Serotonin reuptake inhibition for the prevention of vasovagal syncope: a systematic review and meta-analysis.

PURPOSE: Vasovagal syncope is a common clinical condition that lacks effective medical therapies despite being associated with significant morbidity. Current guidelines suggest that serotonin-specific reuptake inhibitors might suppress vasovagal syncope but supporting studies have been small and heterogenous. The purpose of this study was to evaluate the efficacy of serotonin-specific reuptake inhibitors to prevent syncope in patients with recurrent vasovagal syncope by conducting a systematic review and meta-analysis of published studies. METHODS: Relevant randomized controlled trials were identified from the MEDLINE and Embase databases without language restriction from inception to August 2022, and ClinicalTrials.gov. All studies were conducted in clinical syncope populations and compared the benefit of serotonin versus placebo. Weighted relative risks were estimated using random effects meta-analysis techniques. RESULTS: Three studies (n = 204) met inclusion criteria. Patients were 42 ± 13 years of age and 51% female. Serotonin-specific reuptake inhibitors were found to substantially reduce the likelihood of a patient having at least one recurrence of vasovagal syncope [relative risk (RR) 0.34 (0.20-0.60), p < 0.01] with minimal between-study heterogeneity (I2 = 0%, p = 0.67). Serotonin-specific reuptake inhibitors in two reports provided significant protection against clinical presyncope [RR 0.43 (0.24-0.77), p < 0.01], with minimal between-study heterogeneity (I2 = 0%, p = 0.80). CONCLUSIONS: Serotonin-specific reuptake inhibitors may be effective in preventing syncope induced by head-up tilt testing and in syncope in the community in randomized, double-blinded clinical trials.

Moving from serotonin to serotonin-norepinephrine enhancement with increasing venlafaxine dose: clinical implications and strategies for a successful outcome in major depressive disorder.

INTRODUCTION: Mental health disorders, especially depressive and anxiety disorders, are associated with substantial health-related burden. While the second-generation antidepressants are widely accepted as first-line pharmacological treatment for major depressive disorder (MDD), patient response to such treatment is variable, with more than half failing to achieve complete remission, and residual symptoms are frequently present. AREAS COVERED: Here, the pharmacodynamics of venlafaxine XR are reviewed in relation to its role as both a selective serotonin reuptake inhibitor (SSRI) and a serotonin-norepinephrine-reuptake inhibitor (SNRI), and we look at how these pharmacodynamic properties can be harnessed to guide clinical practice, asking the question 'is it possible to develop a symptom-cluster-based approach to the treatment of MDD with comorbid anxiety utilizing venlafaxine XR?.' Additionally, three illustrative clinical cases provide practical examples of the utility of venlafaxine-XR in real-world clinical practice. The place of venlafaxine XR in managing fatigue/low energy, a frequent residual symptom in MDD, is explored using pooled data from clinical trials of venlafaxine XR. EXPERT OPINION: Venlafaxine XR should be considered as a first-line treatment for MDD with or without comorbid anxiety, and there are clear pharmacodynamic signals supporting a symptom cluster-based treatment paradigm for venlafaxine XR.

Survey-Based Analysis of the Clinical Treatment Status of Irritable Bowel Syndrome in Korea.

