Effect of terahertz waves on the aggregation behavior of neurotransmitters.

Understanding the dynamics of neurotransmitters is crucial for unraveling synaptic transmission mechanisms in neuroscience. In this study, we investigated the impact of terahertz (THz) waves on the aggregation of four common neurotransmitters through all-atom molecular dynamics (MD) simulations. The simulations revealed enhanced nicotine (NCT) aggregation under 11.05 and 21.44 THz, with a minimal effect at 42.55 THz. Structural analysis further indicated strengthened intermolecular interactions and weakened hydration effects under specific THz stimulation. In addition, enhanced aggregation was observed at stronger field strengths, particularly at 21.44 THz. Furthermore, similar investigations on epinephrine (EPI), 5-hydroxytryptamine (5-HT), and γ-aminobutyric acid (GABA) corroborated these findings. Notably, EPI showed increased aggregation at 19.05 THz, emphasizing the influence of vibrational modes on aggregation. However, 5-HT and GABA, with charged or hydrophilic functional groups, exhibited minimal aggregation under THz stimulation. The present study sheds some light on neurotransmitter responses to THz waves, offering implications for neuroscience and interdisciplinary applications.

Carbazole derivatives as promising competitive and allosteric inhibitors of human serotonin transporter: computational pharmacology.

The human serotonin transporters (hSERTs) are neurotransmitter sodium symporters of the aminergic G protein-coupled receptors, regulating the synaptic serotonin and neuropharmacological processes related to neuropsychiatric disorders, notably, depression. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and (S)-citalopram are competitive inhibitors of hSERTs and are commonly the first-line medications for major depressive disorder (MDD). However, treatment-resistance and unpleasant aftereffects constitute their clinical drawbacks. Interestingly, vilazodone emerged with polypharmacological (competitive and allosteric) inhibitions on hSERTs, amenable to improved efficacy. However, its application usually warrants adjuvant/combination therapy, another subject of critical adverse events. Thus, the discovery of alternatives with polypharmacological potentials (one-drug-multiple-target) and improved safety remains essential. In this study, carbazole analogues from chemical libraries were explored using docking and molecular dynamics (MD) simulation. Selectively, two IBScreen ligands, STOCK3S-30866 and STOCK1N-37454 predictively bound to the active pockets and expanded boundaries (extracellular vestibules) of the hSERTs more potently than vilazodone and (S)-citalopram. For instance, the two ligands showed docking scores of -9.52 and -9.59 kcal/mol and MM-GBSA scores of -92.96 and -65.66 kcal/mol respectively compared to vilazodone's respective scores of -7.828 and -59.27 against the central active site of the hSERT (PDB 7LWD). Similarly, the two ligands also docked to the allosteric pocket (PDB 5I73) with scores of -8.15 and -8.40 kcal/mol and MM-GBSA of -96.14 and -68.46 kcal/mol whereas (S)-citalopram has -6.90 and -69.39 kcal/mol respectively. The ligands also conferred conformational stability on the receptors during 100 ns MD simulations and displayed interesting ADMET profiles, representing promising hSERT modulators for MDD upon experimental validation.Communicated by Ramaswamy H. Sarma.

Quantification of tramadol and serotonin by cobalt nickel tungstate in real biological samples to evaluate the effect of analgesic drugs on neurotransmitters.

In this work, CoNiWO4 nanocomposite was used as an electrochemical sensor for the simultaneous electrochemical detection of tramadol and serotonin. The nanocomposite was synthesized using a hydrothermal method and characterized via XRD, SEM, TGA, Zeta, UV, and FTIR. The sensor was developed by depositing CoNiWO4-NPs onto the glassy carbon electrode surface. Tramadol and serotonin were detected by employing cyclic voltammetry (CV), differential pulse voltammetry (DPV), electrochemical impedance spectroscopy (EIS), and chronoamperometry. Analytes were detected at different pH, concentrations, and scan rates. The prepared sensor showed a 0-60 µM linear range, with a LOD of 0.71 µM and 4.29 µM and LOQ of 14.3 µM and 2.3 µM for serotonin and tramadol, respectively. Finally, the modified electrode (CoNiWO4-GCE) was applied to determine tramadol and serotonin in biological samples.

