Serotonin Content Research Articles

Calcitriol protects against reductions in striatal serotonin in rats treated with neurotoxic doses of methamphetamine

The present experiments were designed to examine the ability of calcitriol to protect against methamphetamine (METH)-induced reductions in striatal serotonin (5-HT) release and content. Male Fischer-344 rats were administered vehicle or calcitriol (0.3, 1.0, or 3.0 μg/kg, s.c.) once a day for 8 consecutive days. After the seventh day of treatment the animals were given METH (5 mg/kg, s.c.) or saline 4 times in 1 day at 2 h intervals. Seven days after the METH or saline treatments in vivo microdialysis experiments were conducted to measure potassium and d-amphetamine evoked overflow of 5-HT from the striatum. In animals treated with vehicle and METH there were significant reductions in both potassium and d-amphetamine evoked overflow of 5-HT. The 1.0 and 3.0 μg/kg/day doses of calcitriol provided significant protection against the 5-HT depleting effects of METH. A similar pattern of neuroprotection was found for post-mortem tissue levels of 5-HT. The calcitriol treatments did not prevent hyperthermia during the multiple injections of METH, indicating that the protective effects of calcitriol are not due to prevention of METH-induced increases in body temperature. These results suggest that calcitriol can provide significant protection against the 5-HT depleting effects of neurotoxic doses of METH.

Unravelling Impaired Hypoalgesia at Rest and in Response to Exercise in Patients with Chronic Whiplash-Associated Disorders: Effects of a Single Administration of Selective Serotonin Reuptake Inhibitor versus Selective Norepinephrine Reuptake Inhibitor.

(1) Background: Noradrenaline and serotonin have modulatory roles in pain signaling and in exercise-induced hypoalgesia. Patients with chronic whiplash-associated disorders often show impaired exercise-induced hypoalgesia. Therefore, this study aimed to examine the isolated effect of activating serotonergic or noradrenergic descending pathways on hypoalgesia at rest and in response to exercise in patients with chronic WAD by using respectively a single dose of a selective serotonin reuptake inhibitor (SSRI) and a selective norepinephrine reuptake inhibitor (NRI). (2) Methods: Twenty-five people with chronic WAD participated in this double-blind randomized controlled crossover experiment. Serotonin and noradrenaline concentrations were modulated by the oral ingestion of a single dose of citalopram (i.e., SSRI) or atomoxetine (i.e., SNRI). Quantitative sensory testing (including pressure pain thresholds and conditioned pain modulation) was measured before and after exercise in combination with no medication (1), atomoxetine (2), or citalopram (3) at three different test days. (3) Results: Random-intercept linear mixed models analysis was used to analyze pain outcomes (i.e., pain at rest and exercise-induced hypoalgesia) before and after exercise over the three conditions in patients with chronic WAD. No differences in pain at rest were found between the three conditions before exercise. The effect of exercise on pain outcome measures was not influenced by medication intake. The occupational status of the participants had a significant influence on the effect of exercise and medication on pain outcomes (p < 0.05). Patients working full-time had some positive effect of atomoxetine on pain facilitation (p < 0.05). Unemployed patients had some negative effect of citalopram on pain tolerance and experienced exercise-induced hypoalgesia (p < 0.05). (4) Conclusions: A single dose of citalopram or atomoxetine did not result in changes in hypoalgesia at rest and in response to exercise. These results do not support the use of SSRI or selective NRI to overcome impaired hypoalgesia at rest or in response to exercise in people with chronic WAD. Effect of exercise and medication on pain in patients with chronic WAD is influenced by the occupational status.

Electromagnetic field exposure affects the calling song, phonotaxis, and level of biogenic amines in crickets

The electromagnetic field (EMF) is ubiquitous in the environment, constituting a well-known but poorly understood stressor. Few studies have been conducted on insect responses to EMF, although they are an excellent experimental model and are of great ecological importance. In our work, we tested the effects of EMF (50 Hz, 7 mT) on the cricket Gryllus bimaculatus: the male calling song pattern, female mate choice, and levels of biogenic amines in the brain. Exposure of males to EMF increased the number and shortened the period of chips in their calling song (by 2.7% and 5% relative to the control song, respectively), but not the sound frequency. Aged (3-week-old) females were attracted to both natural and EMF-modified male signals, whereas young (1-week-old, virgin) females responded only to the modified signal, suggesting its higher attractance. Stress response of males to EMF may be responsible for the change in the calling song, as suggested by the changes in the amine levels in their brains: an increase in dopamine (by 50% relative to the control value), tyramine (65%), and serotonin (25%) concentration and a decrease in octopamine level (by 25%). These findings indicate that G. bimaculatus responds to EMF, like stressful conditions, which may change the condition and fitness of exposed individuals, disrupt mate selection, and, in consequence, affect the species’ existence.Graphical

Saffron carotenoids reversed the UCMS-induced depression and anxiety in rats: Behavioral and biochemical parameters, and hippocampal BDNF/ERK/CREB and NR2B signaling markers

