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Pharmacology & Therapeutics Jun 2015Serotonin receptors are prevalent throughout the nervous system and the periphery, and remain one of the most lucrative and promising drug discovery targets for... (Review)
Review
Serotonin receptors are prevalent throughout the nervous system and the periphery, and remain one of the most lucrative and promising drug discovery targets for disorders ranging from migraine headaches to neuropsychiatric disorders such as schizophrenia and depression. There are 14 distinct serotonin receptors, of which 13 are G protein-coupled receptors (GPCRs), which are targets for approximately 40% of the approved medicines. Recent crystallographic and biochemical evidence has provided a converging understanding of the basic structure and functional mechanics of GPCR activation. Currently, two GPCR crystal structures exist for the serotonin family, the 5-HT1B and 5-HT2B receptor, with the antimigraine and valvulopathic drug ergotamine bound. The first serotonin crystal structures not only provide the first evidence of serotonin receptor topography but also provide mechanistic explanations into functional selectivity or biased agonism. This review will detail the findings of these crystal structures from a molecular and mutagenesis perspective for driving rational drug design for novel therapeutics incorporating biased signaling.
Topics: Allosteric Site; Animals; Ergotamine; GTP-Binding Proteins; Heart Valve Diseases; Humans; Migraine Disorders; Models, Molecular; Protein Conformation; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2B; Receptors, Serotonin; Serotonin Receptor Agonists; Signal Transduction; Vasoconstrictor Agents
PubMed: 25601315
DOI: 10.1016/j.pharmthera.2015.01.009 -
CMAJ : Canadian Medical Association... Jan 1988Recent advances in migraine therapy include the recognition of analgesic or ergotamine abuse as a cause of chronic daily migraine, the introduction of effective... (Review)
Review
Recent advances in migraine therapy include the recognition of analgesic or ergotamine abuse as a cause of chronic daily migraine, the introduction of effective non-narcotic drugs such as chlorpromazine, dihydroergotamine and corticosteroids for the treatment of intractable migraine attacks, the increased number of beta-blockers now recognized as effective prophylactic agents and the introduction of calcium-channel blockers for prophylaxis. There is a sufficient variety of antimigraine drugs, and therapy should be successful for most sufferers.
Topics: Acute Disease; Adrenal Cortex Hormones; Adrenergic beta-Antagonists; Analgesics; Calcium Channel Blockers; Chlorpromazine; Dihydroergotamine; Ergotamine; Humans; Methysergide; Migraine Disorders; Narcotics; Pizotyline
PubMed: 2891428
DOI: No ID Found -
Nature Metabolism Aug 2019Dopamine signaling is a crucial part of the brain reward system and can affect feeding behavior. Dopamine receptors are also expressed in the hypothalamus, which is...
Dopamine signaling is a crucial part of the brain reward system and can affect feeding behavior. Dopamine receptors are also expressed in the hypothalamus, which is known to control energy metabolism in peripheral tissues. Here we show that pharmacological or chemogenetic stimulation of dopamine receptor 2 (D2R) expressing cells in the lateral hypothalamic area (LHA) and the zona incerta (ZI) decreases body weight and stimulates brown fat activity in rodents in a feeding-independent manner. LHA/ZI D2R stimulation requires an intact sympathetic nervous system and orexin system to exert its action and involves inhibition of PI3K in the LHA/ZI. We further demonstrate that, as early as 3 months after onset of treatment, patients treated with the D2R agonist cabergoline experience an increase in energy expenditure that persists for one year, leading to total body weight and fat loss through a prolactin-independent mechanism. Our results may provide a mechanistic explanation for how clinically used D2R agonists act in the CNS to regulate energy balance.
Topics: Adipose Tissue, Brown; Animals; Bromocriptine; Dopamine; Female; Humans; Hypothalamus; Injections, Intraventricular; Male; Rats; Signal Transduction; Thermogenesis
PubMed: 31579887
DOI: 10.1038/s42255-019-0099-7 -
The Western Journal of Medicine Sep 1994Headache-prone patients have many highly effective therapeutic options open to them. Used only at the time of headache, sumatriptan succinate by mouth or injection and... (Review)
Review
Headache-prone patients have many highly effective therapeutic options open to them. Used only at the time of headache, sumatriptan succinate by mouth or injection and dihydroergotamine nasal spray are novel choices now or soon to be available. The original migraine therapy, ergotamine, is highly effective in its rectal suppository formulation, when used at a subnauseating dosage. Valproate sodium is the latest addition to the many therapies available for long-term stabilization.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Ergotamine; Headache; Humans; Migraine Disorders; Sumatriptan
PubMed: 7975570
DOI: No ID Found -
British Medical Journal May 1972Classical migraine, including incapacitating visual field defects, repeatedly developed in five young men immediately after blows to the head while playing football and...
