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1.
J Pharmacol Sci ; 151(2): 63-71, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36707180

RESUMO

Mirtazapine, an atypical antidepressant, is known to enhance serotonergic transmission by inhibiting the 5-hydroxytryptamine (5-HT)1A, 5-HT2C, and 5-HT3 receptors. However, the mechanism of action on the 5-HT3 receptor remains unclear. We investigated the inhibitory mechanisms of mirtazapine on 5-HT3 receptors of NCB20 neuroblastoma cells using the whole-cell voltage-clamp method. Mirtazapine inhibited the 5-HT3 receptor currents in a concentration-dependent manner, and the inhibitory effect was influenced by the concentration of 5-HT. When mirtazapine was co-applied to 5-HT, the maximal response of the 5-HT3 receptor current was reduced and EC50 was increased, suggesting that mirtazapine might act as a non-competitive inhibitor. Inhibition of 5-HT3 current by mirtazapine was stronger in pre-application than in co-application, which suggests that mirtazapine might act as a closed state inhibitor. This finding was further supported by no use-dependency of the mirtazapine for 5-HT3 receptor inhibition. Finally, mirtazapine accelerated the desensitization and deactivation process in a concentration-dependent manner. The difference in recovery time showed that mirtazapine drastically influences the desensitization process than the deactivation process. These mechanistic characteristics of mirtazapine support the understanding of the relationship between the 5-HT3 receptor and atypical antidepressants.


Assuntos
Antidepressivos de Segunda Geração , Serotonina , Antidepressivos/farmacologia , Linhagem Celular Tumoral , Mirtazapina , Receptores 5-HT3 de Serotonina , Serotonina/farmacologia , Animais , Cricetinae , Cricetulus
2.
Support Care Cancer ; 32(1): 36, 2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-38105286

RESUMO

PURPOSE: This review is an update of the MASCC/ESMO 2015 recommendations for the prophylaxis of acute and delayed nausea and vomiting induced by multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting. METHODS: A systematic literature search was conducted using PubMed from June 1, 2015, through February 1, 2023. RESULTS: We identified 56 references (16 were duplications or invalid), leaving 40 manuscripts for this search. The panel classified level I evidence (three manuscripts) and level II evidence (14 manuscripts). High-dose chemotherapy and stem cell transplant were discussed in four of these manuscripts, and multiple-day chemotherapy treatment in 15. Some manuscripts covered both topics. Additionally, a search for breakthrough nausea and vomiting resulted in 12 "hits." No new relevant studies were identified. CONCLUSIONS: The recommendations for patients receiving high-dose chemotherapy with stem cell transplants and patients undergoing multiple-day cisplatin were updated. For patients receiving high-dose chemotherapy for stem cell transplant, a combination of a 5-HT3 receptor antagonist with dexamethasone and aprepitant is recommended. Olanzapine could be considered part of the antiemetic regimen. Patients receiving multiple-day cisplatin should receive a 5-HT3 receptor antagonist plus dexamethasone plus aprepitant plus olanzapine. For patients experiencing breakthrough nausea and vomiting, the available evidence suggests using a single dose of olanzapine daily for 3 days.


Assuntos
Antieméticos , Antineoplásicos , Humanos , Aprepitanto/uso terapêutico , Olanzapina/uso terapêutico , Cisplatino/efeitos adversos , Consenso , Serotonina/efeitos adversos , Antineoplásicos/uso terapêutico , Vômito/induzido quimicamente , Vômito/prevenção & controle , Vômito/tratamento farmacológico , Náusea/induzido quimicamente , Náusea/prevenção & controle , Náusea/tratamento farmacológico , Antieméticos/uso terapêutico , Dexametasona/uso terapêutico
3.
Int J Mol Sci ; 24(9)2023 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-37176009

RESUMO

The 5-hydroxytryptamine 3 (5-HT3) receptor belongs to the pentameric ligand-gated cation channel superfamily. Humans have five different 5-HT3 receptor subunits: A to E. The 5-HT3 receptors are located on the cell membrane, but a previous study suggested that mitochondria could also contain A subunits. In this article, we explored the distribution of 5-HT3 receptor subunits in intracellular and cell-free mitochondria. Organelle prediction software supported the localization of the A and E subunits on the inner membrane of the mitochondria. We transiently transfected HEK293T cells that do not natively express the 5-HT3 receptor with an epitope and fluorescent protein-tagged 5HT3A and 5HT3E subunits. Fluorescence microscopy and cell fractionation indicated that both subunits, A and E, localized to the mitochondria, while transmission electron microscopy revealed the location of the subunits on the mitochondrial inner membrane, where they could form heteromeric complexes. Cell-free mitochondria isolated from cell culture media colocalized with the fluorescent signal for A subunits. The presence of A and E subunits influenced changes in the membrane potential and mitochondrial oxygen consumption rates upon exposure to serotonin; this was inhibited by pre-treatment with ondansetron. Therefore, it is likely that the 5-HT3 receptors present on mitochondria directly impact mitochondrial function and that this may have therapeutic implications.