BackgroundDepression is a debilitating condition that affects the mind and the individual's body. The improving effects of saffron on depression and anxiety have long been discussed, with limited information about the molecular mechanism of action. Hypothesis/PurposeInvestigating the effect of saffron carotenoids, Crocin and Crocetin, on depression and anxiety in rats by emphasizing some signaling pathways involved. Study DesignDepression and anxiety were induced in rats via unpredictable chronic mild stress (UCMS). Then different rat groups were treated with Crocin, Crocetin, Fluoxetine, and vehicle. Behavioral tests were done before and after treatment. MethodsThe serum Serotonin and Corticosterone and the expression of some hippocampal signaling proteins were studied. Furthermore, bioinformatics tools were used to predict the interactions of Crocin/ Crocetin with the Serotonin transporter and NMDA receptor subunit NR2B. Then, the patch-clamp was used to study the interaction of Crocetin with the NMDA receptor. ResultsVarious behavioral tests confirmed the induction of depression and the improvement of depression by these natural carotenoids. In addition, Crocin/ Crocetin significantly increased the decreased serum Serotonin and reduced the increased serum Corticosterone in the depressed groups. They also increased or caused a trend of increase in the CREB, ERK, BAD, BDNF, p11, and 5-HT1B expression in the hippocampus of the depressed groups. In addition, there were an increase or a trend in p-CREB/CREB, p-ERK1/2 /ERK1/2, and p-BAD/BAD ratios in the Crocin/ Crocetin treated depressed groups. However, the NR2B and FOXO3a expression showed a trend of decrease in depressed groups after treatment. The bioinformatics data indicated that Crocin/ Crocetin could bind to the Serotonin transporter (SLC6A4) and NR2B subunit of the NMDA receptor. Both carotenoids bind to the same site as Fluoxetine in the SLC6A4. However, they bound to different sites on the NR2B. So, Crocetin binds to NR2B at the same site as Ifenprodil. But Crocin bound to another site. The whole cell patch-clamp recording on the normal rat hippocampus revealed a significant decrease in the NMDA peak amplitude after Crocetin treatment, indicating its inhibitory effect on this receptor. ConclusionThe antidepressant activities of Crocin/ Crocetin are possibly due to their effects on Serotonin and Corticosterone serum concentrations, NR2B expression, and the downstream signaling pathways. Furthermore, these natural carotenoids, like Fluoxetine, induced an increasing tendency in p11 and 5HT1B in depressed rats.

Serotonin Transporter Activity in Mouse Oocytes Is a Positive Indicator of Follicular Growth and Oocyte Maturity.

Serotonin (5-hydroxytryptamine, 5-HT) is known to be a regulator of oocyte maturation in a large number of animal species. In maturing mammalian oocytes, the accumulation of exogenous, maternal serotonin occurs due to the activity of the membrane transporter SERT. In this work, we investigated how SERT activity in oocytes correlates with indicators of follicular selection and oocyte maturity. An immunohistochemical study showed that the difference in the 5-HT intake activity in oocytes does not correlate with the marker of apoptosis in follicular cells, but positively correlates with markers of follicular growth, such as granulosa proliferation and follicle size. Functional analysis of oocytes at different stages of maturation showed that the expression and activity of SERT increases with oocyte maturation. An in vivo experiment on administration of the selective serotonin reuptake inhibitor fluoxetine (20 mg/kg) for 7 days showed a significant decrease in the content of serotonin in both growing GV-oocytes and ovulated mature MII-oocytes. The data obtained clearly indicate that the mechanism of specific membrane transport of serotonin normally ensures the accumulation of serotonin in maturing oocytes, and can be considered as a promising positive marker of their mature status.

Developmental Neurotoxicity of Trichlorfon in Zebrafish Larvae.

Trichlorfon is an organophosphorus pesticide widely used in aquaculture and has potential neurotoxicity, but the underlying mechanism remains unclear. In the present study, zebrafish embryos were exposed to trichlorfon at concentrations (0, 0.1, 2 and 5 mg/L) used in aquaculture from 2 to 144 h post fertilization. Trichlorfon exposure reduced the survival rate, hatching rate, heartbeat and body length and increased the malformation rate of zebrafish larvae. The locomotor activity of larvae was significantly reduced. The results of molecular docking revealed that trichlorfon could bind to acetylcholinesterase (AChE). Furthermore, trichlorfon significantly inhibited AChE activity, accompanied by decreased acetylcholine, dopamine and serotonin content in larvae. The transcription patterns of genes related to acetylcholine (e.g., ache, chrna7, chata, hact and vacht), dopamine (e.g., drd4a and drd4b) and serotonin systems (e.g., tph1, tph2, tphr, serta, sertb, htrlaa and htrlab) were consistent with the changes in acetylcholine, dopamine, serotonin content and AChE activity. The genes related to the central nervous system (CNS) (e.g., a1-tubulin, mbp, syn2a, shha and gap-43) were downregulated. Our results indicate that the developmental neurotoxicity of trichlorfon might be attributed to disorders of cholinergic, dopaminergic and serotonergic signaling and the development of the CNS.