BACKGROUND: The quality-of-life of patients with irritable bowel syndrome is low; incorrect diagnosis/treatment causes economic burden and inappropriate consumption of medical resources. This survey-based study aimed to analyze the current status of irritable bowel syndrome treatment to examine differences in doctors' perceptions of the disease, and treatment patterns. METHODS: From October 2019 to February 2020, the irritable bowel syndrome and Intestinal Function Research Study Group of the Korean Society of Neurogastroenterology and Motility conducted a survey on doctors working in primary, secondary, and tertiary healthcare institutions. The questionnaire included 37 items and was completed anonymously using the NAVER platform (a web-based platform), e-mails, and written forms. RESULTS: A total of 272 doctors responded; respondents reported using the Rome IV diagnostic criteria (amended in 2016) for diagnosing and treating irritable bowel syndrome. Several differences were noted between the primary, secondary, and tertiary physicians' groups. The rate of colonoscopy was high in tertiary healthcare institutions. During a colonoscopy, the necessity of random biopsy was higher among physicians who worked at tertiary institutions. 'The patient did not adhere to the diet' as a reason for ineffectiveness using low-fermentable oligo-, di-, and mono-saccharides, and polyols diet treatment was higher among physicians in primary/secondary institutions, and 'There are individual differences in terms of effectiveness' was higher among physicians in tertiary institutions. In irritable bowel syndrome constipation predominant subtype, the use of serotonin type 3 receptor antagonist (ramosetron) and probiotics was higher in primary/secondary institutions, while serotonin type 4 receptor agonist was used more in tertiary institutions. In irritable bowel syndrome diarrhea predominant subtype, the use of antispasmodics was higher in primary/secondary institutions, while the use of serotonin type 3 receptor antagonist (ramosetron) was higher in tertiary institutions. CONCLUSION: Notable differences were observed between physicians in primary/secondary and tertiary institiutions regarding the rate of colonoscopy, necessity of random biopsy, the reason for the ineffectiveness of low-fermentable oligo-, di-, and mono-saccharides, and polyols diet, and use of drug therapy in irritable bowel syndrome. In South Korea, irritable bowel syndrome is diagnosed and treated according to the Rome IV diagnostic criteria, revised in 2016.

Praziquantel promotes protection against Schistosoma japonicum infection in mice.

Praziquantel (PZQ) is the first line drug for the treatment of schistosomiasis. Several studies have confirmed that PZQ regulates host immunity, and we have recently found that pretreatment with PZQ enhances resistance against Schistosoma japonicum infection in buffaloes. We speculate that PZQ induces physiological changes in mice that prevent S. japonicum infection. To test this hypothesis and provide a practical measure to prevent S. japonicum infection, we determined the effective dose (the minimum dose), protection period and onset time of protection by comparing the worm burden, female worm burden and egg burden in PZQ-pretreated mice and blank control mice. Morphological differences between parasites were observed by measuring the total worm length, oral sucker, ventral sucker and ovary. The levels of cytokines, nitrogen monoxide (NO), 5-hydroxytryptamine (5-HT) and specific antibodies were measured using kits or soluble worm antigens. Hematological indicators on day 0 were analyzed in mice that received PZQ on days -15, -18, -19, -20, -21 and -22. The PZQ concentrations in plasma and blood cells were monitored using high performance liquid chromatography (HPLC). The effective dose was found to be two oral administrations (interval of 24 h) at 300 mg/kg body weight (BW) or one injection at 200 mg/kg BW, and the protection period of PZQ injection was 18 days. The optimal preventive effect was observed at two days post-administration, with a >92% worm reduction rate and significant worm reduction until 21 days after administration. Adult worms from PZQ-pretreated mice were runtish showing a shorter length, smaller organs and fewer eggs in the uteri of females. Detection of cytokines, NO, 5-HT and hematological indicators showed that PZQ induced immune-physiological changes, including higher levels of NO, IFN-γ and IL-2, and a lower level of TGF-ß. No significant difference in the anti-S. japonicum specific antibody levels was observed. The PZQ concentrations in plasma and blood cells 8 and 15 days post-administration were lower than the detection limit. Our results confirmed that pretreatment with PZQ promotes the protection of mice against S. japonicum infection within 18 days. Although we observed some immune-physiological changes in the PZQ-pretreated mice, the exact mechanisms involved in the preventive effect require further study.

An Update on Nondopaminergic Treatments for Motor and Non-motor Symptoms of Parkinson's Disease.

