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Objective: To evaluate the therapeutic effects of trimetazidine (TMZ) in an experimental acute pancreatitis (AP) model induced with sodium taurocholate (STC). Summary of Background Data: At present, AP is considered a disease with no specific treatment. Preventing mitochondrial dysfunction in acinar cells may be an option for specific treatment of AP. TMZ is an anti-ischemic drug with anti-inflammatory, antioxidant, and mitochondrial modulatory effects. Methods: Rats were divided into 4 groups. AP was induced in the AP (n = 7) and AP + TMZ (n = 7) groups by an injection of 4% sodium taurocholate to the pancreatic duct. The sham (n = 6) and drug (n = 6) groups were designated as control groups. The AP + TMZ and drug groups were administered TMZ. Samples were taken at 72 hours, and histopathologic changes as well as biochemical parameters were analyzed. Results: Serum amylase, tissue myeloperoxidase activity, malondialdehyde levels, serum cytokine levels, and mast cell degranulation rates were elevated after induction of AP, whereas tissue antioxidant enzyme activities and cell viability rates [determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay] decreased. These parameters were found to be different in the AP group compared with those in all other groups (P < 0.05). A significant improvement of all parameters was achieved with the TMZ treatment of AP. Histologically, significant differences were found between the AP and AP + TMZ groups in terms of leukocyte infiltration, necrosis, and apoptotic cell counts. Conclusions: In this study, we demonstrated that TMZ treatment protected the mitochondrial function and prevented the activation of the inflammatory cascade in the sodium taurocholate–induced AP model.

This project was supported by the Finnish Academy (grant 277442). AR and RG were supported by the Program of Competitive Growth of Kazan Federal University and the subsidy (6.2313.2017/4.6) allocated to Kazan Federal University for the state assignment in the sphere of scientific activities. TM was supported by Academy of Finland (grant 298071). DN and VG were supported by the EDUFI program., Extracellular ATP activates inflammasome and triggers the release of multiple cytokines in various immune cells, a process primarily mediated by P2X7 receptors. However, the expression and functional properties of P2X7 receptors in native mast cells in tissues such as meninges where migraine pain originates from have not been explored. Here we report a novel model of murine cultured meningeal mast cells and using these, as well as easily accessible peritoneal mast cells, studied the mechanisms of ATP-mediated mast cell activation. We show that ATP induced a time and dose-dependent activation of peritoneal mast cells as analyzed by the uptake of organic dye YO-PRO1 as well as 4,6-diamidino-2-phenylindole (DAPI). Both YO-PRO1 and DAPI uptake in mast cells was mediated by the P2X7 subtype of ATP receptors as demonstrated by the inhibitory effect of P2X7 antagonist A839977. Consistent with this, significant YO-PRO1 uptake was promoted by the P2X7 agonist 2',3'-O-(benzoyl-4-benzoyl)-ATP (BzATP). Extracellular ATP-induced degranulation of native and cultured meningeal mast cells was shown with Toluidine Blue staining. Taken together, these data demonstrate the important contribution of P2X7 receptors to ATP-driven activation of mast cells, suggesting these purinergic mechanisms as potential triggers of neuroinflammation and pain sensitization in migraine., Finnish Academy [277442]; Program of Competitive Growth of Kazan Federal University; Academy of Finland [298071]; EDUFI program; [6.2313.2017/4.6]

Migraine is a primary headache disorder which has complex neurogenic pathophysiological mechanisms still requiring full elucidation. The sensory nerves and meningeal mast cell couplings in the migraine target tissue are very effective interfaces between the central nervous system and the immune system. These couplings fall into three categories: intimacy, cross-talk and a shared fate. Acting as the immediate call-center of the neuroimmune system, mast cells play fundamental roles in migraine pathophysiology. Considerable evidence shows that neuroinflammation in the meninges is the key element resulting in the sensitization of trigeminal nociceptors. The successive events such as neuropeptide release, vasodilation, plasma protein extravasation, and mast cell degranulation that form the basic characteristics of the inflammation are believed to occur in this persistent pain state. In this regard, mast cells and sensory neurons represent both the target and source of the neuropeptides that play autocrine, paracrine, and neuro-endocrine roles during this inflammatory process. This review intends to contribute to a better understanding of the meningeal mast cell and sensory neuron bi-directional interactions from molecular, cellular, functional points of view. Considering the fact that mast cells play a sine qua non role in expanding the opportunities for targeted new migraine therapies, it is of crucial importance to explore these multi-faceted interactions.