Classical migraine, including incapacitating visual field defects, repeatedly developed in five young men immediately after blows to the head while playing football and in no other circumstances. A similar condition occurred in a professional boxer and an isolated attack in a boy footballer. Prophylactic treatment with ergotamine tartrate may not be wholly successful and it may be necessary to give up the sport. Any unitary theory of causation of attacks of migraine must account for prodromal symptoms immediately after head injury.
Topics: Adult; Athletic Injuries; Boxing; Child; Craniocerebral Trauma; Ergotamine; Humans; Male; Migraine Disorders; Sports Medicine
PubMed: 5022042
DOI: 10.1136/bmj.2.5809.326 -
Postgraduate Medical Journal Jan 1982Adverse reactions to ergotamine were noted in 16 out of 41 studies in which therapeutic doses of the drug were given to normal, healthy volunteers. In 17 of the studies... (Clinical Trial)
Clinical Trial
Adverse reactions to ergotamine were noted in 16 out of 41 studies in which therapeutic doses of the drug were given to normal, healthy volunteers. In 17 of the studies 0.25 mg ergotamine was given by injection, 6 i.v. and 11 i.m., in 20 studies 2 mg ergotamine was given by mouth, and 4 subjects received 2 mg ergotamine by suppository. Plasma and urinary ergotamine was measured by radio-immunoassay. Adverse reactions were significantly more frequent in subjects in whom plasma ergotamine exceeded 1.8 ng/ml. Pharmacokinetic data derived from the study are presented and their relevance to the therapeutic use of ergotamine are discussed.
Topics: Administration, Oral; Adolescent; Adult; Ergotamine; Female; Humans; Injections, Intramuscular; Injections, Intravenous; Male; Suppositories
PubMed: 7088766
DOI: 10.1136/pgmj.58.675.6 -
Frontiers in Endocrinology 2023Bromocriptine treatment has been shown to reduce menstrual bleeding and pain in women with adenomyosis in a pilot clinical trial. The underlying mechanism contributing...
OBJECTIVE
Bromocriptine treatment has been shown to reduce menstrual bleeding and pain in women with adenomyosis in a pilot clinical trial. The underlying mechanism contributing to the treatment effect is however unknown. The purpose of this study was to explore the effect of bromocriptine on the proliferation and migration properties of the endometrium in women with adenomyosis, by assessing cellular and molecular changes after six months of vaginal bromocriptine treatment.
METHODS
Endometrial specimens were collected during the proliferative phase from women with adenomyosis (n=6) before (baseline) and after six months of treatment with vaginal bromocriptine. Immunohistochemistry was used to determine changes in the protein expression of Ki67 in the endometrium of women with adenomyosis. Primary endometrial stromal cells isolated at baseline were expanded and exposed to different doses of bromocriptine to determine the optimal half-maximum inhibitory concentration (IC50) using CellTiter-Blue Cell Viability Assay. Cell proliferation was assessed by bromodeoxyuridine ELISA assay and Ki67 gene expression was checked by real-time PCR. The migratory ability of endometrial stromal cells was determined by wound healing and transwell migration assays. Small RNA sequencing was applied on tissues collected from women with adenomyosis before and after bromocriptine treatment to identify differentially expressed microRNAs (miRNAs) after bromocriptine treatment. Bioinformatic methods were used for target gene prediction and the identification of biological pathways by enrichment procedures.
RESULTS
Vaginal bromocriptine treatment reduced the Ki67 protein expression in the endometrium of women with adenomyosis and did not change the prolactin mRNA expression and protein concentration of prolactin in endometrial tissues. Bromocriptine significantly inhibited the proliferative and migrative abilities of endometrial stromal cells derived from women with adenomyosis . Moreover, small RNA sequencing revealed 27 differentially expressed miRNAs between the endometrium of women with adenomyosis before and after six months of vaginal bromocriptine treatment. KEGG pathway analysis on targeted genes of 27 miRNAs showed that several signaling pathways associated with cell proliferation and apoptosis were enriched after bromocriptine treatment.