Molecular Dynamics Refinement of Open State Serotonin 5-HT3A Receptor Structures.

Pentameric ligand-gated ion channels play an important role in mediating fast neurotransmissions. As a member of this receptor family, cation-selective 5-HT3 receptors are a clinical target for treating nausea and vomiting associated with chemotherapy and radiation therapy (Thompson and Lummis, 2006). Multiple cryo-electron microscopy (cryo-EM) structures of 5-HT3 receptors have been determined in distinct functional states (e.g., open, closed, etc.) (Basak et al., 2018; Basak et al., 2018; Polovinkin et al., 2018; Zhang et al., 2015). However, recent work has shown that the transmembrane pores of the open 5-HT3 receptor structures rapidly collapse and become artificially asymmetric in molecular dynamics (MD) simulations. To avoid this hydrophobic collapse, Dämgen and Biggin developed an equilibration protocol that led to a stable open state structure of the glycine receptor in MD simulations (Dämgen and Biggin, 2020). However, the protocol failed to yield open-like structures of the 5-HT3 receptor in our simulations. Here, we present a refined equilibration protocol that involves the rearrangement of the transmembrane helices to achieve stable open state structures of the 5-HT3 receptor that allow both water and ion permeation through the channel. Notably, channel gating is mediated through collective movement of the transmembrane helices, involving not only pore lining M2 helices but also their cross-talk with the adjacent M1 and M3 helices. Thus, the successful application of our refined equilibration protocol underscores the importance of the conformational coupling between the transmembrane helices in stabilizing open-like structures of the 5-HT3 receptor.

Evaluation of the Influence of Biological Factors during the Course of Treatment in Patients with Ovarian Cancer.

The aim of this study was to evaluate the influence of ß-endorphins and serotonin on the course of treatment, disease-free time, and overall survival of patients with ovarian cancer. This study may contribute to the identification of modifiable factors that may influence the treatment of ovarian cancer. The research was carried out in a group of 162 patients of which 139 respondents were included in the research; ovarian cancer was diagnosed in 78 of these patients. The study consisted of three stages. In the first stage of diagnostics, a survey among the patients was carried out. In the second stage-5 mL of blood was collected from each patient (n = 139) in the preoperative period to determine the concentration of ß-endorphin and serotonin. In the third stage-blood samples were collected from those patients who had completed chemotherapy treatment or had surgery. Concentrations of ß-endorphin and serotonin were measured by the Luminex method, using the commercial Luminex Human Discovery Assay kit. The average age of the patients was 62.99 years. The level of ß-endorphin significantly differs among patients diagnosed with ovarian cancer and among patients in the control group (202.86; SD-15.78 vs. 302.00; SD-24.49). A lower level of ß-endorphins was found in the patients with a recurrence of the neoplastic process compared to those without recurrence (178.84; SD-12.98 vs. 205.66; SD-13.37). On the other hand, the level of serotonin before chemotherapy was higher in the group of people with disease recurrence compared to those without recurrence (141.53; SD-15.33 vs. 134.99; SD-10.08). Statistically significantly positive correlations were found between the level of ß-endorphin and both disease-free time (ß-endorphin levels before chemotherapy: rho Spearman 0.379, p < 0.027; ß-endorphin levels after chemotherapy: rho Spearman 0.734 p < 0.001) and survival time (ß-endorphin levels before chemotherapy: rho Spearman 0.267, p < 0.018; ß-endorphin levels after chemotherapy: rho Spearman 0.654 p < 0.001). 1. The levels of serotonin and ß-endorphin levels are significantly related to ovarian cancer and change during treatment. 2. High mean preoperative concentrations of ß-endorphins were significantly related to overall survival and disease-free time.

Nano-analysis Reveals High Fraction of Serotonin Release during Exocytosis from a Gut Epithelium Model Cell.