Objective: Inflammation underlies the pathological basis of most diseases. Substance-P is a key mediator that participates in various inflammatory processes and painful conditions. Mast cells (MCs) have a key role in inflammatory processes via mediators released from their granules. The experimental models for the investigation of pathogenesis and treatment of inflammatory diseases represent merely certain characteristics of inflammatory cases, therefore, more comprehensive models are required. We aimed to compare effects of administrations of the compound-48/80 and mast cell mediator suspension (MCMS) obtained from peritoneal MCs on the inflammation in rats.Methods: Rats were divided into five groups (n=6): Intraperitoneally, Control group received 0.2 ml saline; C-48/80 group received 2 mg/kg compound-48/80; MCMS group received 0.2 ml MCMS; Cr+C-48/80 group received 10 mg/kg cromolyn plus compound-48/80; Cr+MCMS group received cromolyn plus MCMS. Potent inflammatory markers, plasma substance-P levels, and number and degranulation of dural MCs were measured. Data were analyzed using one-way ANOVA followed by Dunnett’s post hoc test.Results: Compound-48/80 increased plasma substance-P levels (p

Objective: The cranial dura mater contains plenty of mast cells and is principally supplied by the middle meningeal artery which has a key role in the generation of headaches. Neurogenic inflammation caused by perivascular nerve activation and dural vasodilation is held responsible for migraine pain. Dural mast cells contribute neurogenic inflammation and migraine via vasoactive and proinflammatory mediators in their secretory granules. In the present study, it was aimed to investigate vasoactive effect of mast cell degranulating agent compound 48/80 induced dural mast cell degranulation on the middle meningeal artery and its anterior and posterior branches. Methods: Isolated skulls obtained from male Wistar rats were divided into 2 halves. The skull cavities with intact the dura mater were applied synthetic interstitial fluid for control group or mast cell degranulating agent compound 48/80 (10 mu g/ml) in synthetic interstitial fluid for treated group at 37 degrees C for 15 min. Diameters of middle meningeal artery and its anterior and posterior branches were measured and mast cells were counted from whole-mount preparations of meningeal dura mater. Results: While compound 48/80 induced massive degranulation of dural mast cells (P, Amaç: Kraniyal dura mater çok sayıda mast hücresi barındırmaktadır ve başlıca baş ağrılarının oluşumunda önemli bir role sahip olan middle meningeal arter tarafından beslenmektedir. Migren baş ağrısı oluşumunda, perivasküler sinir aktivasyonu ve dural vazodilatasyonun yol açtığı nörojenik enflamasyon sorumlu tutulmaktadır. Dural mast hücreleri sekretuar granüllerinde bulunan vazoaktif ve proinflamatuar mediyatörler aracılığıyla nörojenik enflamasyon ve migrene katkıda bulunmaktadır. Sunulan çalışmada bir mast hücre degranülatörü olan compound-48/80 ile oluşturulan dural mast hücre degranülasyonunun middle meningeal arter ve bunun anterior ve posterior dalları üzerine vazoaktif etkisinin araştırılması amaçlanmıştır. Yöntemler: Wistar erkek sıçanlardan elde edilen izole kranyumlar iki yarıya bölündü. Dura materi sağlam hemi-kranyumların boşluğuna kontrol grubu için 37 oC’ de yapay interstisyel sıvı ve çalışma grubu için bir mast hücre degranüle edici madde olan compound-48/80 (10 µg/ml) 15 dakika uygulandı. Middle meningeal arter ve bunun anterior ve posterior dallarının çapları ölçüldü ve meningeal dura mater preparasyonlarından mast hücreleri sayıldı. Bulgular: Compound-48/80 dural mast hücrelerinin kitlesel degranülasyonunu tetiklerken (P