Methylphenidate induces a different response in the dorsal raphe as compared to ventral tegmental area and locus coeruleus: behavioral and concomitant neuronal recordings in adult rats.

Methylphenidate (MPD) is a psychostimulant used to treat attention deficit hyperactivity disorder. MPD exerts its neurocognitive effects through increasing concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the neuronal synapse. This study recorded from adult freely behaving rats a total of 1170 neurons, 403 from the ventral tegmental area (VTA), 409 from locus coeruleus (LC), and 356 from dorsal raphe (DR) nucleus, which are the main sources of DA, NE, and 5-HT to the mesocorticolimbic circuitry, respectively. Electrophysiological and behavioral activities were recorded simultaneously following acute and repetitive (chronic) saline or 0.6, 2.5, or 10.0mg/kg MPD. The uniqueness of this study is the evaluation of neuronal activity based on the behavioral response to chronic MPD. Animals received daily saline or MPD administration on experimental days 1-6 (ED1-6), followed by a 3-day wash-out period, and then MPD rechallenge on ED10. Each chronic MPD dose elicits behavioral sensitization in some animals, while in others, behavioral tolerance. Neuronal excitation following chronic MPD was observed in brains areas of animals exhibiting behavioral sensitization, while neuronal attenuation following chronic MPD was observed in those animals expressing behavioral tolerance. DR neuronal activity was most affected in response to acute and chronic MPD administration and responded differently compared to the neurons recorded from VTA and LC neurons at all doses. This suggests that although not directly related, DR and 5-HT are involved in the acute and chronic effects of MPD in adult rats, but exhibit a different role in response to MPD.

Serotonin secretion by blood platelets: accuracy of high-performance liquid chromatography-electrochemical technique compared with the isotopic test and use in a clinical laboratory

BackgroundMild secretion defects are the most frequent and challenging blood platelet disorders to diagnose. Most δ-granule secretion tests lack validation, are not quantitative, or have unreliable response to weak platelet agonists. ObjectivesTo compare platelet serotonin secretion by HPLC-electrochemical detection technique (HPLC-ECD) with the reference isotopic test (3H-5-HT), evaluating its performance in clinical laboratories. MethodsThe assay validation followed STARD-2015 recommendations. HPLC-ECD measured the nonsecreted serotonin remaining in platelet pellets after aggregation, comparing it with the reference 3H-5-HT assay. We studied subjects with inherited and aspirin-induced blood platelet disorders and assessed the HPLC-ECD operation for routine clinical diagnosis. ResultsCalibration curves were linear (R2 = 0.997), with SD for residuals of 3.91% and analytical sensitivity of 5ng/mL. Intra- and interassay imprecision bias ranged between −8.5% and 2.1% and −9% and 3.1%, respectively. Serotonin recovery and stability were >95%, and the variability range of measurements was −5.5% to 4.6%. Statistical differences detected between tests were biologically irrelevant, with bias of 1.48% (SD, 8.43) and CI agreement of −18% to 15%. Both assays distinctly detected platelet secretion induced by 10 μM epinephrine and 4 μmM adenosine diphosphate. However, HPLC-ECD is quantitative and more sensitive to low serotonin content in blood platelets. Reference cutoffs for each agonist were determined in 87 subjects. Initially, the HPLC-ECD requires relatively expensive equipment and trained operators but has remarkably cheap running costs and a turn-around time of 24-36 hours. We have used this diagnostic tool routinely for >8 years. ConclusionHPLC-ECD assay for platelet serotonin secretion is highly accurate, has advantages over the reference 3H-5-HT test, and is suitable as a clinical laboratory technique.

Oxidative stress in the pathogenesis of Alzheimer's disease: Improvement of memory-deteriorating disease by administration of plant enzyme

Plant enzymes are natural substances with almost no side effects and reported effects on spatial learning and histopathological alterations of the hippocampus in senescence-accelerated mice. In senescence-accelerated mice (SAMP8), this in vivo study examined the effects of a plant enzyme on the brain hippocampus, memory and spatial cognition. In the Morris water maze, a comparison between the control group of SAMR1 mice and the sham control group of SAMP8 mice (SAMP8 without plant enzymes administration) showed a significant reduction in arrival time, and in the probe test, it was divided into 4 divisions. Moreover, there was a significant increase in dwell time and number of crossings of the virtual platform area. The plant enzyme-treated group tended to have a shorter arrival time than the sham group, but not significantly different. Serum peroxy radicals were significantly suppressed in the plant enzyme-treated group compared with the sham group. Plant enzyme inhibited the peroxy radical in comparison to a sham control. With plant enzymes treatment, the lipid peroxidation level was significantly lowered in the brain tissue compared with the sham control group (p &lt; 0.05. Serotonin (5-HT) levels were significantly higher in the brain tissue of plant enzymes -treated mice than in that of sham control mice. There was no significant difference in the brain lipid peroxide concentration between the plant enzyme administration group and the sham group. In contrast, the serotonin concentration in the brain was significantly different between the plant enzymes administration group and the sham control group. The high neuron density (CA1 region) in the hippocampus of animals in the plant enzymes administration group indicates a possible improvement in memory.

