Migraines are a common neurological disorder that significantly reduces quality of life. The sensitization of trigeminal afferents is a key factor in the development of the pain syndrome associated with migraine. Carbon monoxide (CO) is produced endogenously by heme oxygenase (HO), widely expressed in structures involved in pain processing. In our study, the role of CO in an acute and chronic nitroglycerin (NTG)-induced rat migraine model was investigated using behavioral, electrophysiological, biochemical and histological methods. The repeated administration of a CO donor (CORM-2) or an HO-1 inducer (CoPP) decreased mechanical hypersensitivity and photophobia of rats in the NTG-induced migraine model. Additionally, CORM-2 and CoPP prevented an increase in trigeminal afferent excitability, which was evaluated by the frequency of action potentials in response to KCl application. Preliminary CORM-2 or CoPP injections promoted mast cell stability in the meninges and prevented NTG-induced CGRP elevation in blood plasma. Our results suggest that exogenously or endogenously produced CO has a protective potential in preventing inflammation and the sensitization of peripheral trigeminal afferents, the activity of which underlies the occurrence of pain in migraine. This could contribute to the development of new approaches for migraine prevention.

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

The therapeutic potential of ribonucleolytic enzymes as antitumor and antiviral agents is well known. Currently, the cytotoxic and cytostatic properties of RNase A from bovine pancreas, ranpirnase (onconase), its analog amphinase from frog oocytes, and binase from Bacillus pumilus are being intensively studied. However, data on the side effects of RNases are currently insufficient. Detection of the genotoxic effect of RNases is important to justify the prospects for using RNases in antitumor therapy. Identification of possible changes in contractile activity of an isolated segment of the mouse colon, under the influence of RNases may also contribute to the justification of their subsequent application. Both of these indicators characterize frequent consequences of cancer radiotherapy and chemotherapy. In this regard, the aim of this work was to determine the clastogenic and/or aneugenic effect of RNase A and binase in in vivo micronucleus test and evaluate their effect on contractions of mouse proximal colon segments. It has been shown that RNases in therapeutic concentrations are not genotoxic and do not cause changes in spontaneous and carbochol-induced intestinal contractility, which indicates the safety of their use in the treatment of oncological diseases.

Migraine is characterized by severe pain and somatic symptoms like allodynia and photophobia, driven by neuroinflammation that sensitizes the trigeminal vascular system (TVS). This study investigated how neuroinflammation induced by systemic lipopolysaccharide (LPS) affects migraine-related nociceptive signaling. Using a chronic migraine model in rats with nitroglycerin (NTG), we compared prenatal and acute postnatal LPS administration. Rats with prenatal LPS exhibited lower mechanical thresholds and enhanced allodynia and photophobia after NTG. Acute LPS also increased allodynia, but not photophobia. Both LPS groups showed increased mast cell degranulation in the dura mater. Plasma CGRP after NTG administration was elevated in the acute LPS group. Electrophysiology revealed enhanced trigeminal afferent responses to serotonin in both acutely and prenatally LPS-treated rats. Calcium imaging demonstrated increased neuronal responses to serotonin and capsaicin, suggesting an upregulation of serotonin and TRPV1 receptors. Our findings show that LPS-induced neuroinflammation, whether prenatal or acute, promotes sensitization of peripheral and central nociceptive pathways, involving serotoninergic mechanisms.

P2X3 receptors are a validated molecular target in pain syndromes and chronic cough. Known P2X3 inhibitors generally suffer from poor selectivity and efficacy. Taking advantage of peptide combinatorial libraries found in venoms, we describe a P2X3 antagonist from the crab spider Thomisus onustus. This peptide potently inhibits P2X3 in the dorsal root and trigeminal ganglia neurons of rodents, as well as recombinant human P2X3, showing no effect on P2X2 or P2X2/3 receptors. PT6 presents a compact and rigid structure and produces pronounced antinociception in animal models of inflammatory and neuropathic pain at low doses (0.01-0.1 mg/kg subcutaneously). It does not show antinociceptive activity in P2rx3-knockout mice, providing further evidence in favor of its specificity. Importantly, PT6 shows no dysgeusia or ageusia effects, notoriously characteristic of small-molecule P2X3 ligands, and therefore stands out as an attractive hit for analgesic drug discovery.