Nondopaminergic neurotransmitters such as adenosine, norepinephrine, serotonin, glutamate, and acetylcholine are all involved in Parkinson's disease (PD) and promote its symptoms. Therefore, nondopaminergic receptors are key targets for developing novel preparations for the management of motor and non-motor symptoms in PD, without the potential adverse events of dopamine replacement therapy. We reviewed English-written articles and ongoing clinical trials of nondopaminergic treatments for PD patients till 2014 to summarize the recent findings on nondopaminergic preparations for the treatment of PD patients. The most promising research area of nondopaminergic targets is to reduce motor complications caused by traditional dopamine replacement therapy, including motor fluctuations and levodopa-induced dyskinesia. Istradefylline, Safinamide, and Zonisamide were licensed for the management of motor fluctuations in PD patients, while novel serotonergic and glutamatergic agents to improve motor fluctuations are still under research. Sustained- release agents of Amantadine were approved for treating levodopa induced dyskinesia (LID), and serotonin 5HT1B receptor agonist also showed clinical benefits to LID. Nondopaminergic targets were also being explored for the treatment of non-motor symptoms of PD. Pimavanserin was approved globally for the management of hallucinations and delusions related to PD psychosis. Istradefylline revealed beneficial effect on daytime sleepiness, apathy, depression, and lower urinary tract symptoms in PD subjects. Droxidopa may benefit orthostatic hypotension in PD patients. Safinamide and Zonisamide also showed clinical efficacy on certain non-motor symptoms of PD patients. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs may lead to new approaches with positive clinical implications.

Reversal and Preventive Pleiotropic Mechanisms Involved in the Antipsychotic-Like Effect of Taurine, an Essential ß-Amino Acid in Ketamine-Induced Experimental Schizophrenia in Mice.

Schizophrenia is a life disabling, multisystem neuropsychiatric disease mostly derived from complex epigenetic-mediated neurobiological changes causing behavioural deficits. Neurochemical disorganizations, neurotrophic and neuroimmune alterations are some of the challenging neuropathologies proving unabated during psychopharmacology of schizophrenia, further bedeviled by drug-induced metabolic derangements including alteration of amino acids. In first-episode schizophrenia patients, taurine, an essential ß-amino acid represses psychotic-symptoms. However, its anti-psychotic-like mechanisms remain incomplete. This study evaluated the ability of taurine to prevent or reverse ketamine-induced experimental psychosis and the underlying neurochemical, neurotrophic and neuroinmune mechanisms involved in taurine's clinical action. The study consisted of three different experiments with Swiss mice (n = 7). In the drug alone, mice received saline (10 mL/kg/p.o./day), taurine (50 and 100 mg/kg/p.o./day) and risperidone (0.5 mg/kg/p.o./day) for 14 days. In the preventive study of separate cohort, mice were concomitantly given ketamine (20 mg/kg/i.p./day) from days 8 to 14. In the reversal study, mice received ketamine for 14 days before taurine or risperidone treatments from days 8 to 14 respectively. Afterwards, stereotypy behaviour, social, non-spatial memory deficits, and body weights were assessed. Neurochemical (dopamine, 5-hydroxytryptamine, glutamic acid decarboxylase, (GAD)), brain derived-neurotrophic factor (BDNF) and pro-inflammatory cytokines [tumor necrosis factor-alpha, (TNF-α), interleukin-6, (IL-6)] were assayed in the striatum, prefrontal-cortex and hippocampal area. Taurine attenuates ketamine-induced schizophrenia-like behaviour without changes in body weight. Taurine reduced ketamine-induced dopamine and 5-hydroxytryptamine changes, and increased GAD and BDNF levels in the striatum, prefrontal-cortex and hippocampus, suggesting increased GABAergic and neurotrophic transmissions. Taurine decreases ketamine-induced increased in TNF-α and IL-6 concentrations in the striatum, prefrontal-cortex and hippocampus. These findings also suggest that taurine protects against schizophrenia through neurochemical modulations, neurotrophic enhancement, and inhibition of neuropathologic cytokine activities.

Effect of ondansetron for preventing of ovarian hyperstimulation syndrome: in an experimental rat model.