This work was supported by Abant Izzet Baysal University Scientific Research Fund [Grant number: 2016.08.02.1060]., The exact mechanism of migraine pathophysiology still remains unclear due to the complex nature of migraine pain. Salmon calcitonin (SC) exhibits antinociceptive effects in the treatment of various pain conditions. In this study, we explored the mechanisms underlying the analgesic effect of salmon calcitonin on migrane pain using glyceryltrinitrate (GTN)-induced model of migraine and ex vivo meningeal preparations in rats. Rats were intraperitoneally administered saline, GTN (10mg/kg), vehicle, saline+GTN, SC (50g/kg)+GTN, and SC alone. Also, ex vivo meningeal preparations were applied topically 100mol/L GTN, 50mol/L SC, and SC+GTN. Calcitonin gene-related peptide (CGRP) contents of plasma, trigeminal neurons and superfusates were measured using enzyme-immunoassays. Dural mast cells were stained with toluidine blue. c-fos neuronal activity in trigeminal nucleus caudalis (TNC) sections were determined by immunohistochemical staining. The results showed that GTN triggered the increase in CGRP levels in plasma, trigeminal ganglion neurons and ex vivo meningeal preparations. Likewise, GTN-induced c-fos expression in TNC. In in vivo experiments, GTN caused dural mast cell degranulation, but similar effects were not seen in ex vivo experiments. Salmon calcitonin administration ameliorated GTN-induced migraine pain by reversing the increases induced by GTN. Our findings suggested that salmon calcitonin could alleviate the migraine-like pain by modulating CGRP release at different levels including the generation and conduction sites of migraine pain and mast cell behaviour in the dura mater. Therefore salmon calcitonin may be a new therapeutic choice in migraine pain relief., Abant Izzet Baysal University Scientific Research Fund [2016.08.02.1060]

Neurogenic inflammation in the dura mater caused by trigeminal nociceptive activation has been implicated in the pathophysiology of migraine. Vasoactive intestinal polypeptide (VIP) is a powerful neuroprotective neuropeptide that can modulate mast cell behavior. Migraine is also associated with sympathetic insufficiency. This study investigates the effects of VIP on the number of mast cells in the dura mater and on c-Fos expression in the trigeminal nucleus of sympathectomized rats. Experiments were carried out with 32 Sprague-Dawley male rats with body weights of 200–250 g. In the sympathectomized group, the left superior cervical sympathetic ganglion was removed. In the sympathectomized + VIP group, postoperative VIP 25 ng/kg/day (0.2 ml) was administered for 5 days. In the sham group, the ganglion and nerves were exposed but not dissected. Dura maters were stained with toluidine blue, and brainstems were labeled by indirect immunohistochemistry for c-Fos. Sympathectomy significantly increased the number of mast cells in both the ipsilateral and the contralateral dura mater (P

Objective: To examine lung tissue and the number of mast cells related to experimen - tal liver injury under the light microscope. Material and Methods: Adult male Wistar albino rats were used and they were divided into 3 groups with randomly dividing 6 animals in each group. The groups were control, CCL4 and ligation groups. CCl4 (1 ml/kg body weight, intraperitoneal) was administered twice per week, for 8 weeks. In ligation group, common bile duct was ligated with for 3 weeks. Liver and lung tissue samples were taken and stained with hematoxylin-eosin. Lung sections were stained with toluidine blue and parenchymal and pleural mast cells were counted. Re- sults: In ligation and CCl4 groups; interalveolar septal thickening, capillary congestion, edema, in - creased inflammatory cells and degranulated mast cells were observed in the lung tissues. In the ligation group, these changes were more pronounced than CCl4 group. Parenchymal and pleural mast cell numbers were significantly increased in the ligation and CCl4 groups when compared to the control group. Conclusion: Increased mast cell numbers could mediate lung injury induced by liver injury, which called as hepatopulmonary syndrome.