The adverse maternal exposure during pregnancy leads to developmental disorders in the offspring that can be passed on to later generations. Epigenetic regulation of DNA transcription may mediate inherited metabolic diseases. An increase in homocysteine concentration in the blood is associated with epigenetic modifications of the genome, which can alter the fetal brain’s development program and cause cognitive impairment. The aim of our work was to identify changes in sensomotor development, behavioral reactions and cognitive functions of offspring of second generation rats (HcyF2) of hyperhomocysteinemia. Our results indicate that unconditioned reflexes and physical parameters are delayed in HcyF2 rats. In “open field”, HcyF2 rats showed higher levels of anxiety and decreased exploratory and motor activity, while coordination of movements studied in “rotarod” test was not impaired. Decreased limb muscle strength was shown in the “grip strength” test. Additionally, HcyF2 rats demonstrated an impaired learning and longterm memory in the Morris water maze. Biochemical analysis revealed an imbalance in the antioxidant systems, which was attributed to decreased activity of glutathione peroxidases and H2S synthesis enzymes. It was suggested that elevated homocysteine levels during pregnancy may result in epigenetic modifications of the genome, which can impact the metabolism of offspring and be inherited by future generations.

Elevation of the homocysteine concentration in the plasma called hyperhomocysteinemia (hHCY) during pregnancy causes a number of pre- and postnatal developmental disorders. The aim of our study was to analyze the effects of H2S donors -NaHS and N-acetylcysteine (NAC) on blood-brain barrier (BBB) permeability in rats with prenatal hHCY. In rats with mild hHCY BBB permeability assessed by Evans Blue extravasation in brain increased markedly throughout life. Administration of NaHS or NAC during pregnancy attenuated hHCY-associated damage and increased endogenous concentrations of sulfides in brain tissues. Acute application of dl-homocysteine thiolactone induced BBB leakage, which was prevented by the NMDA receptor antagonist MK-801 or H2S donors. Rats with hHCY demonstrated high levels of NO metabolite - nitrites and proinflammatory cytokines (IL-1β, TNF-α, IL-6) in brain. Lactate dehydrogenase (LDH) activity in the serum was higher in rats with hHCY. Mitochondrial complex-I activity was lower in brain of hHCY rats. NaHS treatment during pregnancy restored levels of proinflammatory cytokines, nitrites and activity of the respiratory chain complex in brain as well as the LDH activity in serum. Our data suggest that H2S has neuroprotective effects against prenatal hHCY-associated BBB disturbance providing a potential strategy for the prevention of developmental impairments in newborns.

Irritable bowel syndrome (IBS) is a multifactorial disorder, with altered intestinal motility, visceral hypersensitivity, and dysfunction of the gut-brain axis. The aim of our study was to analyze the role of nitric oxide (NO) in the inhibitory effects of sodium butyrate on spontaneous contractility of proximal colon in a mouse model of IBS. IBS was induced by intracolonic infusion of acetic acid in the early postnatal period. Spontaneous contractions of proximal colon segments were studied in isometric conditions. The amplitude and frequency of colon contractions were higher in the IBS group. Sodium butyrate exerted inhibitory effects on colon contractions, which were less pronounced in IBS group. NO donors decreased spontaneous colon contractility and prevented the inhibitory effects of sodium butyrate in control and IBS groups. Nitric oxide synthase (NOS) inhibition by L-NAME increased contractile activity more effective in the control group and decreased the inhibitory action of sodium butyrate. In IBS group, preliminary application of L-NAME did not prevent sodium butyrate action. Our data indicate that butyrate exerts its inhibitory effects on colon motility at least partially through activation of NO synthesis. In the IBS model group, the NO-dependent mechanisms were less effective probably due to downregulation of NOS.

