks (abortive therapy) and preventing attacks (prophylactic therapy). Abortive medications include triptans, corticosteroids, anti‐histamines, and anti‐emetics. Pharmacologic prophylaxis in conjunction with lifestyle modifications can decrease frequency and severity of symptoms and include tricyclic antidepressants, calcium channel blockers, anti‐epileptic medications, selective serotonin reuptake inhibitors, serotonin‐norepinephrine reuptake inhibitors, beta‐blockers, gepants, and monoclonal antibodies to CGRP. Promising evidence is emerging regarding the ability of migraine medications to positively treat the various otologic symptoms of migraine. Conclusion: Migraine disorder manifesting with primarily cochleovestibular symptoms can be challenging to diagnose and manage for practicing clinicians. Patients with various vestibulopathies that are closely related to migraine may benefit from migraine treatment. Lifestyle choices and prophylactic medications are key to satisfactorily preventing acute migrainous attacks and improve function. [ABSTRACT FROM AUTHOR]

Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications, and discovered by serendipity to be effective in migraine prevention, although often burdened by tolerability issues leading to low adherence. However, the progresses in unravelling the migraine pathophysiology allowed identifying novel putative targets as calcitonin gene-related peptide (CGRP). Nevertheless, despite the revolution brought by CGRP monoclonal antibodies and gepants, a significant percentage of patients still remains burdened by an unsatisfactory response, suggesting that other pathways may play a critical role, with an extent of involvement varying among different migraine patients. Specifically, neuropeptides of the CGRP family, such as adrenomedullin and amylin; molecules of the secretin family, such as pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP); receptors, such as transient receptor potential (TRP) channels; intracellular downstream determinants, such as potassium channels, but also the opioid system and the purinergic pathway, have been suggested to be involved in migraine pathophysiology. The present review provides an overview of these pathways, highlighting, based on preclinical and clinical evidence, as well as provocative studies, their potential role as future targets for migraine preventive treatment. [ABSTRACT FROM AUTHOR]

A bidirectional causal relationship has been established between temporomandibular disorders (TMDs) and chronic headaches. Recent advances in the neurobiology of chronic pain offer a framework for understanding the comorbidity between these two conditions that might reside in the shared biomolecular mechanisms of peripheral and central sensitization. The initiation of these processes is inflammatory in nature and is most likely mediated by key molecules, including calcitonin gene-related peptide (CGRP). This scoping review proposes that CGRP-mediated neuroinflammation in the trigeminal ganglion may partly explain the biomolecular bidirectional link between TMDs and chronic headaches. Finally, clinical implications of this neuropathologic process are briefly discussed. [ABSTRACT FROM AUTHOR]

Migraine is a common condition with disabling attacks that burdens people in the prime of their working lives. Despite years of research into migraine pathophysiology and therapeutics, much remains to be learned about the mechanisms at play in this complex neurovascular condition. Additionally, there remains a relative paucity of specific and targeted therapies available. Many sufferers remain underserved by currently available broad action preventive strategies, which are also complicated by poor tolerance and adverse effects. The development of preclinical migraine models in the laboratory, and the advances in human experimental migraine provocation, have led to the identification of key molecules likely involved in the molecular circuity of migraine, and have provided novel therapeutic targets. Importantly, the identification that vasoconstriction is neither necessary nor required for headache abortion has changed the landscape of migraine treatment and has broadened the therapy targets for patients with vascular risk factors or vascular disease. These targets include nitric oxide synthase (NOS) and several neuropeptides that are involved in migraine. The ability of NO donors and infusion of some of these peptides into humans to trigger typical migraine-like attacks has supported the development of targeted therapies against these molecules. Some of these, such as those targeting calcitonin gene-related peptide (CGRP), have already reached clinical practice and are displaying a positive outcome in migraineurs for the better by offering targeted efficacy without significant adverse effects. Others, such as those targeting pituitary adenylate cyclase activating polypeptide (PACAP), are showing promise and are likely to enter phase 3 clinical trials in the near future. Understanding these nitrergic and peptidergic mechanisms in migraine and their interactions is likely to lead to further therapeutic strategies for migraine in the future. [ABSTRACT FROM AUTHOR]

