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Background Transdermal nitroglycerin (NTG) is a potent smooth muscle relaxant acting as a tocolytic agent by acting on the uterine muscles. The transdermal patch allows for continuous and controlled release of NTG through the skin into the bloodstream. This method offers the advantage of sustained drug delivery over a prolonged period. Objective of the study The study aimed to evaluate the efficacy of NTG patches for the arrest of preterm labor. Materials and methods This retrospective study comprised 100 patients admitted to our tertiary care center, ranging from 27 to 35 weeks of gestation, exhibiting preterm labor, uterine contractions, effacement, and dilatation of the cervix, without comorbidities and complications. Results In this study, it was observed that the incidence of preterm labor was higher among women aged 21-25 years. Pregnancy duration was extended by an average of approximately 28.63 days in our study cohort, with 90% of patients experiencing a prolongation of pregnancy to 48 hours after the application of a transdermal NTG patch. Parity distribution showed 50% of patients having a parity of G2-G4 and 30% being primigravida. However, 40% of the participants reported experiencing side effects, including headaches (15%) and local reactions (25%), while 60% did not experience any adverse effects. Conclusion In this study we found that the application of transdermal NTG patches led to a mean prolongation of pregnancy by 28.63 days, allowing time for the administration of steroids and fetal maturation. The inhibition of preterm contractions was successful, with an efficacy rate of 92%. These findings suggest the potential effectiveness of transdermal NTG patches as a tocolytic agent in managing preterm labor. However, the occurrence of side effects highlights the importance of careful monitoring and management during treatment.

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Migraine is a widespread brain condition described by frequent, recurrent episodes of incapacitating, moderate-to-severe headaches with throbbing pain that are usually one-sided. It is the 2nd most debilitating state lived with disability in terms of years, with a prevalence rate of 15-20%. Significant drops in estrogen levels have been associated with triggering acute migraine attacks in certain cases. Phytoestrogens are plant-derived compounds that resemble estrogen in structure, enabling them to imitate estrogen's functions in the body by attaching to estrogen receptors. Thus, the study was aimed to explore the protective effect of genistein against migraine. Moreover, the role of nitric oxide was also studied in the observed effect of genistein. Nitric oxide (NO) is implicated in migraine pathophysiology due to its role in promoting cerebral vasodilation and modulation of pain perception. Exploring L-NAME, a nitric oxide synthase inhibitor in migraine research helps scientists better understand the role of NO in migraine. Nitroglycerine treatment significantly increased the facial-unilateral head pain and spontaneous pain, as evidenced by the increased number of head scratching and groomings. Nitroglycerine treatment also induced anxiogenic behavior in mice. A significant reduction in the number of entries in the light phase and open arm, respectively. Biochemical analysis indicated a significant increase in inflammatory and oxidative stress in the nitroglycerin group. A significant increase and decrease in brain TBARS and GSH were observed with nitroglycerine treatment, respectively. Moreover, nitroglycerine treatment has uplifted the serum TNF-α level. Genistein (20 mg/kg) significantly mitigated the facial-unilateral head pain, spontaneous pain, photophobia, and anxiety-like behavior induced by nitroglycerine. Biochemical analysis showed that genistein (20 mg/kg) significantly abrogated the nitroglycerine-induced lipid peroxidation and increased serum TNF-α level. Genistein treatment also upregulated the brain GSH level and downregulated the serum TNF-α level. The L-NAME-mediated alleviation of the protective effect of genistein might be attributed to the vasodilatory effect of L-NAME. Conclusively, it can be suggested that genistein might provide relief from migraine pain by inhibiting nitric oxide-mediated vasodilation and oxidative stress.