Objective: Ovarian hyperstimulation syndrome is an iatrogenic condition that occurs in the treatment of infertility. There is no specific treatment available for OHSS. Cabergoline is a dopamine receptor 2 agonist and VEGF-VEGF2 receptor antagonist . Recently, cabergoline has been widely used to prevent the development of OHSS and reduce its severity Serotonin is known as a neurotransmitter and thought to have a role in the mechanism of angiogenesis and in signaling in endothelial cells. Serotonin is said to have similar effects to VEGF . Ondansetron is Selective Serotonin (5-HT3) Receptor Antagonist . It works by blocking the action of serotonin, a natural substance that may cause nausea and vomiting. In the clinical practice today, there is no choice other than cabergoline, to prevent occurrence and reduce severity of OHSS, and sometimes its effects are limited. Methods: In our study, we compared the effect of cabergoline and ondansetron. 32 immature rats were used and the OHSS model was created. Parameters such as hematocrit value , ovarian size, the number of follicles in the ovary, endometrial capillary congestion and thickness values were evaluated and compared. Results: As a result, in our study, it was seen that ondansetron was effective on OHSS in many parameters. It is thought to be as effective as cabergoline. When we look at the literature, this is the first study in which ondansetron was evaluated for this purpose. It would be good to show this effect of ondansetron with other studies.

Protective Effects of Ursodeoxycholic Acid Against Oxidative Stress and Neuroinflammation Through Mitogen-Activated Protein Kinases Pathway in MPTP-Induced Parkinson Disease.

OBJECTIVES: Parkinson disease (PD) is the second most common neurodegenerative disorder, and no disease-modifying medications are available. Ursodeoxycholic acid (UDCA) has been shown to prevent neuronal damage; however, the effect of UDCA on PD is unclear. This study aimed to the role of UDCA on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. METHODS: Mice were divided into 3 experimental groups: the control group, MPTP group, and UDCA-treat group. Mice were tested for behavioral impairments, and slices at the level of the ventral midbrain were collected to perform hematoxylin and eosin and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and immunohistochemistry. To evaluate the levels of dopamine (DA), serotonin (5-HT), antioxidant markers, and inflammatory cytokines, enzyme-linked immunoassays were carried out. The protein (α-synuclein, p38, phospho-p38, c-Jun N-terminal kinase [JNK], and phospho-JNK) expression was examined adopting Western blot. RESULTS: We found that UDCA reduced the MPTP-induced degeneration of DA neurons, improved behavioral impairments, and decreased the protein level of α-synuclein, accompanied with increases of DA and 5-HT. In the present study, UDCA prevented DA neurons from MPTP toxicity with increased superoxide dismutase, catalase, glutathione, and decreased malondialdehyde levels. Ursodeoxycholic acid prevented DA neurons from MPTP toxicity with decreased levels of tumor necrosis factor α, interferon γ, and interleukin (IL)-1ß, IL-6, and IL-10. Our results demonstrated that UDCA inhibited the phosphorylation of JNK and p38MAPK. CONCLUSIONS: This study revealed protective effects of UDCA against oxidative stress and neuroinflammation through mitogen-activated protein kinases pathways in MPTP-induced PD, suggesting that UDCA may be a novel therapeutic candidate for PD.

Advances in sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is the major cause of premature death in epilepsy patients, particularly those with refractory epilepsy. Sudden unexpected death in epilepsy is thought to be related to peri-ictal cardiac dysfunction, respiratory depression, and autonomic dysfunction, albeit the exact etiology is unknown. Sudden unexpected death in epilepsy prevention remains a huge challenge. The sole presence and frequency of generalized tonic-clonic seizures (GTCS) are the most important risk factors for SUDEP, and nocturnal monitoring may lower the risk with the use of remote listening devices. In addition, studies in animal models of SUDEP have discovered that multiple neurotransmitters, including serotonin (5-HT) and adenosine, may be involved in the pathophysiological mechanisms of SUDEP and that these neurotransmitters could be the targets of future pharmacological intervention for SUDEP. The latest research findings on the epidemiology, clinical risk factors, and probable causes of SUDEP are presented in this review.