Electrochemical methods were used to explore the exocytotic nature of serotonin (5-HT) release in human carcinoid BON cells, an in vitro human enterochromaffin cell model, to understand the mechanisms operating the release of gut-derived 5-HT in the intestinal mucosal epithelium. We show that the fractional vesicular 5-HT release in BON cells is 80 % compared to previous work in pancreatic beta cells (34 %). The fractional release increased from 80 % in control BON cells to 87 % with 5-HT preincubation and nearly 100 % with the combination of 5-HT and the 5-HT4 autoreceptor agonist, cisapride. Thus, partial release is the primary mechanism of exocytosis in BON cells, resulting in a variable amount of the vesicular content being released. Factors that control secretion of 5-HT from enterochromaffin cells or BON cells are important as partial release provides a mechanism for development of effective therapeutic strategies to treat gastrointestinal diseases.

Discovery of a new class of multi-target heterocycle piperidine derivatives as potential antipsychotics with pro-cognitive effect.

A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H3 receptors have been evaluated. Of these compounds, the promising candidate 4w displayed high affinities for D2, D3, 5-HT1A, 5-HT2A and H3, a moderate affinity for 5-HT6, negligible effects on the human ether-a-go-go-related gene (hERG) channel, low affinities for off-target receptors (5-HT2C, adrenergic α1 and H1). In addition, the animal behavioral study revealed that, compared to risperidone, compound 4w significantly inhibited apomorphine-induced climbing and MK-801-induced movement behaviors with a high threshold for catalepsy and low liabilities for weight gain and hyperprolactinemia. Results from the conditioned avoidance response test and novel object recognition task demonstrated that 4w had pro-cognitive effects. Thus, the antipsychotic drug-like activities of 4w indicate that it may be a potential polypharmacological antipsychotic candidate drug.

5-HT containing enteroendocrine cells characterised by morphologies, patterns of hormone co-expression, and relationships with nerve fibres in the mouse gastrointestinal tract.

5-HT containing enteroendocrine cells (EEC), the most abundant type of EEC in the gut, regulate many functions including motility, secretion and inflammatory responses. We examined the morphologies of 5-HT cells from stomach to rectum, patterns of hormone co-expression in the stomach and colon, and the relationship of 5-HT cells with nerve fibres. We also reviewed some of the relevant literature. The morphologies of 5-HT cells were distinct, depending on their location in the gut. A noticeable feature of some 5-HT cells in the antrum and colon was their long basal processes, which resembled processes of neurons, whereas 5-HT cells in the small intestinal mucosa lacked basal processes. In the stomach, numerous 5-HT cells, including cells with basal processes, were identified as enterochromaffin-like cells by their expression of histidine decarboxylase. In the colon, we observed a small number of 5-HT cells that were in close contact with, but distinct from, oxyntomodulin (OXM) and PYY immunoreactive EEC. We did not find specific relationships between nerve fibres and the processes of colonic 5-HT cells. We conclude that five major features, i.e., gut region, morphology, hormone content, receptor repertoire and cell lineage, can be used to define 5-HT cells.

Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel.

The endocannabinoid system is a promising target to mitigate pain as the endocannabinoids are endogenous ligands of the pain-mediating receptors-cannabinoid receptors 1 and 2 (CB1 and CB2) and TRPV1. Herein, we report on a class of lipids formed by the epoxidation of N-arachidonoyl-dopamine (NADA) and N-arachidonoyl-serotonin (NA5HT) by epoxygenases. EpoNADA and epoNA5HT are dual-functional rheostat modulators of the endocannabinoid-TRPV1 axis. EpoNADA and epoNA5HT are stronger modulators of TRPV1 than either NADA or NA5HT, and epoNA5HT displays a significantly stronger inhibition on TRPV1-mediated responses in primary afferent neurons. Moreover, epoNA5HT is a full CB1 agonist. These epoxides reduce the pro-inflammatory biomarkers IL-6, IL-1ß, TNF-α and nitrous oxide and raise anti-inflammatory IL-10 cytokine in activated microglial cells. The epoxides are spontaneously generated by activated microglia cells and their formation is potentiated in the presence of anandamide. Detailed kinetics and molecular dynamics simulation studies provide evidence for this potentiation using the epoxygenase human CYP2J2. Taken together, inflammation leads to an increase in the metabolism of NADA, NA5HT and other eCBs by epoxygenases to form the corresponding epoxides. The epoxide metabolites are bioactive lipids that are potent, multi-faceted molecules, capable of influencing the activity of CB1, CB2 and TRPV1 receptors.