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Introduction: Hemorrhagic shock is characterized by derangements of the gastrointestinal microcirculation. Topical therapy with nitroglycerine or iloprost improves gastric tissue oxygenation but not regional perfusion, probably due to precapillary adrenergic innervation. Therefore, this study was designed to investigate the local effect of the parasympathomimetic carbachol alone and in combination with either nitroglycerine or iloprost on gastric and oral microcirculation during hemorrhagic shock. Methods: In a cross-over design five female foxhounds were repeatedly randomized into six experimental groups. Carbachol, or carbachol in combination with either nitroglycerine or iloprost were applied topically to the oral and gastric mucosa. Saline, nitroglycerine, or iloprost application alone served as control groups. Then, a fixed-volume hemorrhage was induced by arterial blood withdrawal followed by blood retransfusion after 1h of shock. Gastric and oral microcirculation was determined using reflectance spectrophotometry and laser Doppler flowmetry. Oral microcirculation was visualized with videomicroscopy. Statistics: 2-way-ANOVA for repeated measurements and Bonferroni post-hoc analysis (mean ± SEM; p < 0.05). Results: The induction of hemorrhage led to a decrease of gastric and oral tissue oxygenation, that was ameliorated by local carbachol and nitroglycerine application at the gastric mucosa. The sole use of local iloprost did not improve gastric tissue oxygenation but could be supplemented by local carbachol treatment. Adding carbachol to nitroglycerine did not further increase gastric tissue oxygenation. Gastric microvascular blood flow remained unchanged in all experimental groups. Oral microvascular blood flow, microvascular flow index and total vessel density decreased during shock. Local carbachol supply improved oral vessel density during shock and oral microvascular flow index in the late course of hemorrhage. Conclusion: The specific effect of shifting the autonomous balance by local carbachol treatment on microcirculatory variables varies between parts of the gastrointestinal tract. Contrary to our expectations, the improvement of gastric tissue oxygenation by local carbachol or nitroglycerine application was not related to increased microvascular perfusion. When carbachol is used in combination with local vasodilators, the additional effect on gastric tissue oxygenation depends on the specific drug combination. Therefore, modulation of tissue oxygen consumption, mitochondrial function or alterations in regional blood flow distribution should be investigated.

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BACKGROUND: The relationship between cumulative low-density lipoprotein cholesterol (LDL-C) exposure and progression of atherosclerosis remains uncertain. OBJECTIVE: The aim of this study was to determine the relationship between cumulative LDL-C level and flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID) and the presence of plaque in the common carotid artery (CCA). METHODS: This was a cross-sectional study. We measured FMD in 8208 subjects, NID in 1822 subjects, and CCA plaque in 591 subjects who were not taking lipid-lowering drugs. The subjects were divided into four groups based on cumulative LDL-C exposure: <4000 mg·year/dL, 4000-4999 mg·year/dL, 5000-5999 mg·year/dL, and ≥6000 mg·year/dL. RESULTS: The odds ratio of the lower quartile of FMD in the cholesterol-year-score <4000 mg·year/dL group was significantly higher than the odds ratios in the other groups. The odds ratio of the lower quartile of NID in the <4000 mg·year/dL group was significantly higher than the odds ratios in the 5000-5999 mg·year/dL and ≥6000 mg·year/dL groups. The odds ratio of the prevalence of CCA plaque in the <4000 mg·year/dL group was significantly higher than that in the ≥6000 mg·year/dL group. CONCLUSIONS: Endothelial dysfunction occurred from cumulative LDL-C exposure of 4000 mg·year/dL, vascular smooth muscle dysfunction occurred from cumulative LDL-C exposure of 5000 mg·year/dL, and prevalence of CCA plaque occurred from cumulative LDL-C exposure of 6000 mg·year/dL. CLINICAL TRIAL REGISTRY INFORMATION: http://www.umin.ac.jp (UMIN000012950, UMIN000012951, and UMIN000012952, UMIN000003409).