The urgent task of modern pediatricians and neonatologists is to predict the course of the early neonatal period, during which the basic adaptive mechanisms of newborn children are in an unstable state. This is particularly important for the study of premature newborns, who are at high risk for an unfavorable outcome.Purpose. The aim of this study was to investigate the nature of early neonatal adaptation in children born between 32- and 36-weeks’ gestation, from mothers with burdened obstetric and gynecological histories and concomitant medical conditions.Material and methods. Out of 75 patients, we divided children born against a background of placental abruption and pre-eclampsia into separate groups. We provide a comparative analysis of their obstetric, gynecological, and medical histories, as well as their pre-dictive factors, somatic status dynamics, and laboratory and instrumental examinationsResults. Analysis of the data showed that in late preterm newborns, the presence of placental abruption in the history of 100% of cases led to the development of general somatic distress, with deterioration in hemodynamic and respiratory parameters, requiring transfer to the second phase of care. In children born preterm due to severe preeclampsia or other causes, stable severe conditions were observed in 33.3 and 39.6%, respectively, and 53.9 to 60% of infants required respiratory support.Conclusion. These findings allow for individualized assessment of a newborn’s condition in the first few days of life, based on predictive factors that may lead to a breakdown in compensatory responses.

Hyperhomocysteinemia (hHCY) is a metabolic disorder characterized by elevated levels of homocysteine in plasma. hHCY correlates with a high risk of migraine headaches, especially migraine with aura. Cortical spreading depression (CSD) is a wave of depolarization passing through neurons and glial cells of the cortex and is considered an electrophysiological correlate of migraine aura. The aim of the present study was to analyze neuronal activity and CSD in the somatosensory cortex of rats in vivo with prenatal hHCY and to assess cortex viability after 2 h of CSD generation. Female rats were fed a diet high in methionine, and their offspring with high homocysteine levels in plasma were further used in experiments. Recurrent CSD was evoked by local KCl application on the dura surface. Neuronal viability was assessed by measuring the activity of lactate dehydrogenase (LDH) in the brain and 2,3,5-triphenyltetrazolium chloride staining of the somatosensory cortex after two hours of CSD generation. Animals with hHCY exhibited higher neuronal activity, and more CSDs were generated in response to KCl, indicating higher cortical excitability. Propagation of recurrent CSD was impaired in supragranular cortical layers, and the recovery of multiple unit activity and evoked sensory potentials after CSD was delayed in the hHCY group. Finally, in animals with prenatal hHCY, an ischemic focus was identified as a consequence of multiple CSDs, along with elevated levels of LDH activity in brain tissues, suggestive of diminished neuronal viability. These findings imply that prolonged elevated levels of homocysteine may not only predispose to migraine with aura but also potentially elevate the risk of migrainous infarction.

