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Archives of Toxicology Aug 2021The consumption of contaminated shellfish with okadaic acid (OA) group of toxins leads to diarrhoeic shellfish poisoning (DSP) characterized by a set of symptoms...
The consumption of contaminated shellfish with okadaic acid (OA) group of toxins leads to diarrhoeic shellfish poisoning (DSP) characterized by a set of symptoms including nausea, vomiting and diarrhoea. These phycotoxins are Ser/Thr phosphatase inhibitors, which produce hyperphosphorylation in cellular proteins. However, this inhibition does not fully explain the symptomatology reported and other targets could be relevant to the toxicity. Previous studies have indicated a feasible involvement of the nervous system. We performed a set of in vivo approaches to elucidate whether neuropeptide Y (NPY), Peptide YY (PYY) or serotonin (5-HT) was implicated in the early OA-induced diarrhoea. Fasted Swiss female mice were administered NPY, PYY(3-36) or cyproheptadine intraperitoneal prior to oral OA treatment (250 µg/kg). A non-significant delay in diarrhoea onset was observed for NPY (107 µg/kg) and PYY(3-36) (1 mg/kg) pre-treatment. On the contrary, the serotonin antagonist cyproheptadine was able to block (10 mg/kg) or delay (0.1 and 1 mg/kg) diarrhoea onset suggesting a role of 5-HT. This is the first report of the possible involvement of serotonin in OA-induced poisoning.
Topics: Animals; Cyproheptadine; Diarrhea; Enzyme Inhibitors; Female; Mice; Neuropeptide Y; Okadaic Acid; Peptide Fragments; Peptide YY; Serotonin; Serotonin Antagonists; Shellfish Poisoning; Time Factors
PubMed: 34148100
DOI: 10.1007/s00204-021-03095-z -
Current Topics in Medicinal Chemistry 2015The serotonin 5-HT(6) receptor (5- HT(6)R) is amongst the recently discovered serotonergic receptors with almost exclusive localization in the brain. Hence, this... (Review)
Review
The serotonin 5-HT(6) receptor (5- HT(6)R) is amongst the recently discovered serotonergic receptors with almost exclusive localization in the brain. Hence, this receptor is fast emerging as a promising target for cognition enhancement in central nervous system (CNS) diseases such as Alzheimer's disease (cognitive function), obesity, schizophrenia and anxiety. The last decade has seen a surge of literature reports on the functional role of this receptor in learning and memory processes and investigations related to the chemistry and pharmacology of 5-HT(6) receptor ligands, especially 5- HT(6) receptor antagonists. Studies show the involvement of multiple neurotransmitter systems in cognitive enhancement by 5-HT(6)R antagonists including cholinergic, glutamatergic, and GABAergic systems. Several of the 5-HT(6)R ligands are indole based agents bearing structural similarity to the endogenous neurotransmitter serotonin. Based on the pharmacophoric models proposed for these agents, drug designing has been carried out incorporating various heterocyclic replacements for the indole nucleus. In this review, we have broadly summarized the medicinal chemistry and current status of this fairly recent class of drugs along with their potential therapeutic applications.
Topics: Central Nervous System Diseases; Ligands; Molecular Structure; Receptors, Serotonin; Serotonin Antagonists; Structure-Activity Relationship
PubMed: 25915615
DOI: 10.2174/1568026615666150427110420 -
Journal of Medicinal Chemistry Sep 2014Alzheimer's disease (AD) is one of the most frequent causes of death and disability worldwide and has a significant clinical and socioeconomic impact. In the search for... (Review)
Review
Alzheimer's disease (AD) is one of the most frequent causes of death and disability worldwide and has a significant clinical and socioeconomic impact. In the search for novel therapeutic strategies, serotonin 5-HT6 receptor (5-HT6R) has been proposed as a promising drug target for cognition enhancement in AD. This manuscript reviews the compelling evidence for the implication of this receptor in learning and memory processes. We have summarized the current status of the medicinal chemistry of 5-HT6R antagonists and the encouraging preclinical findings that demonstrate their significant procognitive behavioral effects in a number of learning paradigms, probably acting through modulation of multiple neurotransmitter systems and signaling pathways. The results of the ongoing clinical trials are eagerly awaited to shed some light on the validation of 5-HT6R antagonists as a new drug class for the treatment of symptomatic cognitive impairment in AD, either as stand-alone therapy or in combination with established agents.