Assuntos
Receptores 5-HT3 de Serotonina , Serotonina , Humanos , Serotonina/metabolismo , Receptores 5-HT3 de Serotonina/genética , Receptores 5-HT3 de Serotonina/metabolismo , Células HEK293 , Ondansetron/farmacologia , Mitocôndrias/metabolismo
4.
J Anesth ; 37(3): 379-386, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36745237

RESUMO

PURPOSE: Postoperative delirium (POD) occurs commonly in older adults, resulting in unfavorable outcomes. Several recent clinical studies have suggested that 5-hydroxytryptamine 3 (5-HT3) receptor antagonists can treat and prevent POD. In this retrospective study, the association between 5-HT3 receptor antagonists and POD was investigated in older adults who underwent hip fracture surgery. METHODS: The electronic medical records of older adults aged ≥ 65 years who underwent hip fracture surgery between January 2011 and June 2018 were reviewed retrospectively. Multivariable logistic regression analysis was used to investigate the association between 5-HT3 receptor antagonists and the occurrence of POD. In addition to the incidence of POD, anesthesia-, surgery-, and patient-related factors related to POD were evaluated. RESULTS: Of the 1025 patients included, 813 (79.3%) were administered 5-HT3 receptor antagonists intraoperatively; 471 (45.9%) were administered ramosetron, and 342 (33.4%) were administered palonosetron. POD was identified in 242 patients (23.6%). Ramosetron and palonosetron reduced the POD incidence by 53% (odds ratio [OR] 0.47; 95% confidence interval [CI] 0.32‒0.71; P < 0.001) and 41% (OR 0.59; 95% CI 0.39‒0.89; P = 0.011), respectively. Additionally, age, American Society of Anesthesiologists physical status class 4, and male were confirmed as risk factors for POD. CONCLUSION: Intraoperative 5-HT3 receptor antagonists may be associated with a reduced risk of POD and can be considered one of the preventive strategies for POD in older adults undergoing hip fracture surgery.


Assuntos
Delírio , Delírio do Despertar , Fraturas do Quadril , Humanos , Masculino , Idoso , Delírio do Despertar/complicações , Estudos Retrospectivos , Serotonina , Palonossetrom , Prevalência , Delírio/epidemiologia , Delírio/etiologia , Delírio/prevenção & controle , Fraturas do Quadril/cirurgia , Fatores de Risco , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle
5.
J Virol ; 95(15): e0075121, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980599

RESUMO

Rotavirus infection is highly prevalent in children, and the most severe effects are diarrhea and vomiting. It is well accepted that the enteric nervous system (ENS) is activated and plays an important role, but knowledge of how rotavirus activates nerves within ENS and to the vomiting center is lacking. Serotonin is released during rotavirus infection, and antagonists to the serotonin receptor subtype 3 (5-HT3 receptor) can attenuate rotavirus-induced diarrhea. In this study, we used a 5-HT3 receptor knockout (KO) mouse model to investigate the role of this receptor in rotavirus-induced diarrhea, motility, electrolyte secretion, inflammatory response, and vomiting reflex. The number of diarrhea days (P = 0.03) and the number of mice with diarrhea were lower in infected 5-HT3 receptor KO than wild-type pups. In vivo investigation of fluorescein isothiocyanate (FITC)-dextran transit time showed that intestinal motility was lower in the infected 5-HT3 receptor KO compared to wild-type mice (P = 0.0023). Ex vivo Ussing chamber measurements of potential difference across the intestinal epithelia showed no significant difference in electrolyte secretion between the two groups. Immediate early gene cFos expression level showed no difference in activation of the vomiting center in the brain. Cytokine analysis of the intestine indicated a low effect of inflammatory response in rotavirus-infected mice lacking the 5-HT3 receptor. Our findings indicate that the 5-HT3 receptor is involved in rotavirus-induced diarrhea via its effect on intestinal motility and that the vagus nerve signaling to the vomiting center occurs also in the absence of the 5-HT3 receptor. IMPORTANCE The mechanisms underlying rotavirus-induced diarrhea and vomiting are not yet fully understood. To better understand rotavirus pathophysiology, characterization of nerve signaling within the ENS and through vagal efferent nerves to the brain, which have been shown to be of great importance to the disease, is necessary. Serotonin (5-HT), a mediator of both diarrhea and vomiting, has been shown to be released from enterochromaffin cells in response to rotavirus infection and the rotavirus enterotoxin NSP4. Here, we investigated the role of the serotonin receptor 5-HT3, which is known to be involved in the nerve signals that regulate gut motility, intestinal secretion, and signal transduction through the vagus nerve to the brain. We show that the 5-HT3 receptor is involved in rotavirus-induced diarrhea by promoting intestinal motility. The findings shed light on new treatment possibilities for rotavirus diarrhea.