ObjectivesInvestigation of chronic homocysteine action on the excitability and N-methyl-D-aspartate (NMDA) sensitivity of the peripheral trigeminovascular system of rats.BackgroundMigraine is a neurological disease that affects 15%-20% of the general population. Epidemiological observations show that an increase of the sulfur-containing amino acid homocysteine in plasma-called hyperhomocysteinemia-is associated with a high risk of migraine, especially migraine with aura. In animal studies, rats with hyperhomocysteinemia demonstrated mechanical allodynia, photophobia, and anxiety, and higher sensitivity to cortical spreading depression. In addition, rats with hyperhomocysteinemia were more sensitive in a model of chronic migraine induced by nitroglycerin which indicated the involvement of peripheral nociceptive mechanisms. The present work aimed to analyze the excitability of meningeal afferents and neurons isolated from the trigeminal ganglion of rats with prenatal hyperhomocysteinemia.MethodsExperiments were performed on male rats born from females fed with a methionine-rich diet before and during pregnancy. The activity of meningeal afferents was recorded extracellularly in hemiskull preparations ex vivo and action potentials were characterized using cluster analysis. The excitability of trigeminal ganglion neurons was assessed using whole-cell patch clamp recording techniques and calcium imaging studies. Meningeal mast cells were stained using toluidine blue.ResultsThe baseline extracellular recorded electrical activity of the trigeminal nerve was higher in the hyperhomocysteinemia group with larger amplitude action potentials. Lower concentrations of KCl caused an increase in the frequency of action potentials of trigeminal afferents recorded in rat hemiskull ex vivo preparations. In trigeminal ganglion neurons of rats with hyperhomocysteinemia, the current required to elicit at least one action potential (rheobase) was lower, and more action potentials were induced in response to stimulus of 2 x rheobase. In controls, short-term application of homocysteine and its derivatives increased the frequency of action potentials of the trigeminal nerve and induced Ca2+ transients in neurons, which are associated with the activation of NMDA receptors. At the same time, in rats with hyperhomocysteinemia, we did not observe an increased response of the trigeminal nerve to NMDA. Similarly, the parameters of Ca2+ transients induced by NMDA, homocysteine, and its derivatives were not changed in rats with hyperhomocysteinemia. Acute incubation of the meninges in homocysteine and homocysteinic acid did not change the state of the mast cells, whereas in the model of hyperhomocysteinemia, an increased degranulation of mast cells in the meninges was observed.ConclusionsOur results demonstrated higher excitability of the trigeminal system of rats with hyperhomocysteinemia. Together with our previous finding about the lower threshold of generation of cortical spreading depression in rats with hyperhomocysteinemia, the present data provide evidence of homocysteine as a factor that increases the sensitivity of the peripheral migraine mechanisms, and the control of homocysteine level may be an important strategy for reducing the risk and/or severity of migraine headache attacks. Homocysteine is an amino acid that is usually present in blood plasma at low levels; however, elevated homocysteine is associated with a higher risk of migraine, and high levels of homocysteine in rats cause higher excitability of the trigeminal system (parts of the brain involved in the sensation of pain). In a laboratory study, we studied the reasons why the trigeminal system was more reactive in rats with high homocysteine. Our findings suggest that controlling homocysteine levels may be a strategy for reducing migraine attacks in humans.

The urgent task of modern pediatrics is the study of the etiology and pathophysiology of community-acquired pneumonia in school-aged children due to difficulties in diagnosis and treatment, as well as the high risk of life-threatening complications and death.Purpose. To investigate the activity of pro-inflammatory and anti-inflammatory responses as measured by cytokine levels in the peripheral blood of children with community-acquired pneumococcal and non-pneumococcal pneumonia.Material and methods. The etiology of community-acquired pneumonia was confirmed by comparing the results of rapid testing of pneumococcus in urine and data from traditional bacteriological methods. The study included 118 children (57 boys and 61 girls) aged 7 to 16 years with various morphological variants of community-acquired pneumonia, which were divided into 2 groups. The first group included 28 children with pneumococcal etiology of community-acquired pneumonia, and the second group included 90 patients with non-pneumococcal community-acquired pneumonia. Levels of interleukins IL-1, IL-4, IL-8 and TNF-α were determined in all children by enzyme immunoassays.Results. In the etiology of community-acquired pneumonia in school-age children, atypical pathogens are responsible for more than 50% of cases. The clinical effectiveness of rapid testing of pneumococcal antigens in urine has been shown, and their use in routine pediatric practice has made it possible to timely identify a group of severe community-acquired pneumonia and reasonably prescribe antibacterial medications. It has been demonstrated that pneumococcal-induced pneumonia is characterized by higher levels of proinflammatory cytokines. These levels, along with the clinical course of the disease, confirm the high level of systemic inflammation. Relatively lower levels of proinflammatory cytokines corresponded to a more mild clinical picture of community-acquired pneumonia of non-pneumococcal etiology, which on the one hand may reflect a relatively «balanced» inflammatory response, and on the other hand determine the protracted and polyclinic course of the infectious process.Conclusion. The etiology of community-acquired pneumonia in school-age children is dominated by atypical pathogens. Community-acquired pneumonia of pneumococcal etiology has more severe clinical courses, and their early identification will allow for the appropriate prescription of initial antibacterial treatment.