Topics: Alzheimer Disease; Binding Sites; Clinical Trials as Topic; Cognition Disorders; Humans; Models, Molecular; Molecular Structure; Protein Structure, Tertiary; Receptors, Serotonin; Serotonin Antagonists
PubMed: 24850589
DOI: 10.1021/jm5003952 -
Archiv Der Pharmazie Jul 2019Serotonin 5-HT receptors, butyrylcholinesterase (BuChE) and oxidative stress are related to the pathophysiology of Alzheimer's disease. Inhibition of BuChE provides...
Serotonin 5-HT receptors, butyrylcholinesterase (BuChE) and oxidative stress are related to the pathophysiology of Alzheimer's disease. Inhibition of BuChE provides symptomatic treatment of the disease and the same effect was demonstrated for 5-HT antagonists in clinical trials. Oxidative stress is regarded as a major and primary factor contributing to the development of Alzheimer's disease; therefore, antioxidant agents may provide a disease-modifying effect. Combining BuChE inhibition, 5-HT antagonism, and antioxidant properties may result in multitarget-directed ligands providing cognition-enhancing properties with neuroprotective activity. On the basis of the screening of the library of 5-HT antagonists against BuChE, we selected two compounds and designed their structural modifications that could lead to improved BuChE inhibitory activity. We synthesized two series of compounds and tested their affinity and functional activity at 5-HT receptors, BuChE inhibitory activity and antioxidant properties. Compound 12 with K and K values against 5-HT receptors of 41.8 and 74 nM, respectively, an IC value of 5 µM against BuChE and antioxidant properties exceeding the activity of ascorbic acid is a promising lead structure for further development of anti-Alzheimer's agents.
Topics: Animals; Antioxidants; Butyrylcholinesterase; Cholinesterase Inhibitors; Electrophorus; Horses; Humans; Models, Molecular; Molecular Structure; Oxidative Stress; Receptors, Serotonin; Serotonin Antagonists; Triazines
PubMed: 31162703
DOI: 10.1002/ardp.201900041 -
The American Journal of Case Reports May 2018BACKGROUND Serotonin syndrome is a condition characterized predominantly by neuromuscular symptoms and altered thermoregulation in response to serotonergic overtone....
BACKGROUND Serotonin syndrome is a condition characterized predominantly by neuromuscular symptoms and altered thermoregulation in response to serotonergic overtone. Treatment is focused on withdrawal of serotonergic agents, which leads to resolution in the majority of cases. In the setting of serotonergic overdose, the onset of serotonin syndrome is usually within 4 to 13 h. Here, we report a case of delayed-onset serotonin syndrome in a patient who ingested a mixture of longer-acting serotonin agonists with serotonin antagonists. CASE REPORT A 24-year-old male was transferred to our medical intensive care unit with hypotension and altered mental status after an overdose of fluoxetine, cyproheptadine, trazodone, olanzapine, risperidone, and bupropion. After approximately 72 h, the patient developed symptoms of fever, lower leg clonus, hyperreflexia, and agitation. He was diagnosed with delayed-onset serotonin syndrome, which responded well to re-administration of cyproheptadine, leading to resolution of symptoms by day 5 of his stay. CONCLUSIONS In this present case, our patient presented with the longest reported delay in the onset of serotonin syndrome after intentional ingestion. This was likely secondary to co-ingestion of long-acting serotonin agonists with protective shorter-acting serotonin antagonists (cyproheptadine and olanzapine). Clinicians should consider delayed-onset serotonin syndrome when patients ingest longer-acting serotonergic agents with serotonin antagonists.
