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Current Molecular Medicine 20235-HT receptor antagonists corresponding to ondansetron, granisetron, tropisetron, and palonosetron are clinically accustomed to treating nausea and emesis in... (Review)
Review
5-HT receptor antagonists corresponding to ondansetron, granisetron, tropisetron, and palonosetron are clinically accustomed to treating nausea and emesis in chemotherapy patients. However, current and previous studies reveal novel potentials of those ligands in other diseases involving the nervous system, such as addiction, pruritus, and neurological disorders, such as anxiety, psychosis, nociception, and cognitive function. This review gathers existing studies to support the role of 5-HT receptors in CIPN modulation. It has been reported that chemotherapy drugs increase the 5-HT content that binds with the 5-HT receptor, which later induces pain. As also shown in pre-clinical and clinical studies that various neuropathic pains could be blocked by the 5-HT receptor antagonists, we proposed that 5-HT receptor antagonists via 5- HT receptors may also inhibit neuropathic pain induced by chemotherapy. Our review suggests that future studies focus more on the 5-HT receptor antagonists and their modulation in CIPN to reduce the gap in the current pharmacotherapy for cancer-related pain.
Topics: Humans; Vomiting; Serotonin; Serotonin 5-HT3 Receptor Antagonists; Antineoplastic Agents; Peripheral Nervous System Diseases
PubMed: 35549869
DOI: 10.2174/1566524022666220512122525 -
Biological & Pharmaceutical Bulletin Jun 2022Nutmeg, a dried seed kernel of a tall evergreen Myristicaceae tree, is widely used as a spice and herbal medicine and is known to have antidepressant-like effects. This...
Nutmeg, a dried seed kernel of a tall evergreen Myristicaceae tree, is widely used as a spice and herbal medicine and is known to have antidepressant-like effects. This study evaluates the mechanisms underlying this antidepressant-like effect and safety of nutmeg n-hexane extract (NNE) in mice. Tail suspension and open field tests showed that NNE (10 mg/kg, per OS (p.o.)) significantly decreased the immobility time of mice without effecting their spontaneous locomotor activity. The reduction of immobility time of mice elicited by NNE was significantly inhibited by ketanserin (5-hydroxytryptamine (5-HT) receptor antagonist), ondansetron (5-HT receptor antagonist), and yohimbine (α receptor antagonist). WAY100635 (5-HT receptor antagonist) tended to inhibit the effect of NNE but without significance. Testing according to the Organisation for Economic Co-operation and Development Guidelines, no mice died due to administrated NNE (2000 mg/kg, p.o.), and behavioral and weight changes were not seen in the acute toxicity test. In the Ames test, no increase in the number of revertant colonies for each bacterial strain test strains TA98 and TA100 by nutmeg powder was observed either with or without metabolic activity by S9 mix. These results suggest that NNE shows an antidepressant-like effect involving various serotonergic and noradrenergic nervous systems and maybe a highly safe natural preparation.
Topics: Animals; Antidepressive Agents; Depression; Hindlimb Suspension; Mice; Myristica; Serotonin; Serotonin Antagonists; Swimming
PubMed: 35314522
DOI: 10.1248/bpb.b21-01059 -
Nature Structural & Molecular Biology Jul 2022Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell...
Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 serotonergic G protein-coupled receptor members encoded in the human genome, of which the 5-hydroxytryptamine (5-HT) receptor (5-HTR) is the least understood and lacks selective tool compounds. Here, we report four high-resolution (2.73-2.80 Å) structures of human 5-HTRs, including an inactive state structure bound to an antagonist AS2674723 by crystallization and active state structures bound to a partial agonist lisuride and two full agonists, 5-carboxamidotryptamine (5-CT) and methylergometrine, by cryo-EM. Leveraging the new structures, we developed a highly selective and potent antagonist for 5-HTR. Collectively, these findings both enhance our understanding of this enigmatic receptor and provide a roadmap for structure-based drug discovery for 5-HTR.
Topics: Humans; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists
PubMed: 35835867
DOI: 10.1038/s41594-022-00796-6 -
Science (New York, N.Y.) Jun 2023LSD and psilocin molecules bind to antidepressant drug targets in the brain, study shows.
LSD and psilocin molecules bind to antidepressant drug targets in the brain, study shows.
Topics: Brain; Hallucinogens; Lysergic Acid Diethylamide; Psilocybin; Antidepressive Agents; Animals; Mice; Receptor, trkB; Receptor, Serotonin, 5-HT2A; Humans; Serotonin 5-HT2 Receptor Antagonists
PubMed: 37289868
DOI: 10.1126/science.adj1031 -
Primary Care Jun 2020Headache is a common episodic and chronic pain syndrome in adolescents. Evaluation of headaches in primary care requires a comprehensive assessment including lifestyle... (Review)
Review
Headache is a common episodic and chronic pain syndrome in adolescents. Evaluation of headaches in primary care requires a comprehensive assessment including lifestyle behaviors and physical examination, as well as an understanding of when to pursue appropriate testing. Primary headache disorders seen in adolescents include migraine and tension-type headache. Pharmacologic management for primary headache includes both acute and prophylactic treatment strategies.