Assuntos
Diarreia/fisiopatologia , Sistema Nervoso Entérico/fisiopatologia , Motilidade Gastrointestinal/fisiologia , Receptores 5-HT3 de Serotonina/metabolismo , Infecções por Rotavirus/patologia , Vômito/fisiopatologia , Animais , Células Enterocromafins/metabolismo , Motilidade Gastrointestinal/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores 5-HT3 de Serotonina/genética , Rotavirus/fisiologia , Serotonina/metabolismo , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia
6.
Int J Mol Sci ; 22(21)2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34769340

RESUMO

5-hydroxytryptamine type 3 (5-HT3) receptors are ligand gated ion channels, which clearly distinguish their mode of action from the other G-protein coupled 5-HT or serotonin receptors. 5-HT3 receptors are well established targets for emesis and gastrointestinal mobility and are used as adjunct targets in treating schizophrenia. However, the distribution of these receptors is wider than the nervous system and there is potential that these additional sites can be targeted to modulate inflammatory and/or metabolic conditions. Recent progress in structural biology and pharmacology of 5-HT3 receptors have provided profound insights into mechanisms of their action. These advances, combined with insights into clinical relevance of mutations in genes encoding 5-HT3 subunits and increasing understanding of their implications in patient's predisposition to diseases and response to the treatment, open new avenues for personalized precision medicine. In this review, we recap on the current status of 5-HT3 receptor-based therapies using a biochemical and physiological perspective. We assess the potential for targeting 5-HT3 receptors in conditions involving metabolic or inflammatory disorders based on recent findings, underscoring the challenges and limitations of this approach.


Assuntos
Imunidade/imunologia , Inflamação/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , Receptores 5-HT3 de Serotonina/química , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Animais , Humanos , Inflamação/metabolismo , Inflamação/patologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia
7.
Molecules ; 26(16)2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34443654

RESUMO

Since westernized diet-induced insulin resistance is a risk factor in Alzheimer's disease (AD) development, and lipopolysaccharide (LPS) coexists with amyloid ß (Aß)1-42 in these patients, our AD novel model was developed to resemble sporadic AD by injecting LPS into high fat/fructose diet (HFFD)-fed rats. The neuroprotective potential of palonosetron and/or methyllycaconitine, 5-HT3 receptor and α7 nAChR blockers, respectively, was evaluated after 8 days of daily administration in HFFD/LPS rats. All regimens improved histopathological findings and enhanced spatial memory (Morris Water Maze); however, palonosetron alone or with methyllycaconitine promoted animal performance during novel object recognition tests. In the hippocampus, all regimens reduced the expression of glial fibrillary acidic protein and skewed microglia M1 to M2 phenotype, indicated by the decreased M1 markers and the enhanced M2 related parameters. Additionally, palonosetron and its combination regimen downregulated the expression of ASC/TMS1, as well as levels of inflammasome downstream molecules and abated cleaved caspase-1, interleukin (IL)-1ß, IL-18 and caspase-11. Furthermore, ACh and 5-HT were augmented after being hampered by the insult. Our study speculates that blocking 5-HT3 receptor using palonosetron overrides methyllycaconitine to combat AD-induced neuroinflammation and inflammasome cascade, as well as to restore microglial function in a HFFD/LPS novel model for sporadic AD.


Assuntos
Aconitina/análogos & derivados , Doença de Alzheimer/tratamento farmacológico , Inflamação/tratamento farmacológico , Palonossetrom/farmacologia , Aconitina/farmacologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Cognição/efeitos dos fármacos , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Inflamação/genética , Inflamação/patologia , Resistência à Insulina/genética , Interleucina-18/genética , Lipopolissacarídeos/farmacologia , Microglia/efeitos dos fármacos , Microglia/patologia , Fragmentos de Peptídeos/genética , Piroptose/efeitos dos fármacos , Ratos , Receptores 5-HT3 de Serotonina/genética , Fatores de Risco , Memória Espacial/efeitos dos fármacos
8.
Med Res Rev ; 40(5): 1593-1678, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32115745