CONCLUSION
Bromocriptine treatment exhibits an anti-proliferative effect in the endometrium of women with adenomyosis and . Bromocriptine might inhibit the proliferation of endometrial tissue in adenomyosis in part through the regulation of dysregulated microRNAs and proliferation-associated signaling pathways.
Topics: Humans; Female; Adenomyosis; Bromocriptine; Ki-67 Antigen; Prolactin; Endometrium; MicroRNAs; Cell Proliferation
PubMed: 36967761
DOI: 10.3389/fendo.2023.1026168 -
JPMA. the Journal of the Pakistan... Sep 2022Diabetes is a multi-faceted syndrome on which the brain is an etiopathogenetic factor, as well as a target organ for damage. Drugs which act on the brain, such as...
Diabetes is a multi-faceted syndrome on which the brain is an etiopathogenetic factor, as well as a target organ for damage. Drugs which act on the brain, such as bromocriptine and antipsychotic drugs, are known to influence glycaemic control. This article describes lemborexant, a dual oxexin receptor antagonist (DORA), and hypothesizes that it may be used as an adjuvant in difficult-to-control diabetes. Its utility should be explored in persons with insomnia and high fasting glucose, unregulated appetite, and diabetes distress.
Topics: Humans; Orexin Receptor Antagonists; Antipsychotic Agents; Bromocriptine; Sleep Initiation and Maintenance Disorders; Adjuvants, Immunologic; Diabetes Mellitus; Glucose
PubMed: 36280998
DOI: 10.47391/JPMA.22-93 -
Toxins Apr 2024Ergot alkaloids (EAs) formed by fungi are one of the most common food contaminants worldwide, affecting cereals such as rye, wheat, and barley. To accurately determine...
Ergot alkaloids (EAs) formed by fungi are one of the most common food contaminants worldwide, affecting cereals such as rye, wheat, and barley. To accurately determine the level of contamination and to monitor EAs maximum levels set by the European Union, the six most common EAs (so-called priority EAs) and their corresponding epimers are quantified using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). The quantification of EAs in complex food matrices without appropriate internal standards is challenging but currently carried out in the standard method EN 17425:2021 due to their commercial unavailability. To address the need for isotopically labeled EAs, we focus on two semi-synthetic approaches for the synthesis of these reference standards. Therefore, we investigate the feasibility of the -demethylation of native ergotamine to yield norergotamine, which can subsequently be remethylated with an isotopically labeled methylating reagent, such as iodomethane (CD-I), to yield isotopically labeled ergotamine and its -epimer ergotaminine. Testing the isotopically labeled ergotamine/-inine against native ergotamine/-inine with HPLC coupled to high-resolution HR-MS/MS proved the structure of ergotamine-CD and ergotaminine-CD. Thus, for the first time, we can describe their synthesis from unlabeled, native ergotamine. Furthermore, this approach is promising as a universal way to synthesize other isotopically labeled EAs.
Topics: Ergotamine; Carbon Isotopes; Tandem Mass Spectrometry; Chromatography, High Pressure Liquid; Isotope Labeling
PubMed: 38668624
DOI: 10.3390/toxins16040199 -
Headache Apr 2012The 5-hydroxytryptamine (5-HT) receptor family mediates the effects of several drugs highly effective in migraine primarily by activating 5-HT(1B) , 5-HT(1D) , and... (Review)
Review
The 5-hydroxytryptamine (5-HT) receptor family mediates the effects of several drugs highly effective in migraine primarily by activating 5-HT(1B) , 5-HT(1D) , and 5-HT(1F) receptors. Ergotamine, dihydroergotamine, and methysergide, as well as the "triptan" sumatriptan, are all agonists for these receptors. The receptor profile and degree of selectivity of these four drugs differ, which is reflected by their side effects that limit their use in the acute and prophylactic treatment of migraine. The acute antimigraine efficacy of these remedies is very much dependent on the formulation used where, in general, parenteral formulations are more effective in reliving the symptoms of a migraine attack.
Topics: Animals; Dihydroergotamine; Ergotamine; Humans; Methysergide; Migraine Disorders; Sumatriptan; Treatment Outcome
PubMed: 22444161
DOI: 10.1111/j.1526-4610.2012.02124.x