Fluoxetine reduces organ injury and improves motor function after traumatic brain injury in mice.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in trauma patients worldwide. Brain injury is associated with significant inflammation, both within the brain and in the peripheral organs. This inflammatory response in TBI leads to a secondary injury, worsening the effects of the original brain injury. Serotonin is also linked to inflammation in the intestine and inflammatory bowel disease, but its role in the gut-brain axis is not known. We hypothesized that using fluoxetine to block serotonin reuptake would reduce organ inflammation and improve outcomes after TBI. METHODS: C57/B6 mice were given a severe TBI using a controlled cortical impact. To measure intestinal permeability, a piece of terminal ileum was resected, the lumen was filled with 4-kDa fluorescein isothiocyanate (FITC)-dextran, and the ends were tied. The intestinal segment was submerged in buffer and fluorescence in the buffer measured over time. To measure lung permeability, 70-kDa FITC-dextran is injected retro-orbitally. Thirty minutes later, the left lung was homogenized and the fluorescence was measured. To measure performance on the rota-rod, mice were placed on a spinning rod, and the time to fall off was measured. Those treated with fluoxetine received a single dose of 5 mg/kg via intraperitoneal injection immediately after injury. RESULTS: Traumatic brain injury was associated with an increase in intestinal permeability to FITC-dextran, increased lung vascular permeability, and worse performance on the rota-rod. Fluoxetine significantly reduced lung and intestinal permeability after TBI and improved performance on the rota-rod after TBI. CONCLUSION: Use of fluoxetine has the potential to reduce lung injury and improve motor coordination in severe TBI patients. Further study will be needed to elucidate the mechanism behind this effect.

Tryptophan metabolites modulate inflammatory bowel disease and colorectal cancer by affecting immune system.

Tryptophan is an essential amino acid, going through three different metabolic pathways in the intestines. Indole pathway in the gut microbiota, serotonin system in the enterochromaffin cells and kynurenine pathway in the immune cells and intestinal lining are the three arms of tryptophan metabolism in the intestines. Clinical, in vivo and in vitro studies showed that each one of these arms has a significant impact on IBD. This review explains how different metabolites of tryptophan are involved in the pathophysiology of IBD and colorectal cancer, as a major complication of IBD. Indole metabolites alleviate colitis and protect against colorectal cancer while serotonin arm follows a more complicated and receptor-specific pattern. Indole metabolites and kynurenine interact with aryl hydrocarbon receptor (AHR) to induce T regulatory cells differentiation, confine Th17 and Th1 response and produce anti-inflammatory mediators. Kynurenine decreases tumor-infiltrating CD8+ cells and mediates tumor cells immune evasion. Serotonin system also increases colorectal cancer cells proliferation and metastasis while, indole metabolites can profoundly decrease colorectal cancer growth. Targeted therapy for tryptophan metabolites may improve the management of IBD and colorectal cancer, e.g. supplementation of indole metabolites such as indole-3-carbinol (I3C), inhibition of kynurenine monooxygenase (KMO) and selective stimulation or inhibition of specific serotonergic receptors can mitigate colitis. Furthermore, it will be explained how indole metabolites supplementation, inhibition of indoleamine 2,3-dioxygenase 1 (IDO1), KMO and serotonin receptors can protect against colorectal cancer. Additionally, extensive molecular interactions between tryptophan metabolites and intracellular signaling pathways will be thoroughly discussed.

N-acetylserotonin Derivative Exerts a Neuroprotective Effect by Inhibiting the NLRP3 Inflammasome and Activating the PI3K/Akt/Nrf2 Pathway in the Model of Hypoxic-Ischemic Brain Damage.

Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the main causes of neonatal disability and death. As a derivative of N-acetylserotonin, N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC) can easily cross the blood-brain barrier and have a long half-life in the brain. In this study, the hypothesis was verified that HIOC plays a neuroprotective role in the HIE model and its potential mechanism was evaluated. Firstly, an HIE rat model was established to deliver HIOC, revealing that it can reduce cerebral infarction volume, cerebral edema, and neuronal apoptosis. The results of immunofluorescence staining, Western blots and RT-PCR further showed that HIOC could inhibit the activation of the NLRP3 inflammasome and the expression of related proteins. Finally, the activation of the phosphatidylinositol-3-kinase (PI3K)/Akt/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by HIOC was verified in vitro and in vivo. It was discovered that HIOC could increase the nuclear translocation of Nrf2, and that this induction can be reversed by the PI3K/Akt pathway inhibitor LY294002. In general terms, the neuroprotective effect of HIOC was confirmed in the HIE model, which is related to the activation of the Pi3k/Akt/Nrf2 signal pathway and the inhibition of the NLRP3 inflammasome.