RESUMO

Serotonin (5-hydroxytryptophan [5-HT]) is a biologically active amine expressed in platelets, in gastrointestinal (GI) cells and, to a lesser extent, in the central nervous system (CNS). This biogenic compound acts through the activation of seven 5-HT receptors (5-HT1-7 Rs). The 5-HT3 R is a ligand-gated ion channel belonging to the Cys-loop receptor family. There is a wide variety of 5-HT3 R modulators, but only receptor antagonists (known as setrons) have been used clinically for chemotherapy-induced nausea and vomiting and irritable bowel syndrome treatment. However, since the discovery of the setrons in the mid-1980s, a large number of studies have been published exploring new potential applications due their potency in the CNS and mild side effects. The results of these studies have revealed new potential applications, including the treatment of neuropsychiatric disorders such as schizophrenia, depression, anxiety, and drug abuse. In this review, we provide information related to therapeutic potential of 5-HT3 R antagonists on GI and neuropsychiatric disorders. The major attention is paid to the structure, function, and pharmacology of novel 5-HT3 R modulators developed over the past 10 years.


Assuntos
Gastroenteropatias , Serotonina , Gastroenteropatias/tratamento farmacológico , Humanos , Náusea , Receptores 5-HT3 de Serotonina , Antagonistas da Serotonina/farmacologia
9.
Invest New Drugs ; 38(2): 507-514, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32036491

RESUMO

Background We examined the efficacy of mirtazapine in preventing delayed nausea and vomiting following highly emetogenic chemotherapy (HEC). Patients and methods Patients who had experienced delayed emesis and would be subsequently scheduled for at least three more cycles of the same chemotherapy were randomly assigned to either a mirtazapine (15 mg daily on days 2-4) or a control group. In addition, both groups received a standard triplet regimen comprising aprepitant, a 5-HT3 receptor antagonist, and dexamethasone (7.5 mg on days 2-4). The chemotherapy regimens were either an epirubicin plus cyclophosphamide regimen or cisplatin-containing regimens. The primary end point was a complete response (no emesis and no rescue treatment) to the delayed phase (25-120 h post-chemotherapy) during Cycle 1. The impact on quality of life (QOL) was assessed using the Functional Living Index-Emesis (FLIE) questionnaire. Results Of 95 enrolled patients, 46 were assigned to the mirtazapine group and 49 to the control group. The complete response rate in the delayed phase during Cycle 1 was significantly higher with mirtazapine than in the control group (78.3% versus 49.0%, P = 0.003). The main adverse effects of mirtazapine were mild to moderate somnolence and weight gain. Mean total FLIE scores were similar between the two arms. Conclusions This is the first randomized prospective study to show that adding mirtazapine has a substantial and statistically significant benefit with good tolerance in patients with breast cancer who have experienced delayed emesis following the same prior HEC. (Trial registration: ClinicalTrials.gov NCT02336750).


Assuntos
Antieméticos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Antagonistas de Dopamina/uso terapêutico , Mirtazapina/uso terapêutico , Náusea/prevenção & controle , Vômito/prevenção & controle , Antieméticos/efeitos adversos , Aprepitanto/uso terapêutico , Cisplatino/efeitos adversos , Ciclofosfamida/efeitos adversos , Dexametasona/uso terapêutico , Antagonistas de Dopamina/efeitos adversos , Epirubicina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Mirtazapina/efeitos adversos , Náusea/induzido quimicamente , Qualidade de Vida , Antagonistas do Receptor 5-HT3 de Serotonina/uso terapêutico , Resultado do Tratamento , Vômito/induzido quimicamente
10.
Pharm Res ; 37(10): 205, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32989520

RESUMO

PURPOSE: Modulation of 5-HT3 receptor in the central nervous system (CNS) is a promising approach for treatment of neuropathic pain. The goal was to evaluate the role of P-glycoprotein (Pgp) in limiting exposure of different parts of the CNS to ondansetron (5-HT3 receptor antagonist) using wild-type and genetic knockout rat model. METHODS: Plasma pharmacokinetics and CNS (brain, spinal cord, and cerebrospinal fluid) disposition was studied after single 10 mg/kg intravenous dose. RESULTS: Pgp knockout resulted in significantly higher concentrations of ondansetron in all tested regions of the CNS at most of the time points. The mean ratio of the concentrations between KO and WT animals was 2.39-5.48, depending on the region of the CNS. Male and female animals demonstrated some difference in ondansetron plasma pharmacokinetics and CNS disposition. Mechanistic pharmacokinetic model that included two systemic disposition and three CNS compartments (with intercompartmental exchange) was developed. Pgp transport was incorporated as an efflux from the brain and spinal cord to the central compartment. The model provided good simultaneous description of all data sets, and all parameters were estimated with sufficient precision. CONCLUSIONS: The study provides important quantitative information on the role of Pgp in limiting ondansetron exposure in various regions of the CNS using data from wild-type and Pgp knockout rats. CSF drug concentrations, as a surrogate to CNS exposure, are likely to underestimate the effect of Pgp on drug penetration to the brain and the spinal cord.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Sistema Nervoso Central/metabolismo , Ondansetron/farmacocinética , Antagonistas do Receptor 5-HT3 de Serotonina/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/deficiência , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Encéfalo/metabolismo , Feminino , Masculino , Camundongos Knockout , Modelos Animais , Neuralgia/metabolismo , Ondansetron/sangue , Ondansetron/líquido cefalorraquidiano , Ratos , Ratos Sprague-Dawley , Antagonistas do Receptor 5-HT3 de Serotonina/sangue , Antagonistas do Receptor 5-HT3 de Serotonina/líquido cefalorraquidiano , Medula Espinal/metabolismo
11.
Can J Physiol Pharmacol ; 98(7): 431-440, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32017606