Endothelin-1 (ET-1) overactivity has been implicated as a factor contributing to glaucomatous neuropathy, and it has been utilized in animal models of retinal ischemia. The functional effects of long-term ET-1 exposure and possible compensatory mechanisms have, however, not been investigated. This was therefore the purpose of our study. ET-1 was delivered into rat eyes via a single intravitreal injection of 500 µM or via transgene delivery using an adeno-associated viral (AAV) vector. Retinal function was assessed using electroretinography (ERG) and the retinal expression of potentially compensatory genes was evaluated by means of qRT-PCR. Acute ET-1 delivery led to vasoconstriction and a significant reduction in the ERG response. AAV–ET-1 resulted in substantial transgene expression and ERG results similar to the acute ET-1 injections and comparable to other models of retinal ischemia. Compensatory changes were observed, including an increase in calcitonin gene-related peptide (CGRP) gene expression, which may both counterbalance the vasoconstrictive effects of ET-1 and provide neuroprotection. This chronic ET-1 ischemia model might be especially relevant to glaucoma research, mimicking the mild and repeated ischemic events in patients with long-term vascular dysfunction. The compensatory mechanisms, and particularly the role of vasodilatory CGRP in mitigating the retinal damage, warrant further investigation with the aim of evaluating new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Introduction: Electroacupuncture (EA) has a favorable impact on blood glucose stability. Blood glucose homeostasis is linked to sexual dimorphism. The majority of research has, however, focused on male participants, and sex differences have not been adequately taken into account. Methods: Here, we investigated how EA intervention affected pancreatic metabolic stress and explored if there were any sex-related changes in the maintenance of pancreatic function following intraperitoneal injection of a 10 g/kg glucose solution. Results: The transient receptor potential vanilloid 1 (TRPV1) calcitonin gene-related peptide (CGRP)-β cell pathway of the male pancreas is vital to maintain glucose metabolism in mice. In contrast, there is a sex bias in TRPV1, which implies that female mice have additional routes for preserving glucose homeostasis. EA is ineffective on Trpv1-/- male mice. It also revealed that TRPV1 in male mice served as a crucial mediator for the EA control of blood glucose. Meanwhile, the sympathetic marker tyrosine hydroxylase showed higher expression in the male pancreas, while the cholinergic marker choline acetyltransferase is expressed predominantly in female mice. Injecting γ-aminobutyric acid into the paraventricular nucleus of male mice caused a disruption in blood glucose and a lack of response to EA. It verified that male mice had a more pronounced sympathetic innervation of the pancreas than female mice. Conclusion: Our research has demonstrated that the TRPV1 sensory afferent nerve and sympathetic efferent nerve are capable of maintaining glucose homeostasis, exhibiting a distinct sexual dimorphism. Furthermore, this regulation is contingent on the EA effect. [ABSTRACT FROM AUTHOR]

Rimegepant is a small‐molecule calcitonin gene–related peptide receptor antagonist (gepant) with demonstrated efficacy and safety in the acute and preventive treatment of migraine. Here, we report the pharmacokinetics and safety of a single 75‐mg oral dose of rimegepant in subjects with severe, moderate, or mild hepatic impairment and matched healthy subjects from an open‐label, single‐dose, 4‐group phase 1 study. Thirty‐six subjects aged 41‐71 years were enrolled, including 6 each with severe, moderate, or mild hepatic impairment and 18 healthy subjects. All subjects completed the study. A <20% increase in total and unbound pharmacokinetics was observed in subjects with mild hepatic impairment and ≤65% increase with moderate hepatic impairment versus matched healthy controls. Total and unbound systemic exposure increased 2.0‐ and 3.9‐fold in the severe hepatic impairment group. In subjects with severe hepatic impairment, geometric mean ratios (severe impairment/controls) for total concentrations were 202.2% for area under the plasma concentration–time curve from time 0 to the last quantifiable concentration, 202.2% for area under the plasma concentration–time curve from time 0 to infinity, and 189.1% for maximum observed plasma concentration. Corresponding geometric mean ratios using unbound concentrations were 388.8% and 388.7%, respectively. Three (8.3%) subjects reported 4 treatment‐emergent adverse events. Rimegepant is not recommended for use in adults with severe hepatic impairment. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a severe adverse reaction to chemotherapeutics, which seriously affects the outcome of chemotherapy and patients' quality of life. Although it is commonly seen, it lacks effective treatment. Our previous study found that ozone could alleviate neuropathic pain. Damage-associated molecular patterns (DAMPs) or Toll-like receptor 4 (TLR4) or tissue factor (TF)-mediated neuroinflammation and microcirculation disturbance is the main reason for CIPN. Suppressors of cytokine signaling (SOCS) 3 is an endogenous negative feedback regulator of inflammation via TLR4 inhibition. Materials and Methods: Oxaliplatin (L-OHP) was used to establish mice's CIPN model. Nociceptive responses were assessed by observing the ICR mice's incidence of foot regression in mechanical indentation response experiments. Cell signaling assays were performed by Western blotting and immunohistochemistry. The mouse leukemia cells of monocyte--macrophage line RAW 264.7 were cultured to investigate the effects of ozone administration on macrophage. Results: Ozone decreased the expression of TF in the blood and sciatic nerve. It upregulated the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-SOCS3 axis to relieve CIPN and inhibit TF expression in vivo. SOCS3 expression was induced by ozone to inhibit the p38/TF signaling in RAW 246.7 cells. Ozone also prevented L-OHP-induced sciatic nerve demyelination. Microglia activation was inhibited, and c-Fos and calcitonin gene-related peptide (CGRP) expression was decreased in the spinal dorsal horn via ozone. Conclusions: In this study, we demonstrated that ozone could alleviate CIPN by upregulating the AMPK-SOCS3 axis to inhibit TF expression, which is a potential treatment for CIPN. [ABSTRACT FROM AUTHOR]