Underactive bladder in aging rats is associated with a reduced number of serotonin-expressing cells in the urethra and is improved by serotonin application to the urethra.

The aim of this study was to determine whether aging-related detrusor underactivity (DU) involves a decrease in 5-hydroxytryptamine (5-HT-positive)-expressing urethral cells and whether 5-HT stimulation of urethral sensory fibers improves detrusor function. Cystometries were performed in young (6 months) and aged (18-24 months) female Wistar rats. Aged rats with voiding contractions (VC) that were 2SD below the mean of those in young rats were considered to have DU. Bladder voiding efficiency (BVE) was calculated during saline or 5-HT solution cystometries. Rats were perfusion-fixed with a fixative solution (paraformaldehyde, PFA 4%) through the circulatory system and the urethra sectioned to count the number of 5-HT-immunoreactive (IR) cells. Isovolumetric cystometry was performed while irrigating the urethra with saline or 5µM-HT solution. Two-tailed unpaired t tests were used to determine the significance of differences. In aged DU rats, the mean (±SD) VC frequency was 0.24 ± 0.07 per minute, with an amplitude of 15 ± 3 cm H2 O. The mean (±SD) number of 5-HT-IR cells in the urethra of aged DU and young rats was 90 ± 11 and 182 ± 25, respectively (P < 0.01). 5-HT improved the mean (±SD) BVE of aged DU rats from 49 ± 3% to 78 ± 2% (P < 0.001). In isovolumetric cystometries, detrusor pressure during irrigation of the urethra with saline was 18 ± 1 cm H2 O, compared with 39 ± 2 cm H2 O during irrigation with 5-HT solution (P < 0.05). In rats, DU associated with aging is accompanied by a decrease in the number of 5-HT-positive cells. The results suggest that decreased 5-HT availability decreases urethral sensory fiber excitation, leading to a decrease the number of effective VC.

Radiobiology at the forefront: Hanns Langendorff and two of his disciples.

Hanns Langendorff (1902-1974) was an eminent radiobiologist and a visionary, who not only helped found the field, but also made significant scientific contributions. He was a member of the first editorial board of IJRB and actually published a paper in its first issue about the radio-protector 5-hydroxytryptamine. Langendorff started working in the field of radiobiology in 1929 and became director of the 'Radiologisches Institut' of Freiburg University in 1936. His studies impressively show the development of radiobiology over decades in areas such as radiation-induced cell death at various stages of development, as well as radiosensitivity of sea urchin, yeast and mammals. Using mice, Langendorff made many early discoveries about spermatogenesis, hematopoiesis, prenatal development, chromosomal damage and metabolic pathways after exposures to X-rays and neutrons. He also investigated aspects of target theory and dosimetry and developed personal dosimeters using films. After the atomic bomb catastrophes in Japan, Langendorff and his collaborators soon began research in mice related to acute radiation sickness and stimulated the development of radioprotectors by studying their mechanisms of action associated with cell death, as well as cellular and metabolic changes involved. Langendorff also trained a cadre of young scientists who advanced the field and brought it to its golden age in the seventies and the eighties. Research activities of two of his disciples are reviewed: Ulrich Hagen and the author. Both made significant contributions: Hagen mainly studying DNA-damage and repair in vitro as well in cells and the author investigating metabolic processes, cellular and chromosomal damage, prenatal effects, genomic instability, individual radio-sensitivity and their connections to cancer therapy.

N-Acetyl Serotonin Protects Neural Progenitor Cells Against Oxidative Stress-Induced Apoptosis and Improves Neurogenesis in Adult Mouse Hippocampus Following Traumatic Brain Injury.