Mast cells, originating from bone marrow pluripotential cells are generally populated near to strategic locations of mammalian body. They store a wide variety of biologically active molecules in their granules and also can de novo synthesize an additional spectrum of mediators, depending on their microenvironment, phenotype and status. Mast cells have numerous receptors that can trigger a wide spectrum of cellular responses, some of them which can be preprogrammed against specific pathogens. Mast cells secrete mediators, go under total degranulation, or degranulate only some of the specific granules with required content according to the environmental conditions, pathogens or signaling molecules binding to their receptors. Mast cells are functionally multi faceted cells. A single cell can behave such as an immune cell, an endocrine cell and even as a sensorial neuron. In this context, mast cells can significantly influence inflammation, tissue remodeling, host defense and homeostasis. Specifically the mast cells proximal to nerve fibers, contain, secrete and respond to, several neuropeptides, suggesting many potential functions for mast cells in health and disease. Mast cells are target cells for neuropeptides and, they have distinct profiles of responsiveness to these molecules. This extends the flexibility of neurogenic signaling pathways via reciprocity. Those neuropeptides have direct and indirect effects on mast cells such as inducing or suppression of degranulation, triggering, modulation or amplification of mediator content and release. The exploration of interactions of mast cells and neurons is a promising field of study which may bring treatments to several diseases. Since mast cells seem to form the major link between neurons and inflammation via neuropeptides, mast cell and mast cell mediator connection may lead to a better understanding of the autocrine, paracrine, and neuro-immune-endocrine systems in physiology and physiopathology. Therefore, mast cell manipulator drug designs, capable of granular content modulation, with effects on, selective mediator release, activity and, ablation of mast cells, would be very beneficial for the treatment of various diseases that mast cells may be involved in.

1. The influence of lipopolysaccharide (LPS)-induced sepsis on the various mast cell phenotypes of rat dura mater were examined both by immunohistochemical and biochemical methods. 2. Three different populations of mast cells were identified in control rats: connective tissue type mast cells (CTMC) which contain rat mast cell protease1 (RMCP1), histamine, serotonin and heparin, mucosal type mast cells (MMC) which contain RMCP2, histamine and serotonin, and intermediate type which contains both RMCP1 and RMCP2 and probably various proportions of amines and heparin. 3. LPS (25 mg kg(-1) i.p.) caused changes in the proportions of the various types of mast cells. The number of MMC and intermediate type mast cells significantly increased and the number of mast cells immunopositive for both heparin and serotonin significantly decreased. Biochemical analysis showed that the histamine concentration of dura increased while its serotonin concentration decreased. 4. While vasoactive intestinal peptide (VIP) (25 ng kg(-1) i.p.) appears to potentiate LPS effects on dura mater mast cells, non-selective inhibition of nitric oxide (NO) synthase by N(g)-nitro-L-arginine methyl ester (L-NAME) (30 mg kg(-1) i.p.) did not influence sepsis-induced mast cell changes. 5. These findings suggest that mast cells of dura mater may play a role in brain protection during sepsis.

PubMed: 10704723, Vasoactive intestinal peptide (VIP) has potent protective activity against sepsis and increases the survival rate of septic rats and mice. The present study was planned to evaluate the effect of VIP on mast cell activity, histamine and methylhistamine levels and oxidative stress in the liver and kidneys of septic rats. The effect of VIP was compared to that of nitric oxide synthesis inhibition, previously tested extensively in septic shock models, with doubtful benefit. The present study showed that endotoxic shock did not lead to oxidative stress in either liver or kidney of the rats. On the other hand, mast cells, based on their location, displayed functional heterogeneity to the septic insults. VIP possibly modulated the specific reactions of the tissues to mediators released from mast cells during septic shock. The most prominent effect of VIP as compared to nitric oxide synthesis inhibition was related to mast cells. In conclusion, the prevention of mast cell reactivity by VIP could be a potential therapeutic strategy in controlling septic shock, This work was supported by the grant from Research Fund of Osmangazi University.