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Cardiovascular mortality has been shown to vary seasonally. However, it has not been determined whether vascular function is affected by the season. The purpose of this study was to investigate the associations of vascular function with season and outdoor temperature. Between April 2007 and March 2022, measurements of flow-mediated vasodilation (FMD) of the brachial artery as an index of endothelial function and nitroglycerine-induced vasodilation (NID) as an index of endothelium-independent vasodilation were performed in 2190 subjects. There was no significant seasonal difference in FMD (spring, 3.9 ± 3.1%; summer, 3.5 ± 3.0%; fall, 3.7 ± 3.0%; winter, 3.6 ± 3.2%; P = 0.14). There was no significant correlation between FMD and daily mean outdoor temperature (r = -0.02, P = 0.25). Multivariate analyses revealed that neither season (ß = -0.020, P = 0.31) nor outdoor temperature (ß = 0.005, P = 0.81) was significantly associated with FMD after adjustment for other confounding factors. There were significant seasonal differences in NID (spring, 12.8 ± 6.3%; summer, 12.0 ± 6.1%; fall, 11.7 ± 6.1%; winter, 12.3 ± 5.9%; P = 0.02). However, multivariate analysis revealed that there was no significant association between season and NID after adjustment for other confounding factors (ß = -0.012, P = 0.56). There was no significant correlation between NID and daily outdoor mean temperature (r = -0.03, P = 0.17). Multivariate analysis revealed that outdoor temperature was not significantly associated with NID (ß = -0.006, P = 0.78). There was no significant association of FMD or NID with season or outdoor temperature, suggesting that it is not necessary to take into account the effects of season and outdoor temperature on vascular function when interpreting the results of FMD and NID measurements. Public trials registry number: UMIN000039512.

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PURPOSE: To evaluate the efficacy and safety of transdermal glycerol trinitrate skin patches as an additive and effective agent for facilitating cervical ripening for labour induction. METHODS: This was a double-blinded prospective randomised clinical trial carried out in a major obstetric unit in India. Women who planned for labour induction were randomly allocated for induction either by combined application of glycerol trinitrate skin patches [GTN patch] and intracervical dinoprostone gel or by the gel only. Sample randomisation was done using a stratified block randomisation technique with a sealed envelope. The numbers designating the group allocation sequence were concealed from doctors, research staff, and investigators. Six hourly improvements were assessed in the modified Bishop's score, induction-delivery time interval, the need for oxytocin, maternal side effects and foetal outcomes. Data were analysed using SPSS software. RESULTS AND DISCUSSION: Recruitment Bishop scores, parity and gestational age were matched in both cases and the control group. The modified Bishop's score was statistically improved in study groups, as evidenced compositely and irrespective of parity. The two groups appeared to have no significant differences regarding other outcomes. The additional application of the GTN patch seems helpful to accelerate the progress of labour but could not yield any favourable labour outcome. The GTN patch does not impose additional feto-maternal adverse effects apart from increased incidences of headaches.

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Background: The use of pulmonary vasodilators for pulmonary arterial hypertension (PAH) has led to a favourable prognosis. In contrast, pulmonary veno-occlusive disease (PVOD) is characterized by the possibility of severe pulmonary oedema after specific PAH therapy. Pulmonary oedema presumably develops in association with pulmonary arterial vasodilation without concomitant pulmonary venodilation. The venous circulation maximally dilates with small amounts of nitroglycerine. Case summary: A 59-year-old woman with advanced PVOD was referred to our hospital. We performed a right heart catheterization after administering combination therapy with selexipag and macitentan, and intravenous nitroglycerine at 0.2 and 0.4 µg/kg/min decreased pulmonary arterial wedge pressure (PAWP) and mean pulmonary arterial pressure (PAP) to minimal levels. The final dose of 1 µg/kg/min yielded an ∼20% decrease in mean PAP and pulmonary vascular resistance (PVR). Discussion: Here, we described the acute effect of intravenous nitroglycerine on PAWP and PVR in a patient with PVOD. This case highlights the venodilation response even in advanced PVOD, suggesting the importance of further research into selective venous dilators as potent therapy.