Unfavorable conditions affecting mothers during pregnancy not only disrupt the development of the offspring, but can also affect subsequent generations. Epigenetic regulation of transcription is among the factors able to mediate hereditary metabolic diseases. Epigenetic modifications of the genome are observed in conditions of elevated blood homocysteine concentrations, which can be accompanied by changes in the fetal brain development program and cognitive impairment. The aim of the present work was to analyze the sensorimotor development, behavioral reactions, and cognitive functions of the offspring of rats with hyperhomocysteinemia in the second generation (HHcyF2). These studies demonstrated delays in the formation of unconditioned reflexes and physical parameters in HHcyF2 rats. Investigations in the open field test showed that these animals displayed high anxiety and decreased exploratory and motor activity, while motor coordination in the rotarod test was not impaired despite a decrease in limb muscle strength in a grip strength test. Learning and long-term memory in the Morris water maze test were impaired in HHcyF2 rats. Biochemical analysis revealed an imbalance in the functioning of antioxidant systems due to decreases in the activity of glutathione peroxidase and the enzymes of hydrogen sulfide synthesis. These studies suggest that high homocysteine levels during pregnancy lead to epigenetic changes in the genome which affect metabolism in the offspring and are transmitted to subsequent generations.

Increasing evidence suggests that the gut microbiota, through the “microbiota–gut–brain axis”, can regulate anxiety, mood, and cognitive abilities such as memory and learning processes. Consistently with this, treatments altering the gut microbiota, such as antibiotics and probiotics, may influence brain function and impact behavior. The mechanisms that underlie the interplay between the intestinal microbiota and the brain have been intensively studied. We aimed to investigate the effects of two probiotic lactobacilli strains, Lacticaseibacillus rhamnosus 12L and Lactiplantibacillus plantarum 8PA3, on behavioral disorders in mice induced by a two-week parenteral treatment with broad-spectrum antibiotics. On completion of the treatment, the mice were subjected to behavioral tests, including the open field test (OFT), novel object recognition test (ORT), and T-maze test. Antibiotic-treated mice demonstrated anxiety-related behavior, decreased cognition, and retarded exploratory activity that were ameliorated by the administration of probiotics. As was determined by high-performance liquid chromatography (HPLC), both tested strains produced serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), as well as dopamine, which was further metabolized into norepinephrine by L. plantarum 8PA3 and epinephrine by L. rhamnosus 12L. Moreover, these lactobacilli were found to harbor catecholamines and 3,4-dihydroxyphenylacetic acid (DOPAC) in their biomass when grown on MRS broth. Additionally, L. plantarum 8PA3 and L. rhamnosus 12L were able to impact oxidative stress via H2O2 production and antioxidant activity, as determined in this study by the ferrous oxidation–xylenol orange (FOX) assay and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay, respectively. The results obtained in this study support the role of probiotics as a promising therapeutic for neurological disorders. However, more investigations are required to confirm the clinical significance of this finding.