The Uniqueness of Tryptophan in Biology: Properties, Metabolism, Interactions and Localization in Proteins.

Tryptophan (Trp) holds a unique place in biology for a multitude of reasons. It is the largest of all twenty amino acids in the translational toolbox. Its side chain is indole, which is aromatic with a binuclear ring structure, whereas those of Phe, Tyr, and His are single-ring aromatics. In part due to these elaborate structural features, the biosynthetic pathway of Trp is the most complex and the most energy-consuming among all amino acids. Essential in the animal diet, Trp is also the least abundant amino acid in the cell, and one of the rarest in the proteome. In most eukaryotes, Trp is the only amino acid besides Met, which is coded for by a single codon, namely UGG. Due to the large and hydrophobic π-electron surface area, its aromatic side chain interacts with multiple other side chains in the protein, befitting its strategic locations in the protein structure. Finally, several Trp derivatives, namely tryptophylquinone, oxitriptan, serotonin, melatonin, and tryptophol, have specialized functions. Overall, Trp is a scarce and precious amino acid in the cell, such that nature uses it parsimoniously, for multiple but selective functions. Here, the various aspects of the uniqueness of Trp are presented in molecular terms.

Simple and reliable serotonin assay in human serum by LC-MS/MS method coupled with one step protein precipitation for clinical testing in patients with carcinoid tumors.

Serotonin (5-hydroxytryptamine, 5-HT) is readily secreted in patients with carcinoid tumors, especially arising from the midgut. Although serotonin assay in human plasma or whole blood has been extensively studied, serotonin assay in human serum by liquid chromatography-tandem mass spectrometry (LC-MS/MS) has received much less attention. In this study, a simple and reliable LC-MS/MS method based on one step protein precipitation for sample pretreatment was developed for clinical assay of serum serotonin. Namely, 150 µL of serum was mixed with 50 µL of internal standard (IS) and 200 µL of 4 wt.% 5-sulfosalicylic acid (SSA) solution for protein precipitation. The supernatant after centrifugation was analyzed directly without further treatment. This method was validated for consistent linearity from 0.94 to 240 ng/mL with CVs ≤ 11.7%, good recovery in the range of 87.5%-104%, excellent analyte stability and low carryover. No obvious matrix effect was observed. Intra- and inter-day imprecision were below 8.03% and 11.5% respectively. Dilution linearity was verified with satisfying linearly dependent coefficients (r2 = 0.9937). The reference interval of serotonin was established from 126 results derived from subjects without carcinoid tumors. Therefore, apart from development of a serum serotonin assay by the LC-MS/MS method, the reference interval (RI) of 5-HT has also been established for clinical testing in patients with carcinoid tumors. In addition, this method has been successfully used in our laboratory, indicating that this robust LC-MS/MS assay with simple sample preparation and short analysis time could offer inspiring potential for clinical testing of 5-HT in routine clinical laboratories.

Targeting Neutrophils for Enhanced Cancer Theranostics.

Improving tumor accumulation and delivery efficiency is an important goal of nanomedicine. Neutrophils play a vital role in both chemically mediating inflammatory response through myeloperoxidase (MPO) and biologically promoting metastasis during inflammation triggered by the primary tumor or environmental stimuli. Herein, a novel theranostic nanomedicine that targets both the chemical and biological functions of neutrophils in tumor is designed, facilitating the enhanced retention and sustained release of drug cargos for improved cancer theranostics. 5-hydroxytryptamine (5-HT) is equipped onto nanoparticles (NPs) loaded with photosensitizers and Zileuton (a leukotriene inhibitor) to obtain MPO and neutrophil targeting NPs, denoted as HZ-5 NPs. The MPO targeting property of 5-HT modified NPs is confirmed by noninvasive positron emission tomography imaging studies. Furthermore, photodynamic therapy is used to initiate the inflammatory response which further mediated the accumulation and retention of neutrophil targeting NPs in a breast cancer model. This design renders a greatly improved theranostic nanomedicine for efficient tumor suppression, and more importantly, inhibition of neutrophil-mediated lung metastasis via the sustained release of Zileuton. This work presents a novel strategy of targeting neutrophils for improved tumor theranostics, which may open up new avenues in designing nanomedicine through exploiting the tumor microenvironment.