In this study, with primary mouse neural progenitor cells (NPCs), we investigated the neuroprotective effect of a tropomyosin-related kinase receptor B (TrkB) agonist, N-acetyl serotonin (NAS), against hydrogen peroxide (H2O2)-induced toxicity. We found that pre-incubation with NAS not only ameliorates H2O2-induced cell viability loss, lactate dehydrogenase (LDH) release, and proliferative and migratory capacity impairments, but counteracts H2O2-triggered production of nitric oxide (NO), reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxy-deoxyguanosine (8-OHdG) in a dose-dependent manner. Additionally, pre-treatment with NAS was able to attenuate H2O2-induced apoptosis in NPCs, evidenced by the decreased percentage of apoptotic cells and altered expression of apoptosis-related factors. Furthermore, in differentiated NPCs, NAS improves H2O2-induced reduction in neurite growth. Mechanistic studies revealed that the protective effects of NAS in NPCs may be mediated by the TrkB/PI3K/Akt/ cAMP response element binding protein (CREB) signaling cascades. In a mouse traumatic brain injury (TBI) model, we found that systemic administration of 30 mg/kg NAS could improve hippocampal neurogenesis, manifested by the increased number of SOX-2-positive cells and increased expression of phosphorylated CREB in the dentate gyrus (DG) area. Treatment with NAS also ameliorates cognitive impairments caused by TBI, as assessed by Y-maze and contextual and cued fear conditioning tests. Taken together, these results provide valuable insights into the neuroprotective and neuroregenerative effects of NAS, suggesting it may have therapeutic potential for the treatment of TBI.

Effect of N-Acetylserotonin on TLR-4 and MyD88 Expression during Intestinal Ischemia-Reperfusion in a Rat Model.

BACKGROUND: Accumulating evidence indicates that changes in intestinal toll-like receptors (TLRs) precede histological injury in a rodent model of necrotizing enterocolitis. N-acetylserotonin (NAS) is a naturally occurring chemical intermediate in the biosynthesis of melatonin. A recent study has shown that treatment with NAS prevents gut mucosal damage and inhibits programmed cell death following intestinal ischemia-reperfusion (IR). The objective of this study was to determine the effects of NAS on TLR-4, myeloid differentiation factor 88 (Myd88), and TNF-α receptor-associated factor 6 (TRAF6) expression in intestinal mucosa following intestinal IR in a rat. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomly assigned to one of the four experimental groups: 1) Sham rats underwent laparotomy; 2) Sham-NAS rats underwent laparotomy and were treated with intraperitoneal (IP) NAS (20 mg/kg); 3) IR rats underwent occlusion of both superior mesenteric artery and portal vein for 20 minutes followed by 48 hours of reperfusion; and 4) IR-NAS rats underwent IR and were treated with IP NAS immediately before abdominal closure. Intestinal structural changes, mucosal TLR-4, MyD88, and TRAF6 mucosal gene, and protein expression were examined using real-time PCR, Western blot, and immunohistochemistry. RESULTS: Significant mucosal damage in IR rats was accompanied by a significant upregulation of TLR-4, MyD88, and TRAF6 gene and protein expression in intestinal mucosa compared with control animals. The administration of NAS decreased the intestinal injury score, inhibited cell apoptosis, and significantly reduced the expression of TLR-4, MyD88, and TRAF6. CONCLUSION: Treatment with NAS is associated with downregulation of TLR-4, MyD88, and TRAF6 expression along with a concomitant decrease in intestinal mucosal injury caused by intestinal IR in a rat.

Estrogen and Serotonin: Complexity of Interactions and Implications for Epileptic Seizures and Epileptogenesis.