RESUMO

The availability of agonists and antagonists to modulate the activity of the 5-hydroxytryptamine (5-HT) type 3 (5-HT3) receptor has renewed interest in its role as a therapeutic target. Ondansetron is a highly selective 5-HT3 receptor antagonist that is well tolerated as an anti-emetic for patients undergoing chemotherapy. Preclinical studies in rat have shown the effects of small doses of ondansetron on cognition, behavioural sensitisation, and epilepsy. However, the pharmacokinetic (PK) profile of ondansetron in rat has not been described, which limits the translational relevance of these findings. Here, we aim to determine, in the rat, the PK profile of ondansetron in the plasma and to determine associated brain levels. The plasma PK profile was determined following acute subcutaneous administration of ondansetron (0.1, 1, and 10 µg/kg). Brain levels were measured following subcutaneous administration of ondansetron at 1 µg/kg. Plasma and brain levels of ondansetron were determined using high-performance liquid chromatography - tandem mass spectrometry. Following administration of all three doses, measured ondansetron plasma levels (≈30-3000 pg/mL) were below levels achieved with doses usually administered in the clinic, with a rapid absorption phase and a short half-life (≈30-40 min). We also found that brain levels of ondansetron at 1 µg/kg were significantly lower than plasma levels, with brain to plasma ratios of 0.45 and 0.46 in the motor and pre-frontal cortices. We discuss our findings in the context of a minireview of the literature. We hope that our study will be helpful to the design of preclinical studies with therapeutic end-points.


Assuntos
Ondansetron/farmacocinética , Antagonistas do Receptor 5-HT3 de Serotonina/farmacocinética , Absorção Fisiológica , Animais , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Injeções Intravenosas , Injeções Subcutâneas , Masculino , Modelos Animais , Ondansetron/administração & dosagem , Ratos , Antagonistas do Receptor 5-HT3 de Serotonina/administração & dosagem , Distribuição Tecidual
12.
Biochem Biophys Res Commun ; 508(2): 590-596, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30509492

RESUMO

The serotonin (5-hydroxytryptamine) type 3 (5-HT3) receptors are transmembrane ligand-gated ion channels. Although several 5-HT3 receptor agonists have been used as preclinical tools, SR 57227A is the most commonly used 5-HT3 receptor agonist with the ability to cross the blood brain barrier. However, the precise pharmacological profile of SR 57227A remains unclear. Therefore, we examined the pharmacological profile of SR 57227A at the 5-HT3A and 5-HT3AB receptors. We microinjected Xenopus laevis oocytes with human 5-HT3A complementary RNA (cRNA) or a combination of human 5-HT3A and human 5-HT3AB cRNA and performed two electrode voltage clamp recordings of 5-HT3A and 5-HT3AB receptor current in the presence of SR 57227A. Results showed that SR 57227A acts as partial agonist/partial antagonist at the 5-HT3 receptor. Interestingly, SR 57227A specifically reduced subsequent current amplitudes induced by 5-HT or SR 57227A. Based on its 5-HT3 receptor partial agonist/partial antagonist properties, we predict that SR 57227A functions as a serotonin stabilizer.


Assuntos
Canais Iônicos de Abertura Ativada por Ligante/metabolismo , Piperidinas/farmacologia , Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Animais , Barreira Hematoencefálica/metabolismo , Humanos , Oócitos , RNA Complementar , Agonistas do Receptor 5-HT3 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Xenopus laevis
13.
J Evol Biol ; 31(8): 1180-1192, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29943391