The Binding of Palonosetron and Other Antiemetic Drugs to the Serotonin 5-HT3 Receptor.

Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most commonly prescribed class of drugs to control chemotherapy-induced nausea and vomiting. These antagonists have been clinically successful drugs since the 1980s, yet our understanding of how they operate at the molecular level has been hampered by the difficulty of obtaining structures of drug-receptor complexes. Here, we report the cryoelectron microscopy structure of the palonosetron-bound 5-HT3 receptor. We investigate the binding of palonosetron, granisetron, dolasetron, ondansetron, and cilansetron using molecular dynamics, covering the whole set of antagonists used in clinical practice. The structural and computational results yield detailed atomic insight into the binding modes of the drugs. In light of our data, we establish a comprehensive framework underlying the inhibition mechanism by the -setron drug family.

Serotonin-Stearic Acid Bioconjugate-Coated Completely Biodegradable Mn3O4 Nanocuboids for Hepatocellular Carcinoma Targeting.

In this study, a serotonin-stearic acid (ST-SA)-based bioconjugate was synthesized for the surface modification of manganese oxide-based nanocuboids (MNCs) for delivering of anticancer drug (i.e., doxorubicin hydrochloride (DOX)) to human liver cancer cells. MNCs were synthesized by chemical precipitation method, and their surface was modified with ST-SA bioconjugate for targeting of MNCs to cancer cells. The ST-SA@MNCs along with DOX showed good colloidal stability, high drug encapsulation (98.3%), and drug loading efficiencies (22.9%) as well as pH-responsive biodegradation. Coating with ST-SA conjugate provided a shield to MNCs which sustained their degradation in an acidic environment. The release of DOX was higher (81.4%) in acidic media than under the physiological conditions (20.5%) up to 192 h. The in vitro anti-proliferation assay showed that ST-SA@MNCs exhibit higher cell growth inhibition compared to that of pure DOX after 48 h of treatment. The cellular uptake and apoptosis studies revealed the enhanced uptake of ST-SA@MNCs in contrast to the MNCs due to overexpressed ST receptor on hepatocellular carcinoma cells and triggered the generation of reactive oxygen species in the cells. Therefore, these results indicated that the DOX-loaded, ST-SA stabilized MNCs improved the therapeutic index of DOX and would be a promising therapeutic candidate for tumor therapy.

Efficiency of Penetration of Dopamine and Serotonin Peptide Derivatives through the Artificial Membranes.

A mass spectrometric method has been developed for determining the content of dopamine and serotonin derivatives, which allows evaluating the efficiency of their penetration through artificial membranes depending on the structure of their peptide fragment. In this case, the diffusion of dopamine and serotonin derivatives through the membrane occurred as a result of competitive interactions. It was shown which compounds in this mixture more easily penetrate through artificial membranes. It was found that the most promising in terms of overcoming the BBB are Boc-Pro-Srt and Boc-Pro-DOPA.

Simultaneous electrochemical sensing of serotonin, dopamine and ascorbic acid by using a nanocomposite prepared from reduced graphene oxide, Fe3O4 and hydroxypropyl-ß-cyclodextrin.