A burgeoning literature documents the confluence of ovarian steroids and central serotonergic systems in the injunction of epileptic seizures and epileptogenesis. Estrogen administration in animals reduces neuronal death from seizures by up-regulation of the prosurvival molecule i.e. Bcl-2, anti-oxidant potential and protection of NPY interneurons. Serotonin modulates epileptiform activity in either direction i.e administration of 5-HT agonists or reuptake inhibitors leads to the activation of 5-HT3 and 5-HT1A receptors tending to impede focal and generalized seizures, while depletion of brain 5-HT along with the destruction of serotonergic terminals leads to expanded neuronal excitability hence abatement of seizure threshold in experimental animal models. Serotonergic neurotransmission is influenced by the organizational activity of steroid hormones in the growing brain and the actuation effects of steroids which come in adulthood. It is further established that ovarian steroids bring induction of dendritic spine proliferation on serotonin neurons thus thawing a profound effect on serotonergic transmission. This review features 5-HT1A and 5-HT3 receptors as potential targets for ameliorating seizure-induced neurodegeneration and recurrent hypersynchronous neuronal activity. Indeed 5-HT3 receptors mediate cross-talk between estrogenic and serotonergic pathways, and could be well exploited for combinatorial drug therapy against epileptogenesis.

Serotonin Exhibits Accelerated Bleomycin-Induced Pulmonary Fibrosis through TPH1 Knockout Mouse Experiments.

BACKGROUND: Pulmonary fibrosis is a chronic progressive fibrosis interstitial lung disease that is characterized by inflammatory infiltration and fibrotic changes. 5-Hydroxytryptamine (5-HT) is an important regulatory factor in inflammation, immunomodulation, and fibrosis. The aim of this study was to investigate the role of 5-HT in bleomycin- (BLM-) induced pulmonary fibrosis through wild-type C57BL/6 (WT) and TPH1 knockout (KO) mouse experiments. METHODS: The mice were grouped as follows: WT control group, KO control group, WT BLM group, and KO BLM group. Mice were administrated bleomycin hydrochloride through intratracheal instillation to induce pulmonary fibrosis. Mice were sacrificed 0, 7, 14, and 21 days after modeling, and bronchoalveolar lavage fluid (BALF) and lung tissues were collected to determine the severity of fibrotic changes. RESULTS: The results showed that the weight loss of mice in the WT BLM group was more severe than that in the KO BLM group. H&E and Sirius Red staining revealed that 5-HT markedly aggravated histological damage and fibrotic changes in the lung. Significantly lower levels of hydroxyproline, Ashcroft fibrosis score, total BALF protein and cells, BALF tumor necrosis factor- (TNF-) α and interleukin- (IL-) 6, TNF-α and IL-6 mRNA, malondialdehyde (MDA), and myeloperoxidase- (MPO-) positive cells in the lung tissues, and fibrosis-associated proteins were discovered in the mice from the KO BLM group compared with the WT BLM group. CONCLUSION: 5-HT aggravated pulmonary fibrosis mainly by promoting the inflammation, exudation of proteins and cells, oxidative stress, and upregulation of fibrosis-associated genes in the lung tissues.

[Gastroesophageal variceal bleeding in cirrhotic patients: the possibilities of effective hemostasis]. / Varikoznye pishchevodno-zheludochnye krovotecheniia pri tsirroze pecheni: vozmozhnosti éffektivnogo gemostaza.

AIM: To improve the results of treatment of gastroesophageal variceal bleeding (GEVB) in cirrhotic patients with thrombocytopenia. MATERIAL AND METHODS: A total experience of the clinic includes 338 GEVB patients, endoscopic variceal ligation (EVL) and transjugular intrahepatic portosystemic shunt (TIPS) were performed in 162 and 157 cases respectively. Nevertheless, just the efficacy of initial pharmacological hemostatic therapy was analyzed. RESULTS: Administration of serotonin adipinate 30-50 mg/day during 3-5 days in addition to standard initial therapy allowed us to achieve permanent hemostasis during initial treatment if EVL was impossible. Serotonin adipinate induces thrombocytes' adhesion and improves fibrin clot strength. This therapy markedly decreases mortality (33.3% vs 46.7%), incidence of recurrent bleeding (46.4% vs 60.0%). Also it contributes successful hemostasis with endoscopic ligation and effective portal decompression by TIPS procedure.