RESUMO

Traits that undergo massive natural selection pressure, with multiple events of positive selection, are hard to find. Social behaviour, in social animals, is crucial for survival, and genetic networks involved in behaviour, such as those of serotonin (5-HT) and other neurotransmitters, must be the target of natural selection. Here, we used molecular analyses to search for signals of positive selection in the 5-HT system and found such signals in the M3-M4 intracellular domain of the 5-HT3A serotonin receptor subunit (HTR3A) in primates. We detected four amino acid sites with signs of putatively positive selection (398, 403, 432 and 416); the first three showed indications of being selected in New World monkeys (NWM, Platyrrhini), specifically in the Callitrichinae branch. Additionally, we searched for associations of these amino acid variants with social behavioural traits (i.e. sex-biased dispersal, dominance and social monogamy) using classical and Bayesian methods, and found statistically significant associations for unbiased sex dispersal (398L and 416S), unbiased sex dominance (416S) and social monogamy (416S), as well as significant positive correlation between female dispersal and 403G. Furthermore, we found putatively functional protein motifs determined by three selected sites, of which we highlight a ligand motif to GSK3 in the 416S variant, appearing only in Platyrrhini. 5-HT, 5-HT3A receptor and GSK3 are part of a network that participates in neurodevelopment and regulates behaviour, among other functions. We suggest that these genetic variations, together with those found in other neurotransmitter systems, must contribute to adaptive behaviours and consequently to fitness in NWMs.


Assuntos
Comportamento Animal/fisiologia , Platirrinos/genética , Platirrinos/fisiologia , Seleção Genética , Serotonina/metabolismo , Animais , Evolução Molecular , Regulação da Expressão Gênica/fisiologia , Filogenia , Serotonina/genética
14.
Pediatr Blood Cancer ; 65(2)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28941006

RESUMO

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) in children remains to be a major side effect despite antiemetic treatment. Palonosetron is a new generation 5-HT3 receptor antagonists effective against acute and delayed nausea and vomiting. This study aimed to compare the therapeutic values of palonosetron and ondansetron in preventing pediatric CINV. METHODS: A prospective, randomized, double-blind, parallel controlled study was conducted in 0-18 years old cancer patients administered highly emetogenic chemotherapy, with different dosage of palonosetron or ondansetron, both followed by dexamethasone. The patients were observed for vomiting and nausea from 0 to 120 hr after chemotherapy initiation. All adverse events (AEs) during the study period were recorded. This study was registered with the Chinese Clinical Trial Registry, number ChiCTR-TRC-14004891. RESULTS: Between August 2014 and July 2016, 565 patients were randomly assigned to receive 5 µg/kg palonosetron (n = 185), 10 µg/kg palonosetron (n = 186), and 3 × 150 µg/kg ondansetron (n = 194), of whom 181, 185, and 189, respectively, were included in the efficacy analysis. Complete response (CR) rates during the acute phase were 69.1, 69.7, and 64.6%, respectively, in the 5 µg/kg palonosetron, 10 µg/kg palonosetron, and ondansetron groups. In the delayed phase, 10 µg/kg palonosetron (CR, 53.5%) showed superiority to 5 µg/kg palonosetron (CR, 39.8%) and ondansetron (CR, 32.8%) groups (P < 0.05). The most frequently observed drug-related AEs were nervous system disorders, mainly headache, with an incidence of 2.8, 2.2, and 2.6% in each group, respectively. CONCLUSION: Combination of palonosetron plus dexamethasone is highly effective in controlling acute and delayed CINV, with palonosetron superior to ondansetron.


Assuntos
Antieméticos/administração & dosagem , Isoquinolinas/administração & dosagem , Náusea/tratamento farmacológico , Ondansetron/administração & dosagem , Quinuclidinas/administração & dosagem , Vômito/tratamento farmacológico , Adolescente , Antieméticos/efeitos adversos , Criança , Pré-Escolar , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Lactente , Recém-Nascido , Isoquinolinas/efeitos adversos , Masculino , Náusea/induzido quimicamente , Neoplasias/tratamento farmacológico , Ondansetron/efeitos adversos , Palonossetrom , Estudos Prospectivos , Quinuclidinas/efeitos adversos , Vômito/induzido quimicamente
15.
Eur J Clin Pharmacol ; 74(10): 1201-1214, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29858921