Introduction . The study of the set of mechanisms of inflammation regulation plays an important role in shaping understanding of the local and general protective and adaptive processes in paediatric respiratory infections. The cytokine system is taken as universal, pleiotropic regulators of the cascade of inflammatory, immune and metabolic processes. Nowadays, the drugs with the potential for effecting the course of cytokine reactions are of great interest. Aim . To evaluate the efficacy of the impact of low molecular weight interferon inducers with a wide range of biological activity on the severity of clinical symptoms and the level of pro- and anti-inflammatory cytokines of peripheral blood in paediatric respiratory infections. Materials and methods . 98 children with ARVI aged 4 to 11 years were examined, of which 57 children received meglumine acridone acetate as etiotropic antiviral therapy at recommended age-related doses and were included in the treatment group. 41 children receiving only symptomatic treatment were included in the comparison group. Results and discussions . Clinically, the use of meglumine acridone acetate resulted in decreased duration of the major symptoms of acute viral respiratory infections among children, reduced risk of complications, and decreased inflammatory manifestations. It was shown that the minimum levels of interleukin-1, -4 and -8 were typical for healthy children, which confirmed the activation of cytokine reactions only in the process of development of pathological symptoms from various organs and systems. An increase in all the studied cytokine levels was observed in ARVI, while the dominance in growth of pro-inflammatory cytokines with underlying slightly increased level of anti-inflammatory interleukin-4 was observed in severe general toxic syndrome and catarrhal signs. In similar cases, a balanced decrease in the levels of anti- and pro-inflammatory cytokines and a relatively rapid regression of clinical symptoms was noted during the meglumine acridone acetate therapy. Conclusions . The use of meglumine acridone acetate contributes to the rapid relief of the major clinical symptoms of acute respiratory viral infections, and shortens the duration of the disease. The nature of cytokine reactions can serve as a marker of an unfavourable course of ARVI. The prescription of low-molecular interferon inducers balances an increase in the levels of pro- and anti-inflammatory cytokines of peripheral blood.

According to modern concepts, the composition and diversity of the intestinal microbiota play an essential role in maintaining immunity, homeostasis, and, in general, the physiological functions of the host organism. Recently the positive role of the microbiota and its metabolites especially short-chain fatty acids, in the metabolism and functional activity of skeletal muscles was reported. The aim of our work was to analyze muscle strength and motor coordination in mice after injection of broad-spectrum antibiotics with simultaneous administration of a microbiota metabolite—one of the representatives of short-chain fatty acids—butyric acid. In addition, we determined the level of malondialdehyde, the concentration of total glutathione and the activity of glutathione peroxidases in the muscles of the hind limbs in mice with administration of antibiotics and butyric acid. The administration of antibiotics to adolescent mice for two weeks induced higher mortality and decrease of weight, and also caused significant changes in motor behavior, including an increase in horizontal motor activity, decrease in vertical motor activity, muscle strength, and motor coordination. A higher level of oxidative stress was found in the muscle tissues of the hind limbs of mice treated with antibiotics. At the same time, oral administration of butyric acid prevented the observed changes and improved not only behavioral disorders, but also partially reduced the level of oxidative stress. In conclusion, metabolite of normal microbiota has a positive effect on the functional and biochemical parameters of skeletal muscles in dysbiosis, which can be used to prevent loss of muscle function in various pathological conditions.

In this study we investigated the role of voltage dependent (K V ), Ca 2+ -activated (K Ca ), and inward rectifier (K ir ) potassium channels in the effects of hydrogen sulfide donor (H 2 S) sodium hydrosulfide (NaHS) on spontaneous contractile activity of rat jejunum. It was shown that NaHS dose-dependently (10–500 μM) reduced the tonus of the preparation, as well as the amplitude and frequency of spontaneous contractions of jejunum preparations under isometric conditions; the half-maximal effective concentration (EC 50 ) of the inhibitory effect of NaHS on the amplitude of contractions was 165 μM. The blocker of K V channels 4-AP (200 μM) caused an increase in the amplitude of spontaneous contractions. NaHS (200 μM) decreased the amplitude and frequency of spontaneous activity of the preparation in the presence of 4-AP as well as in the control, and the effect on basal tonus was less pronounced. Blockers of large conductance K Ca channels (BK), non-specific TEA (3 mM) and specific paxillin (1 μM), increased the amplitude of spontaneous contractions, while the depressing effect of NaHS was completely preserved. The selective blocker of small conductance K Ca channels (SK) NS8593 (4 μM) did not affect the tonus of the preparation and the parameters of spontaneous contractions; it did not prevent the effect of NaHS. The activator of K ATP channels diazoxide (100 μM) caused a decrease in the basal tonus of the preparation, as well as the amplitude and frequency of spontaneous contractions. Diazoxide and the K ATP channel blocker glibenclamide (50 μM) prevented the effect of NaHS on the tonus of the preparation. BaCl 2 , the K ir channel blocker (30 μM), caused an increase in the amplitude of spontaneous contractions and prevented the development of the NaHS inhibitory effects on the frequency and amplitude of spontaneous contractions; the decrease in tonus was less pronounced than in the control. Thus, a decrease in the basal tonus of the rat jejunum preparation under the action of the H 2 S donor was associated with activation of K ir channels, including K ATP channels, whereas the effect of H 2 S on amplitude and frequency was mediated by an increase in Ba 2+ -sensitive conductivity.