Topics: Benzodiazepines; Bupropion; Cyproheptadine; Dopamine Uptake Inhibitors; Drug Overdose; Fluoxetine; Humans; Male; Olanzapine; Risperidone; Serotonin Agents; Serotonin Antagonists; Serotonin Receptor Agonists; Serotonin Syndrome; Selective Serotonin Reuptake Inhibitors; Time Factors; Trazodone; Young Adult
PubMed: 29795058
DOI: 10.12659/AJCR.909063 -
European Journal of Medicinal Chemistry Mar 2016To discover a novel 5-HT7R antagonist for treatment of depression, we designed N-acyl-carbazole derivatives which were synthesized and biologically evaluated against...
To discover a novel 5-HT7R antagonist for treatment of depression, we designed N-acyl-carbazole derivatives which were synthesized and biologically evaluated against 5-HT7R. Among total 30 compounds synthesized, four compounds 27-30 showed good binding affinities with Ki values of <100 nM. The compound 28, 1-(9H-carbazol-9-yl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)hexan-1-one, showed good selectivity over other serotonin receptor subtypes and turned out to be a novel selective 5-HT7R antagonist following functional assays. The compound 28 showed moderate activity on hERG channel and good stability in microsomal stability test. The compound 28 exhibited a good pharmacokinetic profile with 67.8% oral bioavailability and good penetration to the brain. The compound 28 was also tested in in vivo depression animal model and showed antidepressant effect in the forced swimming test. Therefore, the selective 5-HT7R antagonist 28 can be considered as a good lead for discovery of novel 5-HT7R antagonists as antidepressants.
Topics: Acylation; Animals; Antidepressive Agents; CHO Cells; Carbazoles; Cricetulus; HEK293 Cells; Humans; Male; Mice; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin Antagonists; Structure-Activity Relationship
PubMed: 26852005
DOI: 10.1016/j.ejmech.2016.01.043 -
Phytochemistry Oct 2017Fourteen phloroglucinols, named hyperciumoxide A-N, and a known compound were isolated from air-dried aerial parts of Hypericum scabrum. The structures of these...
Fourteen phloroglucinols, named hyperciumoxide A-N, and a known compound were isolated from air-dried aerial parts of Hypericum scabrum. The structures of these compounds were deduced on the basis of extensive 1D- and 2D-NMR experiments. Hepatoprotective properties against D-galactosamine-induced HL-7702 cell damage of isolated compounds were evaluated. Meanwhile, these compounds were also tested for antidepressant activity by inhibiting reuptake of tritiated serotonin ([H]-5-HT) and Noradrenalinet ([H]-NE) in rat brain synaptosomes.
Topics: Animals; Antidepressive Agents; Brain; Cyclohexanones; Drugs, Chinese Herbal; HL-60 Cells; Heterocyclic Compounds, Bridged-Ring; Humans; Hypericum; Liver; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Phloroglucinol; Plant Components, Aerial; Rats; Serotonin Antagonists
PubMed: 28675829
DOI: 10.1016/j.phytochem.2017.06.011 -
The Journal of Nutrition Jul 2020L-tryptophan (Trp) has been reported to regulate gut immune responses during inflammation. However, the underlying mechanisms are largely unknown.
BACKGROUND
L-tryptophan (Trp) has been reported to regulate gut immune responses during inflammation. However, the underlying mechanisms are largely unknown.
OBJECTIVE
We investigated the role of Trp supplementation on the serotonin receptor (HTR)-mediated immune response in the colon of mice with dextran sodium sulfate (DSS)-induced colitis.
METHODS
In Experiment 1, male C57BL/6 mice were randomly assigned to 1 of 4 groups: Control (Con) or L-Trp supplementation [0.1 mg/(g body weight·d) in drinking water] (Trp) with (+DSS) or without 2% DSS in drinking water from days 8 to 14 of the 17-d study. In Experiments 2 and 3, Trp + DSS (Expt. 2) or DSS (Expt. 3) mice were treated as described above and subcutaneously administered with HTR1A or HTR4 antagonists (or their combination) or an HTR2 agonist from days 8 to 14 of the 15-d study. Changes in immune cell phenotypes, inflammatory mediators, and related cell signaling molecules were assessed by flow cytometry, real-time PCR, or Western blot. The mRNA abundances of Trp hydroxylase (Tph1), serotonin reuptake transporter (Slc6a4), and Htr in the colon were also assessed.