WOS: 000220538100058, PubMed ID: 14751391, Objectives. To elucidate the action of vasoactive intestinal peptide (VIP) on detorsion injury and the heterogeneity of mast cells in the testes of rats. Methods. Prepubertal male Sprague-Dawley rats were used in six groups. Group I was the control group (sham operation); group 2 had 2 hours of torsion; group 3, 2 hours of torsion and 1 hour of detorsion after administration of saline; group 4 had 2 hours of torsion and 4 hours of detorsion after administration of saline; group 5, 2 hours of torsion and 1 hour of detorsion after administration of intraperitoneal VIP (25 ng/kg); and group 6, 2 hours of torsion and 4 hours of detorsion after intraperitoneal VIP. The 2 hours of torsion was created by rotating the right testis 7200 in a clockwise direction. VIP (25 ng/kg) was injected intraperitoneally 1 minute before the 1 and 4 hours of detorsion. At the end of the experiment, catalase enzyme activity was measured polarographically, and superoxide dismutase, malondialdehyde, and protein were measured spectrophoto metrically. Nitric oxide was measured by capillary electrophoresis in the testicular tissue. Routine histologic examination of testicular mast cells was done under light microscopy; the histochemistry was also analyzed. Results. Torsion significantly induced oxidative stress, mast cell degranulation, and tissue damage. Detorsion attenuated oxidative stress without any diminution of the histologic damage to the tissue. VIP significantly protected the testicular tissue from detorsion injury. It also inhibited mast cell activity while increasing the heparin content. Conclusions. VIP can protect testicular tissue from detorsion injury. Heparin-containing mast cells seem to be important mediator cells for this protection

Both nitric oxide (NO) and mast cells play important roles in adipose and vascular tissue biology. Chronic cold stress decreases the sensitivity of vascular smooth muscle to various contractile agents including norepinephrine (NE). In our previous cold exposure study we found that the contractile response of isolated rat aortas to NE was significantly reduced, and the number of rat aortic adventitial mast cells decreased. Histologically and functionally, white and brown adipose tissue (WAT and BAT) can be distinguished. Beyond its significance in energy store/release and heat production, adipose tissue secretes multiple signaling molecules that have endocrine and paracrine role in the regulation of vascular functions. The aims of the present study were to examine chronic cold exposure-induced alterations in (i) the concentration of NO released from selected regions of WAT and BAT in female and male rats, (ii) the histochemistry of white and brown adipose mast cells, and (iii) whether adipose-derived NO affects the contraction of isolated rat aorta to NE. Twelve females and 12 males Spraque-Dawley rats (150-200 g body weight) were used. The rats were exposed to a cold/freely moving stress for 2 hours each day for 5 consecutive days. At the end of cold exposure, the rats were sacrificed, and samples of thoracic aorta with associated periadventitial adipose tissue (tunica adiposa) were obtained. WAT and BAT were isolated from subcutaneous abdominal and interscapular areas, respectively. The concentration of NO was measured by capillary electrophoresis and mast cells were evaluated histochemically. The response of aorta smooth muscles to NE was recorded in the isolated organ bath. To determine whether adipose-derived NO affects aorta contraction to NE, cumulative dose response curves to NE (10 -8 -10 -3 M) were obtained with or without isolated WAT/BAT suspended in the organ bath medium. In control animals, a gender-related significant difference in NO production in both WAT and BAT was found, NO levels being significantly higher in female than male rats. Data from the contractile response of isolated aorta to NE suggest that receptor affinity to NE is significantly different between female and male controls. Presence of BAT and WAT (isolated from cold-exposure animals) in the bath changed the response of aorta smooth muscle to NE. Displaying a gender dimorphism, BAT/WAT-derived NO, or other vasorelaxing factors, seem to reduce receptor density and/or affinity to NE. Adipose mast cell histochemistry also showed diversity in respect to subtype, gender, and cold exposure. Altogether, we found (i) a gender difference in adipose-released NO and in adipose mast cell histochemistry to cold exposure, and (ii) peripheral adipose tissues affect aortic contractile responses to NE likely by a NO-mediated pathway during cold exposure, suggesting that adipose tissue may limit cold-induced excessive vasoconstriction. Our ongoing study aims at the evaluation of whether aortic tunica adiposa itself could also contribute to this phenomenon. Adipobiology 2009; 1: 67-75.