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.

Introduction. The study of the mechanisms of adaptation and consequences of deadaptation in newborns, and especially premature babies in the first days of life is an integral part of neonatal practice. The cytokine system is considered as sensitive and informative indicators of homeostatic disorders in newborns of different gestational ages.Aim. To assess the features of the early neonatal period in newborns of different gestational ages according to the nature of changes in the levels of interleukin-1, -4, -8 in the cord blood and on the 3-4th day of the infant's life.Materials and methods. 108 newborns were examined, of which 64 premature infants of the gestational age of 32 (0/7) - 36 (6/7) weeks were included in the treatment group: moderately premature infants (32 (0/7) - 33 (6/7) weeks) and late premature infants (34 (0/7) - 36 (6/7) weeks). The control group included 44 conditionally healthy full-term infants born between 37 (0/7) and 41 (6/7) week of gestation: early full-term (37 (0/7) - 38 (6/7) weeks) and full-term intants (more than 39 (0/7) weeks).Results and discussion. The full-term infants, as well as late premature infants, whose clinical status was assessed as satisfactory, usually showed minimum levels of all studied cytokines. If the early neonatal period was complicated, high levels of interleukin-1 and -8 with underlying slightly elevated levels of anti-inflammatory interleukin-4 were observed. This fact supports the activation of cytokine reactions during manifestation of pathological symptom groups generated by various organs and systems in the early neonatal period.Conclusion. The nature of cytokine reactions can serve as a marker of unfavourable course of the early neonatal period in premature infants and a criterion that justifies the implementation of necessary corrective measures.

In this work, we analyzed the role of voltage-gated (KV), calcium-activated (KCa), and inward-rectifier potassium channels (Kir) in the effects of hydrogen sulphide (H2S) donor sodium hydrosulphide (NaHS) on the spontaneous contractile activity of the rat jejunum. Experiments were performed on jejunum segments under isometric contraction conditions. It was shown that NaHS reduced the basal tension of the segments, the amplitude, and the frequency of spontaneous contractions in a dose-dependent manner (10–500 μM); the half-effective concentration (EC50) of the inhibitory effect of NaHS on amplitude was 165 μM. The KV channel blocker 4-AP (200 µM) increased the amplitude of spontaneous contractions and subsequent application of NaHS (200 μM) suppressed the amplitude and frequency of spontaneous activity as well as in the control; the effect on tonic tension was less pronounced. TEA (3 mM), a non-specific blocker, and paxillin (1 µM), a specific blocker of large conductance KСа (ВK) channels, increased the amplitude of spontaneous contractions, while the inhibitory effect of NaHS was completely preserved. The selective blocker of small conductance KCa (SK) channels NS8593 (4 μM) did not affect the tension and the parameters of spontaneous contractions and did not prevent the effects of NaHS. Diazoxide (100 μM), the opener of КATP channels, caused a decrease in the basal tone, the amplitude and frequency of spontaneous contractions. Diazoxide and KATP channel blocker glibenclamide (50 μM) prevented the effects of NaHS on the basal tone. The Kir-channel blocker BaCl2 (30 µM) increased the amplitude of spontaneous contractions and eliminated the inhibitory effects of NaHS on the frequency and amplitude of spontaneous contractions, and the basal tension decrease was less pronounced compared to control. Thus, a decrease in the tonic tension of a rat jejunum preparation under the action of an H2S donor is associated with the activation of Kir, including КATP channels, while the effects of H2S on the amplitude and frequency of spontaneous contractions are mediated by an increase in Ba2+-sensitive conductance.