RESULTS
Trp supplementation before DSS treatment upregulated the expression of colonic Slc6a4 (0.49 compared with 0.30), Htr1a (1.14 compared with 0.65), and Htr4 (1.08 compared with 0.70), downregulated the expression of Htr2a (1.54 compared with 1.89), and decreased the colonic serotonin concentration (11.5 compared with 14.8 nmol/g tissue) (P < 0.01). Trp regulated the DSS-induced immune response partly through attenuating the activation of toll-like receptor 4 (TLR4)-STAT3 signaling and nucleus p-65. Either an HTR2 agonist or HTR1A and HTR4 antagonists reversed the effects of Trp.
CONCLUSIONS
In mice treated with DSS, Trp supplementation before DSS administration improved colonic immune responses partly by reducing colonic serotonin and subsequent interactions with HTR1A and HTR4, which are known to be present on neutrophils and macrophages.
Topics: Animals; Colitis; Colon; Dextran Sulfate; Diet; Dietary Supplements; Homeostasis; Male; Mice; Mice, Inbred C57BL; Piperazines; Random Allocation; Serotonin; Serotonin Antagonists; Tryptophan
PubMed: 32386234
DOI: 10.1093/jn/nxaa129 -
Brain Research Nov 2019The aim of the present study was to investigate and compare the effects of acute and chronic (21-day) administration of agonist (WAY-181187) and antagonist (SB-742457)...
The aim of the present study was to investigate and compare the effects of acute and chronic (21-day) administration of agonist (WAY-181187) and antagonist (SB-742457) of the 5-hydroxytryptamine 6 receptor (5-HTR) on MK-801-induced memory impairments in novel object recognition (NORT) and Y-maze continuous spontaneous alternation tests (Y-CAT). Further, the expression of the brain-derived neurotrophic factor (BDNF) in rat hippocampus was measured after 21-day administration to investigate BDNF participation in the pro-cognitive effects of 5-HTR ligands. We found that acute administration of WAY-181187, as well as SB-742457, reversed the effects of MK-801 in NORT and Y-CAT, and that this influence persisted after prolonged application in NORT but not in Y-CAT. Both 5-HTR ligands increased hippocampal BDNF protein expression, but WAY-181187 was much more potent than SB-742457 and alleviated the MK-801-induced inhibition of BDNF signaling pathways better, which seems to translate into a stronger WAY-181187 effect in behavioral tests. Collectively, both the 5-HTR agonist and the antagonist, administered acutely and chronically, prevent memory impairments and alterations in BDNF signaling induced by MK-801 in rats. The present results confirm the pro-cognitive properties of both types of 5-HTR ligands and suggest that BDNF pathways may be involved in their mechanism of action.
Topics: Animals; Brain-Derived Neurotrophic Factor; Dizocilpine Maleate; Exploratory Behavior; Male; Memory; Quinolines; Rats, Wistar; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Signal Transduction; Sulfones; Thiazoles; Tryptamines
PubMed: 31412259
DOI: 10.1016/j.brainres.2019.146375 -
ACS Chemical Neuroscience Mar 2019Credit should be granted to medicinal chemists with a solid background in organic chemistry and computational chemistry, able to read, understand, and discuss the... (Review)
Review
Credit should be granted to medicinal chemists with a solid background in organic chemistry and computational chemistry, able to read, understand, and discuss the biological data, in order to design new and more efficient therapeutic approaches for Alzheimer's disease.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Biomedical Research; Cholinesterase Inhibitors; Humans; Serotonin Antagonists; tau Proteins
PubMed: 30707547
DOI: 10.1021/acschemneuro.9b00034