Prenatal SAMe Treatment Changes via Epigenetic Mechanism/s USVs in Young Mice and Hippocampal Monoamines Turnover at Adulthood in a Mouse Model of Social Hierarchy and Depression.

The role of hippocampal monoamines and their related genes in the etiology and pathogenesis of depression-like behavior, particularly in impaired sociability traits and the meaning of changes in USVs emitted by pups, remains unknown. We assessed the effects of prenatal administration of S-adenosyl-methionine (SAMe) in Sub mice that exhibit depressive-like behavior on serotonergic, dopaminergic and noradrenergic metabolism and the activity of related genes in the hippocampus (HPC) in adulthood in comparison to saline-treated control Sub mice. During postnatal days 4 and 8, we recorded and analyzed the stress-induced USVs emitted by the pups and tried to understand how the changes in the USVs' calls may be related to the changes in the monoamines and the activity of related genes. The recordings of the USVs showed that SAMe induced a reduction in the emitted flat and one-frequency step-up call numbers in PND4 pups, whereas step-down type calls were significantly increased by SAMe in PND8 pups. The reduction in the number of calls induced by SAMe following separation from the mothers implies a reduction in anxiety, which is an additional sign of decreased depressive-like behavior. Prenatal SAMe increased the concentrations of serotonin in the HPC in both male and female mice without any change in the levels of 5HIAA. It also decreased the level of the dopamine metabolite DOPAC in females. There were no changes in the levels of norepinephrine and metabolites. Several changes in the expression of genes associated with monoamine metabolism were also induced by prenatal SAMe. The molecular and biochemical data obtained from the HPC studies are generally in accordance with our previously obtained data from the prefrontal cortex of similarly treated Sub mice on postnatal day 90. The changes in both monoamines and their gene expression observed 2-3 months after SAMe treatment are associated with the previously recorded behavioral improvement and seem to demonstrate that SAMe is effective via an epigenetic mechanism.

Effect of "Tiaoshen Tongluo" acupuncture on nerve function injury, muscle tension and neurotransmitters through Nrf2/ROS pathway in spastic rats after stroke

To observe the effect of "Tiaoshen Tongluo" acupuncture (TTA) at "Dingzhongxian" (MS5) and right "Dingpangxian" (MS8) on neurological injury, muscle tension and neurotransmitters through nuclear transcription factor E2 related factor 2 (Nrf2)/reactive oxygen species (ROS) signaling pathway in spastic rats after stroke, so as to explore its mechanisms underlying relief of post-stroke spasm (PSS). A total of 90 male SD rats were randomly divided into 6 groups, i.e. sham operation, PSS model, medication, non-acupoint acupuncture, TTA, TTA+ML385 groups, with 15 rats in each group. The PSS model was established by middle cerebral artery occlusion. After modeling, rats of the medication group were treated by gavage of baclofen (0.4 mg/kg), once daily for 7 days. For rats of the non-acupoint acupuncture group, the spot about 10 mm above the iliac crest and below the armpit of the affected side was needled, and for those of the TTA group and TTA+ML385 group, EA stimulation (1 mA, 2 Hz/15 Hz) was applied to MS5 and right MS8 for 10 min, once daily for 7 consecutive days. Intraperitoneal injection of ML385 ［ a specific nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor, 30 mg/kg］ was given to rats of the TTA+ML385 group before TTA was performed. The rats' neurological deficit score (0-4 points) was evaluated by referring to Zea Longa's methods and the muscular spasm degree of the quadriceps femoris of the left hindlimb (0-4 points) assessed by using Ashworth scale (MAS). The muscular tension of the left quadriceps femoris was measured by using a tension sensor, and Hoffman (H)-reflex response and M and H waves of electromyogram of the muscle between the metatarsals of the left foot were measured using an electrophysiological recorder. The cerebral infarction volume was measured after 2,3,5-triphenyltetrazolium chloride (TTC) staining. The contents of γ-aminobutyric acid (GABA), glycine (Gly), glutamic acid (Glu) and aspartic acid (Asp) of the right cortical infarct area were detected by using high performance capillary electrophoresis, and the contents of 5-hydroxytryptamine (5-HT), dopamine (DA) and norepinephrine (NE) were detected by fluorescence spectrophoto-metry, as well as the level of ROS in the right cerebral cortical infarction tissues was detected by dihydroethidium staining. The expression levels of Nrf2 and heme oxygenase-1 (HO-1) proteins in the infarcted cerebral area were detected using Western blot. Compared with the sham operation group, the neurological deficit score, MAS score, percentage of cerebral infarction volume, Hmax/Mmax ratio, contents of Glu and Asp and ROS level were significantly increased (P<0.001), whereas the muscle tone, stimulation threshold for inducing H-reflex, GABA, Gly, 5-HT, DA and NE contents, cerebral Nrf2 and HO-1 protein expression levels were apparently decreased (P<0.001) in the model group. In comparison with the model group, the neurological deficit score, MAS score, percentage of cerebral infarction volume, Hmax/Mmax ratio, contents of Glu, Asp and ROS levels were decreased (P<0.001), and the muscle tone, stimulation threshold for inducing H-reflex, GABA, Gly, 5-HT, DA and NE contents, Nrf2 and HO-1 protein expressions were increased (P<0.001, P<0.01) in both the medication and TTA groups. No significant differences were found between the non-acupoint group and model group, and between the medication and TTA groups in all the indexes mentioned above (P>0.05). After administration of ML385, the effects of TTA in reducing neurological deficit score, MAS score, Hmax/Mmax, percentage of cerebral infarct volume, Glu, Asp, ROS, and up-regulating H-reflex threshold, GABA, Gly, 5-HT, DA, NE, Nrf2 and HO-1 levels were eliminated (P<0.001，P<0.05,P<0.01). TTA can improve neurological behavior and muscle spasm in rats with PSS, which may be associated with its functions in regulating the levels of neurotransmitters in the cortical infarcted area by activating the Nrf2/ROS signaling pathway.