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BACKGROUND: Preterm labor is one of the most important causes of hospitalization during pregnancy and can lead to serious complications in neonates. OBJECTIVE: This study aims to compare the effect of transdermal nitroglycerin (TNG) patches and sublingual tablets of Isosorbide dinitrate (ISD) for the prevention of preterm delivery. METHODS: A total of 110 healthy pregnant women aged 18-35 years with a healthy and alive fetus and gestational age between 24-34 weeks who had at least 8 regular uterine contractions per hour were included in this single-blinded clinical trial. After exclusion, the women were randomly divided into TNG (n = 50) and ISD (n = 49) groups. After the first dose of medication (TNG or ISD), patients who developed complications such as hypotension, headache, or both, were also excluded from the study. RESULTS: A total of 58 patients completed the treatment course (29 patients in each group). A significant difference in delayed preterm labor and recovery time was reported between the TNG and ISD groups. CONCLUSION: Complications and the number of contractions were not statistically different in the two groups. We concluded that the TNG patch is more effective than ISD in delaying labor. Both drugs are likely to have a similar incidence of side effects.

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Background: Uncontrolled elevation of intraoperative blood pressure can result in deleterious effects with increased risk of morbidity and mortality. Objectives: We aimed to compare nitroglycerine infusion with dexmedetomidine infusion in controlling accidental intraoperative uncontrolled hypertension. Methods: This comparative study was conducted on 73 hypertensive patients undergoing cancer surgeries who experienced uncontrolled intraoperative hypertension. The data of 38 patients were retrieved from the medical records for the nitroglycerine group and 35 patients were prospectively enrolled for the dexmedetomidine group. Group N received nitroglycerine infusion (0.3 - 1 µg/kg/min), while group D received dexmedetomidine infusion (0.2 - 0.7 µg/kg/h). Results: Both groups were comparable regarding their demographic data and clinical characteristics. Systolic, diastolic, and mean arterial pressure (MAP) values were significantly lower in group N compared to group D during the period between 60 and 120 minutes intraoperatively (P < 0.001). Heart rate values were significantly lower in group D than in group N (P < 0.001). Postoperative sedation scores were better for group D with lower analgesic requirements (P < 0.001). Conclusions: Dexmedetomidine infusion can be used to manage the uncontrolled intraoperative elevation of blood pressure in selected patient population.

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Background and Aim: In this study, the aim was to research the effects of smoking habits on controlled hypotension administered with nitroglycerin during ear-nose-throat surgery. Materials and Methods: This study administered controlled hypotension with nitroglycerin and total intravenous anesthesia to a total of 80 patients undergoing septoplasty operations. The patients were divided into two groups of 40 non-smokers (Group 1) and 40 smokers (Group 2). Intravenous propofol infusion was used for anesthesia maintenance. Nitroglycerin with 0.25-1 µg/kg/min dose was titrated to provide controlled hypotension. During this process, the hemodynamic parameters of patients, total propofol and nitroglycerin amounts used, operation duration, and duration of controlled hypotension were recorded at the end of the operation. At the end of the operation, the surgeon assessed the lack of blood in the surgical field with Fromme Scale. Results: Fromme scale values were significantly higher in Group 2 compared to Group 1. The MAP values at 10, 20, 30 min, and end of operation were lower, while 10- and 20-min heart rate values were higher in Group 2 compared to Group 1. Conclusion: Nitroglycerin, chosen for controlled hypotension to reduce hemorrhage in the surgical field during nasal surgery, was shown to cause more pronounced hypotension and reflex tachycardia due to endothelial dysfunction linked to nicotine in patients who smoke. Despite lower pressure values in the smoking group, the negative effects of nicotine on platelet functions combined with similar effects of nitroglycerin to increase bleeding amounts.