RESUMO

BACKGROUND: Dexamethasone has many desirable pharmacologic properties for perioperative use. Its antiemetic potential has been a focus of many recent trials. METHODS: Trials comparing dexamethasone to 5-HT3-receptor antagonists (5HT3-RA) for 24 h postoperative vomiting incidences published till August 2017 were searched in the medical database. Comparisons for antiemetic efficiency variables (vomiting incidence, nausea incidence, rescue antiemetic need, and patients with complete response) during early (until 6 h) and late postoperative phase were made. Comparative analgesic requirements were also evaluated. RESULTS: Twenty randomized controlled double-blinded trials were included in the final analysis. Twenty-four-hour vomiting incidence was similar (Fixed-effects, P = 0.86, I2 = 2.94%). Trial sequential analysis (TSA) confirmed non-inferiority of dexamethasone for 24-h vomiting incidence. (α = 5%, ß = 20%, δ = 10%) with "information size" being 1619 (required > 573). Equivalence was also verified from early and delayed nausea rate as well using TSA. Pooled results did not demonstrate superiority/inferiority of 5-HT3-RAs over dexamethasone in all other antiemetic efficacy variables (early and delayed). Heterogeneity was found to be low in all of the comparisons. Linear-positive dose-response curve for dexamethasone 24-h vomiting and nausea incidence was seen (correlation coefficient being 0.21 and 0.28, respectively). Dexamethasone reduced the analgesic need (MH-odds of 0.64 (95% CI being 0.44 to 0.93) P = 0.02, I2 = 0)). Possibility of publication bias could not be ruled out (Egger's test, X-intercept = 1.41, P = 0.04). CONCLUSIONS: Dexamethasone demonstrates equal antiemetic efficacy compared to 5-HT3 receptor antagonists. The agents perform equally well both in early postoperative phase and up to 24 h after surgery. Use of dexamethasone replacing 5-HT3 RAs offers an additional advantage of lowering the opioid requirements during the perioperative period.


Assuntos
Dexametasona/farmacologia , Náusea e Vômito Pós-Operatórios/tratamento farmacológico , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Antieméticos/farmacologia , Humanos , Resultado do Tratamento
16.
Support Care Cancer ; 26(Suppl 1): 5-9, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29556808

RESUMO

Chemotherapy-induced nausea and vomiting (CINV) is one of the most feared side effects experienced by patients with cancer. The precise physiologic mechanisms responsible for acute and delayed CINV continue to be elucidated and have provided an opportunity to develop antiemetic therapies targeting these pathways. The emergence of receptor antagonists targeting serotonin and neurokinin-1 have revolutionized the prevention of CINV, significantly reducing the impact of this side effect and improving patient quality of life. However, several areas of unmet need remain, including adequate prevention of nausea, rather than just vomiting, in patients receiving chemotherapy for cancer. Prevention of delayed CINV and anticipatory CINV, as well as management of breakthrough CINV, also continues to challenge patients and clinicians. Ongoing research continues to address these areas to improve antiemetic therapies and guidelines.


Assuntos
Antieméticos/uso terapêutico , Náusea/induzido quimicamente , Neoplasias/complicações , Qualidade de Vida/psicologia , Vômito/induzido quimicamente , Humanos , Náusea/fisiopatologia , Neoplasias/tratamento farmacológico , Vômito/fisiopatologia
17.
Support Care Cancer ; 26(Suppl 1): 29-33, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29556813

RESUMO

For patients with cancer, the threat of chemotherapy-induced nausea and vomiting (CINV) can greatly influence treatment decisions and overall quality of life. Clinicians now have numerous effective antiemetic therapies to offer to patients, but selecting the optimal strategy can be complicated. Integration of current CINV guidelines, emerging data from recent clinical trials, and patient-specific risk factors can greatly improve antiemetic prophylaxis. Two challenging clinical scenarios are presented and discussed to provide insight on how to best approach these types of treatment decisions and apply recent advances in CINV prevention and management to patient care.


Assuntos
Antieméticos/uso terapêutico , Náusea/induzido quimicamente , Neoplasias/complicações , Qualidade de Vida/psicologia , Vômito/induzido quimicamente , Adulto , Idoso , Feminino , Humanos , Conhecimento , Neoplasias/tratamento farmacológico , Padrões de Prática Médica , Fatores de Risco
18.
Support Care Cancer ; 26(Suppl 1): 19-27, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29556812

RESUMO

Recent years have witnessed significant improvements in the prevention and management of chemotherapy-induced nausea and vomiting (CINV), allowing patients to complete their prescribed chemotherapy regimens without compromising quality of life. This reduction in the incidence of CINV can be primarily attributed to the emergence of effective, well-tolerated antiemetic therapies, including serotonin (5-hydroxytryptamine or 5-HT3) receptor antagonists, neurokinin-1 (NK-1) receptor antagonists, and the atypical antipsychotic olanzapine. While 5-HT3 receptor antagonists are highly effective in the prevention of acute CINV, NK-1 receptor antagonists and olanzapine have demonstrated considerable activity against both acute and delayed CINV. Various combinations of these three types of agents, along with dexamethasone and dopamine receptor antagonists, are now becoming the standard of care for patients receiving moderately or highly emetogenic chemotherapy. Optimal use of these therapies requires careful assessment of the unique characteristics of each agent and currently available clinical trial data.