P-313 Dysregulation of endometrial stromal serotonin homeostasis impairs decidualization in patients with recurrent implantation failure via phosphatidylcholine metabolism

Abstract Study question Does abnormal serotonin homeostasis contribute to impaired endometrial decidualization in patients with recurrent implantation failure (RIF)? Summary answer Abnormal serotonin homeostasis in patients with RIF, which is accompanied by decreased expression of monoamine oxidase (MAO), affects decidualization of endometrial stromal cells. What is known already Previous studies have found that the expression of MAO, which metabolizes serotonin, is reduced in the endometrium of patients with RIF, and serotonin can induce disruption of implantation in rats. However, whether abnormal serotonin homeostasis leads to impaired decidualization in patients with RIF and the mechanism remains unclear. Study design, size, duration Endometrial samples from 31 patients with RIF and 31 fertile patients were used to investigate the expression levels of MAOA, MAOB, and serotonin. We isolated human endometrial stromal cells to investigate the role of MAOA, MAOB and serotonin in inducing decidualization in vitro and further explored the mechanism using RNA-seq and LC/MS analyses. Participants/materials, setting, methods The levels of serotonin in the endometrium of patients with RIF were detected by ELISA and immunohistofluorescence, and the key genes of abnormal serotonin metabolism were analyzed combined with single-cell sequencing data. The effects of MAO on the decidualization of stromal cells were investigated using human endometrial stromal cells in vitro induced decidualization model and mouse artificially induced decidualization model. The potential mechanisms of MAO regulating decidualization were explored by RNA-seq and LC/MS analysis. Main results and the role of chance We found that women with RIF have abnormal serotonin metabolism in the endometrium and attenuated MAO in endometrial stromal cells. Endometrial decidualization was accompanied by increased MAO in vivo and in vitro. Attenuated MAO caused increased local serotonin content in the endometrium, impairing stromal cell decidualization. RNA-seq and LC/MS analyses showed that abnormal lipid metabolism, especially phosphatidylcholine metabolism, was involved in MAO-deficiency induced defective decidualization. Furthermore, decidualization defects were rescued by phosphatidylcholine supplementation. Limitations, reasons for caution This study found that impaired serotonin metabolic homeostasis and abnormally reduced MAO expression were one of the reasons for repeated implantation failure. However, the source and other potential function of serotonin in the endometrium remain to be further explored. Wider implications of the findings This study shows new insights into the mechanisms of serotonin homeostasis in human endometrial decidualization and provides new biomarkers or targets for the treatment of patients with RIF. Trial registration number not applicable

P-313 Dysregulation of endometrial stromal serotonin homeostasis impairs decidualization in patients with recurrent implantation failure via phosphatidylcholine metabolism