Reduced graphene oxide containing Fe3O4 nanoparticles was decorated with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) to construct a novel nanocomposite (3D-rGO/Fe3O4/HP-ß-CD). The composite was placed on a glassy carbon electrode (GCE) to design an electrochemical sensor for detecting simultaneously serotonin (5-HT), dopamine (DA), and ascorbic acid (AA). The interconnected porous reduced graphene oxide framework tightly anchored to the Fe3O4 magnetic nanoparticles warrants good electrical conductivity and efficient catalytic activity. The HP-ß-CD acts as a supramolecular host with high recognition ability for 5-HT, DA and AA. Well-separated oxidation peaks and increased peak currents were observed for 5-HT, DA, and AA individually and in mixtures by differential pulse voltammetry (DPV). The following figures of merit were found for simultaneous electrochemical determination of 5-HT, DA, and AA: (a) Well separated peaks at around 0.316, 0.16 and - 0.044 V; (b) linear responses in the 0.01 - 25 µM, 0.02 - 25 µM and 10 - 350 µM; (c) detection limits of 3.3 nM, 6.7 nM and 3.3 µM (S/N = 3), and (d) recoveries of 96.9-103%, 97.3%-102% and 96.3-105% from spiked serum samples, respectively. All relative standard deviation (RSD) are less than 4%. Graphical abstractSchematic representation of simultaneous detecting serotonin (5-HT), dopamine (DA) and ascorbic acid (AA) for three-dimensional reduced-graphene oxide/Fe3O4/hydroxypropyl-ß-cyclodextrin (3D-rGO/Fe3O4/HP-ß-CD) by differential pulse voltammetry (DPV) approach.

A Strategy for Quality Control of Vespa magnifica (Smith) Venom Based on HPLC Fingerprint Analysis and Multi-Component Separation Combined with Quantitative Analysis.

As a folk medicine of the Jingpo minority in Yunnan province, the venom of Vespa magnifica has been commonly used for the treatment of rheumatoid arthritis. Quality standardization of the wasp venom is a necessary step for its pharmaceutical research and development. To control the quality of the wasp venom, a method based on high-performance liquid chromatography (HPLC) was developed for chemical fingerprint analysis. In the chromatographic fingerprinting, chemometrics procedures, including similarity analysis (SA), hierarchical clustering analysis (HCA), and principal component analysis (PCA), were applied to classify 134 batches (S1-S134) of wasp venom from different origins. The HPLC fingerprint method displayed good precision (Relative standard deviation, RSD < 0.27%), stability (in 16 h, RSD < 0.34%), and repeatability (RSD < 1.00%). Simultaneously, four compounds (VMS1, VMS2, VMS3, and VMS4) in the wasp venom were purified and identified. VMS1 was 5-hydroxytryptamine, and the other compounds were three peptides that were sequenced as follows: Gly-Arg-Pro-Hyp-Gly-Phe-Ser-Pro-Phe-Arg-Ile-Asp-NH2 (VMS2), Ile-Asn-Leu-Lys-Ala-Ile-Ala-Ala-Leu-Ala-Lys-Lys-Leu-Leu-NH2 (VMS3), and Phe-Leu-Pro-Ile-Ile-Gly-Lys-Leu-Leu-Ser-Gly-Leu-Leu-NH2 (VMS4). The quantifications for these components were 110.2 mg/g, 26.9 mg/g, 216.3 mg/g, and 58.0 mg/g, respectively. The results of this work indicated that the combination of the chemical fingerprint and quantitative analysis offers a reasonable way to evaluate the quality of wasp venom.

Regulation of Noise-Induced Loss of Serotonin Transporters with Resveratrol in a Rat Model Using 4-[18F]-ADAM/Small-Animal Positron Emission Tomography.

Serotonin (5-HT) plays a crucial role in modulating the afferent fiber discharge rate in the inferior colliculus, auditory cortex, and other nuclei of the ascending auditory system. Resveratrol, a natural polyphenol phytoalexin, can inhibit serotonin transporters (SERT) to increase synaptic 5-HT levels. In this study, we investigated the effects of resveratrol on noise-induced damage in the serotonergic system. Male Sprague-Dawley rats were anaesthetized and exposed to an 8-kHz tone at 116 dB for 3.5 h. Resveratrol (30 mg/kg, intraperitoneal injection [IP]) and citalopram (20 mg/kg, IP), a specific SERT inhibitor used as a positive control, were administered once a day for four consecutive days, with the first treatment occurring 2 days before noise exposure. Auditory brainstem response testing and positron emission tomography (PET) with N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM, a specific radioligand for SERT) were used to evaluate functionality of the auditory system and integrity of the serotonergic system, respectively, before and after noise exposure. Finally, immunohistochemistry was performed 1 day after the last PET scan. Our results indicate that noise-induced serotonergic fiber loss occurred in multiple brain regions including the midbrain, thalamus, hypothalamus, striatum, auditory cortex, and frontal cortex. This noise-induced damage to the serotonergic system was ameliorated in response to treatment with resveratrol and citalopram. However, noise exposure increased the hearing threshold in the rats regardless of drug treatment status. We conclude that resveratrol has protective effects against noise-induced loss of SERT.