Assuntos
Antieméticos/uso terapêutico , Náusea/induzido quimicamente , Qualidade de Vida/psicologia , Vômito/induzido quimicamente , Feminino , Humanos , Masculino
19.
J Neurosci ; 36(5): 1456-70, 2016 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-26843630

RESUMO

The 5-HT3 receptors are serotonin-gated ion channels that physically couple with purinergic P2X2 receptors to trigger a functional cross-inhibition leading to reciprocal channel occlusion. Although this functional receptor-receptor coupling seems to serve a modulatory role on both channels, this might not be its main physiological purpose. Using primary cultures of rat hippocampal neurons as a quantitative model of polarized targeting, we show here a novel function for this interaction. In this model, 5-HT3A receptors did not exhibit by themselves the capability of distal targeting in dendrites and axons but required the presence of P2X2R for their proper subcellular localization. 5-HT3AR distal targeting occurred with a delayed time course and exhibited a neuron phenotype dependency. In the subpopulation of neurons expressing endogenous P2X2R, 5-HT3AR distal neuritic localization correlated with P2X2R expression and could be selectively inhibited by P2X2R RNA interference. Cotransfection of both receptors revealed a specific colocalization, cotrafficking in common surface clusters, and the axonal rerouting of 5-HT3AR. The physical association between the two receptors was dependent on the second intracellular loop of the 5-HT3A subunit, but not on the P2X2R C-terminal tail that triggers the functional cross-inhibition with the 5-HT3AR. Together, these data establish that 5-HT3AR distal targeting in axons and dendrites primarily depends on P2X2R expression. Because several P2XR have now been shown to functionally interact with several other members of the 4-TMD family of receptor channels, we propose to reconsider the real functional role for this receptor family, as trafficking partner proteins dynamically involved in other receptors targeting. SIGNIFICANCE STATEMENT: So far, receptor targeting mechanisms were found to involve intracellular partner proteins or supramolecular complexes that couple receptors to cytoskeletal elements and recruit them into cargo vesicles. In this paper, we describe a new trafficking mechanism for the neuronal serotonin 5-HT3A ionotropic channel receptor, in which the role of routing partner is endowed by a functionally interacting purinergic receptor: the P2X2 receptor. This work not only unveils the mechanism by which 5-HT3 receptors can reach their axonal localization required for the control of neurotransmitter release, but also suggests that, in addition to their modulatory role, the family of P2X receptors could have a previously undescribed functional role of trafficking partner proteins dynamically involved in the targeting of other receptors.


Assuntos
Ativação do Canal Iônico/fisiologia , Canais Iônicos de Abertura Ativada por Ligante/metabolismo , Receptores Purinérgicos P2X2/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Animais , Células Cultivadas , Feminino , Humanos , Canais Iônicos de Abertura Ativada por Ligante/química , Camundongos , Neurônios/metabolismo , Ligação Proteica/fisiologia , Transporte Proteico/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X2/química , Receptores 5-HT3 de Serotonina/química , Xenopus laevis
20.
Cell Mol Neurobiol ; 37(4): 595-606, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27324798

RESUMO

One of the hypotheses about the pathogenesis of posttraumatic stress disorder (PTSD) is the dysfunction of serotonin (5-HT) neurotransmission. While certain 5-HT receptor subtypes are likely critical for the symptoms of PTSD, few studies have examined the role of 5-HT3 receptor in the development of PTSD, even though 5-HT3 receptor is critical for contextual fear extinction and anxiety-like behavior. Therefore, we hypothesized that stimulation of 5-HT3 receptor in the dorsal hippocampus (DH) could prevent hippocampal autophagy and the development of PTSD-like behavior in animals. To this end, we infused SR57227, selective 5-HT3 agonist, into the DH after a single prolonged stress (SPS) treatment in rats. Three weeks later, we evaluated the effects of this pharmacological treatment on anxiety-related behaviors and extinction of contextual fear memory. We also accessed hippocampal autophagy and the expression of 5-HT3A subunit, Beclin-1, LC3-I, and LC3-II in the DH. We found that SPS treatment did not alter anxiety-related behaviors but prolonged the extinction of contextual fear memory, and such a behavioral phenomenon was correlated with increased hippocampal autophagy, decreased 5-HT3A expression, and increased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. Furthermore, intraDH infusions of SR57227 dose-dependently promoted the extinction of contextual fear memory, prevented hippocampal autophagy, and decreased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. These results indicated that 5-HT3 receptor in the hippocampus may play a critical role in the pathogenesis of hippocampal autophagy, and is likely involved in the pathophysiology of PTSD.


Assuntos
Autofagia , Extinção Psicológica , Medo , Hipocampo/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Animais , Autofagia/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Ratos Sprague-Dawley , Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Agonistas do Receptor 5-HT3 de Serotonina/farmacologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/fisiopatologia
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