Abstract Study question Does abnormal serotonin homeostasis contribute to impaired endometrial decidualization in patients with recurrent implantation failure (RIF)? Summary answer Abnormal serotonin homeostasis in patients with RIF, which is accompanied by decreased expression of monoamine oxidase (MAO), affects decidualization of endometrial stromal cells. What is known already Previous studies have found that the expression of MAO, which metabolizes serotonin, is reduced in the endometrium of patients with RIF, and serotonin can induce disruption of implantation in rats. However, whether abnormal serotonin homeostasis leads to impaired decidualization in patients with RIF and the mechanism remains unclear. Study design, size, duration Endometrial samples from 31 patients with RIF and 31 fertile patients were used to investigate the expression levels of MAOA, MAOB, and serotonin. We isolated human endometrial stromal cells to investigate the role of MAOA, MAOB and serotonin in inducing decidualization in vitro and further explored the mechanism using RNA-seq and LC/MS analyses. Participants/materials, setting, methods The levels of serotonin in the endometrium of patients with RIF were detected by ELISA and immunohistofluorescence, and the key genes of abnormal serotonin metabolism were analyzed combined with single-cell sequencing data. The effects of MAO on the decidualization of stromal cells were investigated using human endometrial stromal cells in vitro induced decidualization model and mouse artificially induced decidualization model. The potential mechanisms of MAO regulating decidualization were explored by RNA-seq and LC/MS analysis. Main results and the role of chance We found that women with RIF have abnormal serotonin metabolism in the endometrium and attenuated MAO in endometrial stromal cells. Endometrial decidualization was accompanied by increased MAO in vivo and in vitro. Attenuated MAO caused increased local serotonin content in the endometrium, impairing stromal cell decidualization. RNA-seq and LC/MS analyses showed that abnormal lipid metabolism, especially phosphatidylcholine metabolism, was involved in MAO-deficiency induced defective decidualization. Furthermore, decidualization defects were rescued by phosphatidylcholine supplementation. Limitations, reasons for caution This study found that impaired serotonin metabolic homeostasis and abnormally reduced MAO expression were one of the reasons for repeated implantation failure. However, the source and other potential function of serotonin in the endometrium remain to be further explored. Wider implications of the findings This study shows new insights into the mechanisms of serotonin homeostasis in human endometrial decidualization and provides new biomarkers or targets for the treatment of patients with RIF. Trial registration number not applicable Study funding No Funding source Funding by national/international organization(s)

Shaoyao Gancao decoction alleviates the central hyperalgesia of recurrent NTG-induced migraine in rats by regulating the NGF/TRPV1/COX-2 signal pathway

Ethnopharmacological relevanceShaoyao Gancao Decoction (SGD) is well known as an effective prescription for analgesia composed of two herbs, and is noted as traditional Chinese medicine morphine. It is widely used in various conditions causing pain, including migraine. However, there is currently no research exploring the mechanism of action in the treatment of migraines. Aim of the studyThe current research was devised to determine the underlying regulatory mechanism of SGD, by verifying its role in the NGF/TRPV1/COX-2 signal pathway. Materials and methodsThe active components in SGD were identified by UHPLC-MS. A migraine model was prepared by subcutaneous (s.c.) injection of nitroglycerin (NTG) into the neck to detect migraine-like behavior, orbital hyperalgesia threshold changes, and the therapeutic effect of SGD. The mechanism of SGD in remedying migraine was studied through transcriptome sequencing (RNA-seq), which was further validated utilizing Elisa, Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting (WB) experiments. ResultsIn the SGD chemical composition analysis, 45 components were identified including gallic acid, paeoniflorin and albiforin. In the behavioral experiments, SGD treatment significantly decreased the score of migraine-like head scratching in the NTG-induced migraine model (Mod) rats, while the hyperalgesia threshold increased outstandingly on days 10, 12, and 14 (P < 0.01, P < 0.001 or P < 0.0001). In migraine biomarkers experiment, compared with the Mod group, the 5-hydroxytryptamine (5-HT) contents were outstandingly enhanced by SGD treatment, while nitric oxide (NO) contents were markedly declined (P < 0.01). In the RNA-seq test, the down-regulated genes of SGD inhibiting hyperalgesia migraine included the neurotrophic factor (NGF) and transient receptor potential vanillic acid subfamily protein 1 receptor (TRPV1). The down-regulation pathway is the inflammatory mediator regulation of TRP channels. In gene set enrichment analysis (GSEA), SGD decreased the over-expression of protooncogene tyrosine-protein kinase Src (SRC) and TRPV1 in this pathway, and the two genes clustered at its lower end, with similar functions. PPI network results show that NGF interacts with TRPV1. Further verification shows that when compared with Mod group, the plasma cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) protein expression levels and the dura mater calcitonin gene-related peptide (CGRP), extracellular signal-regulated kinase (ERK), p-ERK, SRC and NGF protein expression levels in the SGD group were remarkably decreased (P < 0.01, P < 0.001 or P < 0.0001), and the expression level of TRPV1 protein showed a downward trend (P = 0.06). The expression levels of COX-2, NO, CGRP, TRPV1, SRC and NGF mRNA in the dura mater was overtly down-regulated (P < 0.05, P < 0.01 or P < 0.001). ConclusionsSGD has a significant inhibitory effect on the NGF/TRPV1/COX-2 signaling pathway that mediates central hyperalgesia migraine, thus suggesting the molecular mechanism of SGD in improving the symptoms of migraine may be related to the central hyperalgesia neurotransmitter that regulates the pathogenesis of migraine.