High-dose intravenous immunoglobulin to treat spontaneous heparin-induced thrombocytopenia syndrome.

Essentials Spontaneous HIT syndrome clinically/serologically resembles HIT but without proximate heparin. Rarely, spontaneous HIT syndrome complicates total knee arthroplasty surgery. Mesenteric vein thrombosis is a rare presentation of spontaneous HIT syndrome. IVIg rapidly corrects thrombocytopenia by inhibiting heparin-independent platelet activation. SUMMARY: Spontaneous heparin-induced thrombocytopenia (HIT) syndrome is an autoimmune HIT (aHIT) disorder characterized by thrombocytopenia, thrombosis, and HIT antibodies despite no proximate heparin exposure. For unknown reasons, many cases occur after total knee arthroplasty. A 52-year-old woman presented 12 days posttotal knee replacement (aspirin thromboprophylaxis) with gastrointestinal bleeding (superior mesenteric vein thrombosis); the platelet count was 63 × 109 L-1 . After bowel resection and a brief course of heparin, treatment was changed to argatroban followed by fondaparinux. In addition, high-dose intravenous immunoglobulin (IVIg), 1 g kg-1 on 2 consecutive days, resulted in abrupt platelet count rise from 21 (nadir) pre-IVIg to 137 (post-IVIg), and 2 days later to 200 × 109 L-1 . Heparin-independent serum-induced serotonin-release abruptly decreased from 91% (pre-IVIg) to 14% (post-IVIg); although serotonin-release later rebounded to 49%, the patient's platelet counts remained normal. Our observations support the emerging concept that high-dose IVIg is effective for treating aHIT disorders, including spontaneous HIT syndrome.

Other Antidepressants.