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Backgrounds A significant contributor to newborn morbidity and mortality is preterm birth. Several techniques have been employed to identify patients at risk of premature labour. However, these predictors are not always effective because of their multifactorial aetiology. Preterm labour can be suppressed largely through tocolysis. This study compared the effectiveness and safety of transdermal nitroglycerine and oral nifedipine in preventing premature labour. Methods This study was done at Acharya Vinoba Bhave Rural Hospital, Sawangi, Wardha, Maharashtra, from December 2020 to November 2022, on 130 women presenting with preterm labour pains between 28 and 37 weeks of gestational age. All the women selected were randomized into two equal groups by using the envelope method. Sixty-five women were given a nitroglycerine patch (Group A), and the rest (65 women) were given an oral nifedipine tablet (group B). The variables studied were mean days of prolongation of pregnancy, treatment outcome, steroid coverage, along with feto-maternal outcomes among both groups. Results The percentage of women whose pregnancy was prolonged for at least 48 hours in the nitroglycerine group was 75.3%, and in the nifedipine group it was 93.8%. Failure to achieve tocolysis, defined as delivery within 48 hours, was seen significantly more in the nitroglycerine group (24.6%) than in the nifedipine group (6.1%). The overall foetal outcomes were comparable in both groups. Conclusion Oral nifedipine was found to be superior to transdermal nifedipine patches in terms of efficacy and safety in the management of preterm labour, with a better side effect profile.

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BACKGROUND: Postoperative cognitive dysfunction is a noteworthy complication of deliberate hypotensive anesthesia. The aim of this work was to compare the effect of deliberate hypotensive anesthesia using nitroglycerine versus phentolamine on event-related potentials and cognitive function in patients undergoing septoplasty surgery. METHODS: This prospective randomized controlled trial was conducted on 80 patients indicated for septoplasty under general anesthesia; 40 patients received intra-operative Nitroglycerine and 40 patients received intra-operative Phentolamine. Cognitive assessment (using Paired Associate Learning test (PALT) and Benton Visual Retention test (BVRT)) and P300 recording were done for all included patients pre-operatively and one week postoperatively. RESULTS: The scores of PALT and Benton BVRT significantly declined one week following surgery in both Nitroglycerine and Phentolamine groups. There was no statistically significant difference between Nitroglycerine and Phentolamine groups in the postoperative decline in either PALT or BVRT (P-value = 0.342, 0.662 respectively). The values of P300 latency showed a significant delay one week following surgery in both Nitroglycerine and Phentolamine groups (P-value ≤ 0.001, 0.001), but in Nitroglycerine group, the delay is significantly higher than in Phentolamine group (P-value = 0.003). The values of P300 amplitude significantly decreased one week following surgery in both Nitroglycerine and Phentolamine groups (P-value ≤ 0.001, 0.001), but there was no statistically significant difference between Nitroglycerine and Phentolamine groups (P-value = 0.099). CONCLUSION: Phentolamine is preferred over nitroglycerin in deliberate hypotensive anesthesia because it has less harmful effect on cognitive function than nitroglycerin.

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Nitric oxide is one of the endogenous molecules that play a key role in migraine. However, the interaction between NO and the main players in the nociceptive activity of the meningeal trigeminal afferents-TRPV1 and P2X3 receptors-remains unstudied. In the current project, the effects of acute and chronic NO administration on the activity of TRPV1 and P2X3 receptors in the peripheral afferents were studied using electrophysiological recording of action potentials of the trigeminal nerve in the rat hemiskull preparations. The data obtained indicate that exogenous and endogenous NO increased the activity of the trigeminal nerve independent on the inhibition of the TRPV1 and P2X3 receptors. The activity of the trigeminal nerve triggered by ATP changed neither in acute incubation in the NO donor-sodium nitroprusside (SNP) nor in the chronic nitroglycerine (NG)-induced migraine model. Moreover, the chronic NG administration did not increase in the number of degranulated mast cells in the rat meninges. At the same time, the capsaicin-induced activity of the trigeminal nerve was higher with chronic NO administration or after acute NO application, and these effects were prevented by N-ethylmaleimide. In conclusion, we suggested that NO positively modulates the activity of TRPV1 receptors by S-nitrosylation, which may contribute to the pro-nociceptive action of NO and underlie the sensitization of meningeal afferents in chronic migraine.