10-dehydrogingerdione amends tramadol-elicited neurotransmitters disturbance and apoptosis in the brain of male rats by repleting non-enzymatic antioxidants

Tramadol is analgesic medication to relief acute and chronic pain, referred to as alternative to opioid drugs however its abuse or overdosage may resulted in neuronal toxicity. This is attributed to severe fluctuations of neurotransmitters pattern along with cerebral inflammation and oxidative damage. Present work was undertaken to illustrate the cytoprotective effect of 10-dehydrogingerdione (10-DHGD) on the brain tissues of experimental rats due to Tramadol intake and its underlying mechanism. 24 male wistar rats were randomized into 4 equal groups. Group (1), received tramadol in a dose level 20 mg/kg intrapertioneal (i.p) daily for 30 days and referred to Tramadol group. Group (2), received both of 10-DHGD (10 mg/kg, orally) one hour before tramadol intake (dose as mentioned before) daily for 30 days. Group (3) received 10-DHGD only (10 mg/kg, orally) and daily for 30 days. Group (4), received no drugs and referred to control group for comparison. Tramadol significantly reduced Norepinephrin (NE), dopamine, serotonin and glutathione (reduced) contents of Cerebral cortex. lipid peroxidation, nuclear factor kappa B (NFkB), inducible nitric oxide synthase (INOS) levels and caspase-3 immunoreactivity showed however significant increase. Of note, 10-DHGD significantly increased neurotransmitters, glutathione contents while Malondialdehyde (MDA), Nitric oxide (NO), NFkB, INOS additionally caspase-3 immunoexpression showed significant decrease i.e counteracted to certain extent tramadol effect. These findings may refer to the cytoprotective potential of 10-DHGD against the neurotoxicity exerted by tramadol intake, most probably mediated via enhancement of endogenous antioxidants system.

On the degree of effectiveness of surgical aids for mechanical jaundice

Relevance. The problem of mechanical jaundice is the most urgent in abdominal surgery. This is primarily because the frequency of this pathology is steadily increasing, and the mortality rate does not have a distinct downward trend. Surgical tactics in case of mechanical jaundice remains multivariate, and a differentiated approach is needed for treating this contingent of patients, which is decisive in improving the results of surgical aids.The aim of the study. To improve the results of treatment of patients with mechanical jaundice of calculous etiology.Materials and methods. The analysis of the results of treatment and specially conducted studies in 554 patients with mechanical jaundice of calculous etiology was carried out. The patients underwent ultrasound, CT, and MRI. The concentration of adrenaline, norepinephrine, dopamine, 11-oxycorticosteroids, histamine, and serotonin, as well as toxic metabolic products were determined. The state of the autonomic nervous system was assessed by determining the autonomic index and mathematical analysis of the heart rate using variational pulsometry.Results. All the patients were operated on. Priority was given to stage-by-stage surgical tactics combining endoscopic decompression of the biliary tract with endoscopic papillosphincterotomy in the early stages of hospitalization and open surgical treatment after cupping the clinic of mechanical jaundice. There was a 3-fold increase in the number of endoscopic interventions. The mortality rate for the entire period decreased by 2.1 times. The reason for the results obtained is the degree of trauma of the operation. The parameters of the musculoskeletal, autonomic nervous, and sympathoadrenal systems were determined in patients divided into three groups. In the first group, primary open surgery on the biliary tract was performed, in the second — endoscopic papillosphincterotomy and abdominal surgery on the biliary tract, in the third — only endoscopic papillosphincterotomy. Endoscopic papillosphincterotomy had the most sparing effect on the functioning of the cardiovascular system and normalization of vegetative homeostasis. The volume of the surgical aid for mechanical jaundice affects the content of the sympathoadrenal system and biologically active substances in the blood plasma. When performing abdominal operations, compared with minimally invasive ones, the concentration of adrenaline, norepinephrine, serotonin, histamine, and 11-oxycorticosteroids in the blood increased by 1.5–2.5 times.Conclusion. The effectiveness and priority of minimally invasive operations for treating mechanical jaundice have been confirmed. The use of endoscopic resolution of biliary hypertension makes it possible to reduce the mortality rate against the background of a steady trend toward normalization of the indicators of the sympathoadrenal system and variational pulsometry.

Eucalyptol prevents pilocarpine-induced seizure and neuronal damage in mice, through the cholinergic, monoaminergic and antioxidant pathways

Current antiepileptic drugs can inhibit seizure occurrence but are not effective in preventing its onset. Moreover, they produce several side effects, which may impact the efficacy of the treatment. In addition, it has been stimulating the prospection of new molecules isolated from aromatic plants, with potential anticonvulsant and neuroprotective activities and less side effects. This study aimed to evaluate, though behavioural and neurochemical methodologies, the anticonvulsant, and neuroprotective effects of eucalyptol on mice subjected to the pilocarpine-induced seizure model. Eucalyptol (100, 200 and 400 mg/kg, p.o.) was administered in mice prior to pilocarpine (350 mg/kg, i.p.) and the following behavioural parameters were assessed: Latency to First Seizure (LFS), Seizure Intensity (SI) and Latency to Death (LD). In addition, an oxotremorine-induced tremors test was performed to evaluate the cholinergic system involvement on the eucalyptol effects. Neurochemical tests were also performed, including determination of hippocampal (HC) concentration of thiobarbituric acid reactive substances (TBARS) and nitrite/nitrate and striatal (ST) concentration of noradrenaline, dopamine, and serotonin. Lastly, histopathological, and morphometric hippocampal analysis were conducted. Eucalyptol increased the latency to first seizure and latency to death, inhibited oxotremorine-induced tremors, decreased hippocampal TBARS and nitrite/nitrate overproduction, increased striatal noradrenaline and dopamine levels and prevented hippocampal neurodegeneration. These results demonstrate the potential anticonvulsant, neuroprotective and antioxidant effects of eucalyptol, probably through a conjunction of mechanisms including muscarinic cholinergic antagonism, oxidative stress mitigation and the monoaminergic system modulation, which appears to effectively control the seizure onset.