Topics: Adolescent; Adolescent Health; Analgesics; Anticonvulsants; Child; Diet; Exercise; Female; Headache; Humans; Life Style; Male; Migraine Disorders; Primary Health Care; Serotonin Antagonists; Sex Factors; Sleep; Tryptamines
PubMed: 32423712
DOI: 10.1016/j.pop.2020.02.004 -
Current Drug Targets 2021Natural products, such as phenylpropanoids, which are found in essential oils derived from aromatic plants, have been explored during non-clinical psychopharmacology... (Review)
Review
BACKGROUND
Natural products, such as phenylpropanoids, which are found in essential oils derived from aromatic plants, have been explored during non-clinical psychopharmacology studies, to discover new molecules with relevant pharmacological activities in the central nervous system, especially antidepressant and anxiolytic activities. Major depressive disorder is a highly debilitating psychiatric disorder and is considered to be a disabling public health problem, worldwide, as a primary factor associated with suicide. Current clinically administered antidepressants have late-onset therapeutic actions, are associated with several side effects, and clinical studies have reported that some patients do not respond well to treatment or reach complete remission.
OBJECTIVE
To review important new targets for antidepressant activity and to select phenylpropanoids with antidepressant activity, using Molegro Virtual Docker and Ossis Data Warris, and to verify substances with more promising antidepressant activity.
RESULTS AND CONCLUSION
An in silico molecular modeling study, based on homology, was conducted to determine the three-dimensional structure of the 5-hydroxytryptamine 2A receptor (5- HT2AR), then molecular docking studies were performed and the predisposition for cytotoxicity risk among identified molecules was examined. A model for 5-HT2AR homology, with satisfactory results, was obtained indicating the good stereochemical quality of the model. The phenylpropanoid 4-allyl-2,6-dimethoxyphenol showed the lowest binding energy for 5-HT2AR, with results relevant to the L-arginine/nitric oxide (NO)/cGMP pathway, and showed no toxicity within the parameters of mutagenicity, carcinogenicity, reproductive system toxicity, and skin-tissue irritability, when evaluated in silico; therefore, this molecule can be considered promising for the investigation of antidepressant activity.
Topics: Antidepressive Agents; Depressive Disorder, Major; Eugenol; Humans; Molecular Docking Simulation; Propanols; Serotonin 5-HT2 Receptor Antagonists
PubMed: 32881667
DOI: 10.2174/1389450121666200902171838 -
International Journal of Molecular... Dec 2020Interstitial lung disease (ILD) encompasses a heterogeneous group of more than 200 conditions, of which primarily idiopathic pulmonary fibrosis (IPF), idiopathic... (Review)
Review
Interstitial lung disease (ILD) encompasses a heterogeneous group of more than 200 conditions, of which primarily idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, hypersensitivity pneumonitis, ILD associated with autoimmune diseases and sarcoidosis may present a progressive fibrosing (PF) phenotype. Despite different aetiology and histopathological patterns, the PF-ILDs have similarities regarding disease mechanisms with self-sustaining fibrosis, which suggests that the diseases may share common pathogenetic pathways. Previous studies show an enhanced activation of serotonergic signaling in pulmonary fibrosis, and the serotonin (5-HT) receptors have been implicated to have important roles in observed profibrotic actions. Our research findings in support by others, demonstrate antifibrotic effects with 5-HT receptor antagonists, alleviating several key events common for the fibrotic diseases such as myofibroblast differentiation and connective tissue deposition. In this review, we will address the potential role of 5-HT and in particular the 5-HT receptors in three PF-ILDs: ILD associated with systemic sclerosis (SSc-ILD), ILD associated with rheumatoid arthritis (RA-ILD) and IPF. Highlighting the converging pathways in these diseases discloses the 5-HT receptor as a potential disease target for PF-ILDs, which today have an urgent unmet need for therapeutic strategies.
Topics: Animals; Humans; Idiopathic Pulmonary Fibrosis; Inflammation; Lung Diseases, Interstitial; Models, Biological; Receptor, Serotonin, 5-HT2B; Serotonin 5-HT2 Receptor Antagonists
PubMed: 33379351
DOI: 10.3390/ijms22010225 -
British Journal of Anaesthesia Jul 2023Postoperative nausea and vomiting (PONV) has been identified as a big (very frequently encountered) little (not linked to life-threatening outcomes) problem. Traditional...