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BACKGROUND: Long-term physiological dysfunction in coronary/systemic vasculature may persist in individuals with Kawasaki disease even in the absence of coronary artery abnormalities. We perform a systematic review and meta-analyses of studies assessing long-term vascular function in Kawasaki disease. METHODS: PubMed, Embase, and Web of Science databases were searched for relevant literature published till May 2021. Patients with Kawasaki disease were included as cases and healthy age/sex-matched individuals as controls. Newcastle Ottawa Scale was used to assess the study quality. Outcome measures were differences in markers of vascular function 1 year after diagnosis of Kawasaki disease. Data were analysed using Review Manager software. Comprehensive meta-analysis software was used for meta-regression. To assess the certainty of evidence, GRADE Profiler software was utilised. RESULTS: Of 2280 citations, 49 case-control studies (comprising 2714 cases and 2118 controls) were included for data synthesis. Decreased flow-mediated dilatation [3.83, 95%CI 0.94-6.72] and increased pulse-wave velocity [39.34 cm/sec, 95%CI 20.86-57.83], arterial stiffness [0.35, 95%CI 0.11-0.59], and common carotid artery intima-media thickness were noted in patients with Kawasaki disease. No significant difference was observed for nitroglycerine-mediated dilatation and endothelial peripheral artery tonometry (endo-PAT). Significant inter-study heterogeneity was observed for flow-mediated dilatation, arterial stiffness, carotid artery intima-media thickness, and endo-PAT. The GRADE evidence was of 'very low quality' for all outcome measures except 'moderate quality' for pulse-wave velocity. CONCLUSIONS: Evidence suggests the presence of long-term endothelial dysfunction in patients with Kawasaki disease even in the absence of coronary artery abnormalities. Avoidance of development of other cardiovascular risk factors seems prudent in patients with Kawasaki disease.

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Peri-stent restenosis following stent implantation is a major clinical problem. We have previously demonstrated that ultrasound-facilitated liposomal delivery of pioglitazone (PGN) to the arterial wall attenuated in-stent restenosis. To evaluate ultrasound mediated arterial delivery, in Yucatan miniswine, balloon inflations were performed in the carotid and subclavian arteries to simulate stent implantation and induce fibrin formation. The fibrin-binding peptide, GPRPPGGGC, was conjugated to echogenic liposomes (ELIP) containing dinitrophenyl-L-alanine-labelled pioglitazone (DNP-PGN) for targeting purposes. After pre-treating the arteries with nitroglycerine, fibrin-binding peptide-conjugated PGN-loaded ELIP (PAFb-DNP-PGN-ELIP also termed atheroglitatide) were delivered to the injured arteries via an endovascular catheter with an ultrasound core, either with or without ultrasound application (EKOSTM Endovascular System, Boston Scientific). In arteries treated with atheroglitatide, there was substantial delivery of PGN into the superficial layers (5 µm from the lumen) of the arteries with and without ultrasound, [(1951.17 relative fluorescence units (RFU) vs. 1901.17 RFU; P-value = 0.939)]. With ultrasound activation there was increased penetration of PGN into the deeper arterial layers (up to 35 µm from the lumen) [(13195.25 RFU vs. 7681.00 RFU; P-value = 0.005)]. These pre-clinical data demonstrate ultrasound mediated therapeutic vascular delivery to deeper layers of the injured arterial wall. This model has the potential to reduce peri- stent restenosis.

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Patients at each shock stage may behave and present differently with a spectrum of shock severity and adverse outcomes. Shock severity, shock aetiology, and several factors should be integrated in management decision-making. Although the contemporary shock stages classification provided a standardized shock severity assessment, individual agents or management strategy has not yet been studied in the context of each shock stage. The pre-shock state may comprise a wide range of presentations. Nitrate therapy has potential benefit in myocardial infarction and acute heart failure. Herein, this review aims to discuss the potential use of nitrate therapy in the context of the pre-shock state or stage B of the contemporary shock classification given its various presentations.