Investigations on some indicators in the blood of cattle with orosthenic activity tongue rolling.

Hematological studies were carried out in cattle with tongue-rolling hyperactivity in order to establish the etiopathogenetic mechanisms of this behavioral disorder. Cattle were divided into two groups: Group 1 (n = 12), control animals that did not demonstrate the tongue-rolling orosthenic activity, and Group 2 (n = 12), cattle that manifested this stereotyped behavior. Blood samples were collected from all cattle twice at 10-day intervals from Vena jugularis for analysis of red blood cell counts, hemoglobin (HGB) content, mean corpuscular volume (MCV), mean corpuscular HGB (MCH), mean corpuscular HGB concentration (MCHC), hematocrit (HCT), white blood cell counts (WBC), and differential white cell counts [lymphocytes (LYM), monocytes (MON), and granulocytes (GRAs)]. Some blood biochemical constituents were assayed: calcium, inorganic phosphorus, magnesium, plasma total protein, blood glucose, total bilirubin, urea, creatinine, chlorides, cholesterol, triglycerides, and albumin, as well as the enzyme activities of aspartate amino-transferase (AST), alanine amino-transferase (ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase (γ-GT), lactate dehydrogenase (LDH), and creatine kinase (CK). Blood concentrations of the hormones adrenaline, noradrenaline, cortisol, adrenocorticotropic hormone (ACTH), dopamine, serotonin, free thyroxine, thyroid-stimulating hormone, and trace elements manganese, copper, and iron were determined. It was found out that the cattle with tongue-rolling hyperactivity did not demonstrate changes in red blood picture (HGB, HCT, MCV, MCH, MCHC), white blood picture (WBC, LYM, MON, GRA), blood biochemistry (Ca, P, Mg, TP, Glu, TB, urea, creatine, Cl, Chole, TG, and Alb), AST, ALT, ALP, γ-GT, LDH, and CK activities, Cu, and Fe levels. In the study, increased concentrations of adrenaline, noradrenaline, cortisol, ACTH, and serotonin were established. The data demonstrating increased levels of adrenaline, noradrenaline, cortisol, and ACTH confirmed the etiological role of environmental stressors in the emergence of oral hyperactivity. Increased serotonin concentrations in the blood suggest that cattle with the stereotype are probably "happy" with tongue rolling. The lack of changes in blood trace elements manganese, copper, and iron allowed excluding their deficiency as a probable cause in the etiology of the disorder.

Effect of Gabapentin-Fluoxetine Derivative GBP1F in a Murine Model of Depression, Anxiety and Cognition.

Gabapentin is a commonly prescribed antiepileptic agent for seizures, which is also used for pain and addiction management. Due to growing evidence of its abuse liability, there has been an incentive to synthesise potentially useful gabapentin derivatives devoid of adverse effects. A gabapentin adduct with a fluoxetine moiety, GBP1F, was assessed for any sedative, cognitive, anxiolytic, or antidepressant-like actions in murine behavioral models. Selected groups of mice were used for each behavioral paradigm, and the effect of GBP1F (5, 10, and 15 mg/kg) was assessed using spontaneous locomotor activity, the tail suspension test, elevated plus maze test, and the Y maze test models. Immediately following behavioral experiments, postmortem striatal and hippocampal tissues were evaluated for the effect of GBP1F on concentrations of dopamine, DOPAC, HVA, serotonin, 5-HIAA, vitamin C, and noradrenaline using high performance liquid chromatography with electrochemical detection. GBP1F induced a mild suppression of locomotor activity, ameliorated anxiety and depression-like behavior, did not alter cognitive behavior, and raised serotonin and 5-HIAA concentrations in the hippocampus and striatum. GBP1F also positively enhanced dopamine and vitamin C tissue levels in the striatum. Thus, GBP1F represents a compound with anxiolytic- and antidepressant-like effects though further studies are warranted at the molecular level to focus on the precise mechanism(s) of action.

Quantification of Seroconversion from the Growth Period of Banana by an Interdisciplinary Study

The author aims to explore the quantitative relationship between the growth period and the serotonin content curve of bananas and the influence of influencing factors on serotonin content and practical improvement measures. It was concluded that serotonin content decreases sequentially from green and yellow peel to the appearance of anthracnose in bananas. This idea could provide ideas for serotonin research from a horticultural perspective and could be further explored in the laboratory.