This chapter addresses the following FDA-approved medications for the treatment of major depressive disorder available for use in the United States including bupropion, mirtazapine, trazodone, vortioxetine, and vilazodone. These medications do not belong to one of the previously featured classes of antidepressants discussed in the preceding chapters. Each medication featured in this chapter has a unique structure and properties that target diverse receptors in the central nervous system. These diverse targets are distinct from other classes of medications used to treat major depressive disorder. This chapter will provide an overview of each medication's indication for use, history of development, pharmacology, metabolism, dosing recommendations, onset of action, use in special populations, safety and tolerability, adverse effects, potential interactions with additional medications, and data regarding possible overdose with available treatments.Bupropion was initially developed for its combined effects on the norepinephrine and dopamine neurotransmitters. Currently, bupropion is the only antidepressant on the market in the United States with no appreciable activity on serotonin concentrations in the central nervous system. Bupropion is extensively metabolized in humans into three active metabolites including hydroxybupropion, threohydrobupropion, and erythrohydrobuproprion each with substantial antidepressant activity. The most serious side effect of bupropion is the development of seizures, so the dose must be gradually titrated to a maximum dose of 450 mg per day of the immediate-release formulation and 400 mg per day of the sustained-release formulation. Additional adverse effects include agitation, dry mouth, insomnia, headaches, migraines, nausea, vomiting, constipation, and tremor. The onset of action of bupropion is 2 weeks with full efficacy attained at 4 weeks of treatment. Bupropion produced similar depression remission rates when compared to SSRIs with a median time to relapse of 44 weeks. Bupropion has additionally been approved for smoking cessation and may have a combined role in treating nicotine cravings and depression.Mirtazapine has a unique method of action by enhancing norepinephrine and serotonin neurotransmission by blocking the alpha-2 presynaptic adrenoceptors resulting in increased release of serotonin at the nerve terminals. Mirtazapine additionally binds to the 5-HT2, 5-HT3, and H1 receptors resulting in increased sedation, which is the most common side effect. Additional side effects include increased appetite and weight gain, dizziness, and transient elevations in cholesterol levels and liver function tests. Mirtazapine is unlike any other antidepressant in that it also has a hormonal effect that reduces cortisol levels within the body. Patients on mirtazapine showed significant improvement in symptoms of major depressive disorder within the first 1-2 weeks of treatment with long-term studies at 40 weeks showing continued improvements in response rates in addition to lower relapse rates. Mirtazapine has an antagonistic effect at the central presynaptic 5-HT2 receptors and alpha-2 adrenergic inhibitory autoreceptors and heteroreceptors resulting in increased norepinephrine release with an indirect release of serotonin due to increased noradrenergic input to the raphe nucleus. Mirtazapine has an effective dose range from 15 to 45 mg once daily with a long half-life preventing dose adjustments more often than every 1-2 weeks.Trazadone is a 5-HT2A and 5-HT2C receptor antagonist and selective serotonin reuptake inhibitor. While trazodone has only been FDA approved for use in the treatment of major depressive disorder, it has been used off label for numerous conditions including insomnia, anxiety, dementia, Alzheimer's disease, substance abuse, schizophrenia, bulimia, and fibromyalgia. The most common adverse reaction is drowsiness, followed by dizziness, dry mouth, and nervousness. In the United States, trazadone is the second most commonly prescribed agent used to treat insomnia. The hypnotic action of this medication at lower doses is attributed primarily to the antagonism of the 5-HT2A receptors, H1 receptors, and alpha-1 adrenergic receptors. The most active metabolite is m-chlorophenylpiperazine produced by the CYP3A4 enzyme, which is a more profound inhibitor of serotonin reuptake as compared to the parent molecule of trazadone. The maximum outpatient dose should not exceed 400 mg per day in divided doses, but in hospitalized patients, the dose may be increased to a maximum dose of 600 mg daily in divided doses while the patient is being actively monitored for side effects. One third of inpatients and one half of outpatients had a significant therapeutic response to trazadone by the end of the first week with the remainder of patients responding in 2-4 weeks of therapy.Vortioxetine is a novel antidepressant classified by the World Health Organization as a N06AX antidepressant that was derived from studies targeting the combination of direct serotonin transporter inhibition and 5-HT1A receptor modulation leading to rapid desensitization of the somatodendritic 5-HT1A autoreceptors and activation of the postsynaptic 5-HT1A receptors. This medication is an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors, an agonist at 5-HT1A receptors, and a partial agonist at 5-HT1B receptors. Blockade of the 5-HT3 receptor was noted to produce increased levels of serotonin, dopamine, norepinephrine, acetylcholine, and histamine in the prefrontal cortex and hippocampus, which are known to be associated with the development of depression. The most common adverse effect is nausea followed by sexual dysfunction, constipation, and vomiting. The maximum dose of vortioxetine is 20 mg daily with improvement in symptoms of depression noted at 2 weeks with a full therapeutic effect observed at 4-6 weeks.Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist. This medication works by enhancing serotonergic activity in the central nervous system through selective inhibition of serotonin reuptake with no significant effects noted on norepinephrine or dopamine uptake. Vilazodone additionally binds with high affinity to the 5-HT1A receptors as a partial agonist resulting in faster onset of action, greater efficacy, and better tolerability with reduced sexual side effects when compared to other SSRIs. The most common adverse effects were diarrhea, nausea, vomiting, and insomnia. Additional reported adverse effects included dizziness, dry mouth, fatigue, abnormal dreams, decreased libido, arthralgias, and palpitations which were self-limited with resolution in 4-5 days after starting the medication. The recommended therapeutic dose of vilazodone is 40 mg daily with improvement noted in depressive symptoms within 1 week of initiating therapy with increased remission rates noted at 6 weeks of therapy.The medications featured in this chapter do not fall within the major categories of antidepressant classes but add additional unique mechanisms for the treatment of major depressive disorder. Each medication targets different receptors in the central nervous system involved in the development of depression. Resolution of depressive symptoms and response rates of these medications are similar to SSRIs with reduced side effects that can often lead to discontinuation of therapy. Use of these unique medications allows clinicians to target specific symptoms and comorbidities often associated with depression resulting in improved symptom resolution and long-term maintenance of remission.