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This study aimed to investigate the antimigraine potential of quercetin in migraine pain induced by nitroglycerin (NTG), 10 mg/kg, intraperitoneal injection in rats. Quercetin was administered orally for 1 week, and behavioral parameters associated with pain were assessed 30 min after NTG injection. At the end of the study, the rats were killed so that immunohistochemical examination of their brains could be performed. The time and frequency of rearing and sniffing in the category of exploratory behavior, walking in the category of locomotor behavior, and total time spent in the light chamber were reduced in the disease control group compared with the normal group during the assessment of behavioral parameters. Pathologic migraine criteria, such as increased levels of calcitonin gene-related peptide and increased release of c-fos cells, were more prominent in the caudal nucleus triceminalis of the NTG control group. In the treatment groups, behavioral and pathological measures were less severe after pretreatment with quercetin at doses of 250 and 500 mg/kg. Therefore, it was concluded that quercetin improved the pain behavior of migraine patients in the NTG-induced migraine rat model. Quercetin is thought to have antimigraine effects due to its antioxidant and anti-inflammatory potential. Quercetin may therefore be a novel agent that can treat or prevent migraine pain and associated avoidance behaviors.

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Preclinical data point to the contribution of transient receptor potential ankyrin 1 (TRPA1) channels to the complex mechanisms underlying migraine pain. TRPA1 channels are expressed in primary sensory neurons, as well as in glial cells, and they can be activated/sensitized by inflammatory mediators. The aim of this study was to investigate the relationship between TRPA1 channels and glial activation in the modulation of trigeminal hyperalgesia in preclinical models of migraine based on acute and chronic nitroglycerin challenges. Rats were treated with ADM_12 (TRPA1 antagonist) and then underwent an orofacial formalin test to assess trigeminal hyperalgesia. mRNA levels of pro- and anti-inflammatory cytokines, calcitonin gene-related peptide (CGRP) and glia cell activation were evaluated in the Medulla oblongata and in the trigeminal ganglia. In the nitroglycerin-treated rats, ADM_12 showed an antihyperalgesic effect in both acute and chronic models, and it counteracted the changes in CGRP and cytokine gene expression. In the acute nitroglycerin model, ADM_12 reduced nitroglycerin-induced increase in microglial and astroglial activation in trigeminal nucleus caudalis area. In the chronic model, we detected a nitroglycerin-induced activation of satellite glial cells in the trigeminal ganglia that was inhibited by ADM_12. These findings show that TRPA1 antagonism reverts experimentally induced hyperalgesia in acute and chronic models of migraine and prevents multiple changes in inflammatory pathways by modulating glial activation.

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The pathophysiological mechanism underlying migraine-associated peripheral hypersensitivity remains unclear. Acid-sensing ion channels (ASICs) and transient receptor potential ankyrin 1 (TRPA1) are known to be causative pathogenic factors of mechanical and cold allodynia, respectively. Here, we sought to investigate their involvement in cold and mechanical allodynia of the face and hindpaws, respectively, in a mouse model of repetitive nitroglycerin (NTG)-induced migraine. NTG (10 mg/kg) was administered to the mice every other day for 9 days, followed 90 min later by HC-030031 (a TRPA1 blocker) or amiloride (a non-selective ASIC blocker). Mechanical or cold sensitivity of the hindpaw and facial regions was quantified using von-Frey filaments or acetone solution, respectively. Immunohistochemistry revealed that c-Fos expression was significantly increased in the trigeminal nucleus caudalis region but not in the spinal cord. Amiloride treatment only reduced NTG-induced hindpaw mechanical allodynia, whereas HC-030031 treatment only improved facial cold allodynia. Interestingly, the number of c-Fos positive cells decreased to a similar level in each drug treatment group. These findings demonstrate that facial cold allodynia and hindpaw mechanical allodynia are differentially mediated by activation of TRPA1 and ASIC, respectively, in mice with repetitive NTG-induced hypersensitivity.