Postoperative nausea and vomiting (PONV) has been identified as a big (very frequently encountered) little (not linked to life-threatening outcomes) problem. Traditional drugs (dexamethasone, droperidol or similar drugs, serotonin receptor antagonists) each have significant but limited effect, leading to an increasing use of combination therapies. High-risk patients, often identified through use of risk scoring systems, remain with a significant residual risk despite combining up to three traditional drugs. A recent correspondence in this Journal proposes the use of up to five anti-emetic drugs to further minimise the risk. This disruptive strategy was supported by favourable initial results, absence of side-effects and lower acquisition costs of the added new drugs (aprepitant and palonosetron) because of their recent loss of patent protection. These results are provocative and hypothesis generating, but need confirmation and do not warrant immediate changes in clinical practice. The next steps will also necessitate wider implementation of protocols protecting patients from PONV and a search for additional drugs and techniques aimed at treating established PONV.
Topics: Humans; Postoperative Nausea and Vomiting; Antiemetics; Droperidol; Serotonin Antagonists; Risk Factors; Vomiting; Dexamethasone; Drug Therapy, Combination
PubMed: 37179157
DOI: 10.1016/j.bja.2023.04.004 -
Sexual Medicine Reviews Oct 2019Flibanserin, a multifunctional serotonin receptor agonist and antagonist, is currently approved in the United States and Canada for the treatment of acquired,... (Review)
Review
INTRODUCTION
Flibanserin, a multifunctional serotonin receptor agonist and antagonist, is currently approved in the United States and Canada for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. A post hoc analysis of HSDD clinical trial data found that flibanserin treatment was associated with statistically significant weight loss relative to placebo, even though study patients were not selected for being overweight/obese and were provided no expectation for weight reduction or interventions intended to promote weight loss.
AIM
To understand possible mechanisms by which flibanserin may produce weight loss.
METHODS
A literature review was performed using Medline database for relevant publications on the mechanisms of action by which flibanserin may provide weight loss and the links between sexual function and weight management.
MAIN OUTCOME MEASURES
Examination of (i) biopsychosocial factors regulating sexual desire, food intake, and weight regulation; (ii) clinical pharmacology of flibanserin; (iii) neurobiology of brain reward circuitry; and (iv) identification of possible mechanisms common to flibanserin and weight loss.
RESULTS
Based on flibanserin clinical trial data, there was no consistent correlation between weight loss and improvement in sexual function, as assessed by HSDD outcome measures. Nausea, a common adverse event associated with flibanserin use, also did not appear to be a contributing factor to weight loss. Hypothetical links between flibanserin treatment and weight loss include modulation of peripheral 5-HT receptors and factors such as improved mood and improved sleep.
CONCLUSION
Mechanisms of flibanserin-induced weight loss have not been well characterized but may involve indirect beneficial effects on peripheral 5-HT receptors and central regulation of mood and sleep. Future research may better elucidate the links between sexual function and weight management and the mechanism(s) by which flibanserin use may result in weight loss. Simon JA, Kingsberg SA, Goldstein I, et al. Weight Loss in Women Taking Flibanserin for Hypoactive Sexual Desire Disorder (HSDD): Insights into Potential Mechanisms. Sex Med Rev 2019;7:575-586.
Topics: Arousal; Benzimidazoles; Energy Intake; Female; Humans; Libido; Serotonin Antagonists; Serotonin Receptor Agonists; Sexual Dysfunctions, Psychological; Weight Loss
PubMed: 31196764
DOI: 10.1016/j.sxmr.2019.04.003 -
Journal of Biochemical and Molecular... Sep 2019This study was performed to investigate the effect of ondansetron, a serotonin receptor (5-HT3) antagonist, in the alleviation of diclofenac-induced kidney injuries....
This study was performed to investigate the effect of ondansetron, a serotonin receptor (5-HT3) antagonist, in the alleviation of diclofenac-induced kidney injuries. NMRI mice were randomly divided into six groups and treated with (A) untreated control group, (B) diclofenac (100 mg/kg), (C) ondansetron (1 mg/kg), (D to F) ondansetron (0.1, 0.5, and 1 mg/kg, respectively) and diclofenac (100 mg/kg) for last 3 days of experiment. The oxidative stress tests strongly demonstrated the negative synergistic effects of diclofenac and ondansetron, regarding the observation of dose-dependent enhancement of malondialdehyde concentration, and reduction of glutathione content, and superoxide dismutase and catalase activity. Histopathological analyses revealed dose-dependent tubular epithelial cells degeneration, outstanding mononuclear cells infiltration, clear necrosis at the papillary region of kidney, dilation, and vascular hyperemia in mice kidney tissues treated with ondansetron and diclofenac. Conclusively, these findings suggested the possible ondansetron-diclofenac interaction through the induction of oxidative stress.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Catalase; Diclofenac; Dose-Response Relationship, Drug; Drug Synergism; Glutathione; Kidney; Mice; Ondansetron; Serotonin Antagonists; Superoxide Dismutase
PubMed: 31332906
DOI: 10.1002/jbt.22378