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1.
J Mol Model ; 30(10): 350, 2024 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-39325274

RESUMEN

CONTEXT: Alzheimer's disease (AD) is the leading cause of dementia around the world, totaling about 55 million cases, with an estimated growth to 74.7 million cases in 2030, which makes its treatment widely desired. Several studies and strategies are being developed considering the main theories regarding its origin since it is not yet fully understood. Among these strategies, the 5-HT6 receptor antagonism emerges as an auspicious and viable symptomatic treatment approach for AD. The 5-HT6 receptor belongs to the G protein-coupled receptor (GPCR) family and is closely implicated in memory loss processes. As a serotonin receptor, it plays an important role in cognitive function. Consequently, targeting this receptor presents a compelling therapeutic opportunity. By employing antagonists to block its activity, the 5-HT6 receptor's functions can be effectively modulated, leading to potential improvements in cognition and memory. METHODS: Addressing this challenge, our research explored a promising avenue in drug discovery for AD, employing Artificial Neural Networks-Quantitative Structure-Activity Relationship (ANN-QSAR) models. These models have demonstrated great potential in predicting the biological activity of compounds based on their molecular structures. By harnessing the capabilities of machine learning and computational chemistry, we aimed to create a systematic approach for analyzing and forecasting the activity of potential drug candidates, thus streamlining the drug discovery process. We assembled a diverse set of compounds targeting this receptor and utilized density functional theory (DFT) calculations to extract essential molecular descriptors, effectively representing the structural features of the compounds. Subsequently, these molecular descriptors served as input for training the ANN-QSAR models alongside corresponding biological activity data, enabling us to predict the potential efficacy of novel compounds as 5-hydroxytryptamine receptor 6 (5-HT6) antagonists. Through extensive analysis and validation of ANN-QSAR models, we identified eight new promising compounds with therapeutic potential against AD.


Asunto(s)
Enfermedad de Alzheimer , Diseño de Fármacos , Relación Estructura-Actividad Cuantitativa , Receptores de Serotonina , Antagonistas de la Serotonina , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Receptores de Serotonina/metabolismo , Receptores de Serotonina/química , Humanos , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Antagonistas de la Serotonina/uso terapéutico , Redes Neurales de la Computación , Modelos Moleculares
2.
Neurosci Lett ; 837: 137903, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-39025433

RESUMEN

Lysergic acid diethylamide (LSD) is a synthetic psychedelic compound with potential therapeutic value for psychiatric disorders. This study aims to establish Caenorhabditis elegans as an in vivo model for examining LSD's effects on locomotor behavior. Our results demonstrate that LSD is absorbed by C. elegans and that the acute treatment reduces animal speed, similar to the role of endogenous serotonin. This response is mediated in part by the serotonergic receptors SER-1 and SER-4. Our findings highlight the potential of this nematode as a new experimental model in psychedelic research.


Asunto(s)
Caenorhabditis elegans , Alucinógenos , Dietilamida del Ácido Lisérgico , Animales , Caenorhabditis elegans/efectos de los fármacos , Dietilamida del Ácido Lisérgico/farmacología , Alucinógenos/farmacología , Locomoción/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Conducta Animal/efectos de los fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Serotonina/metabolismo
3.
J Biosci ; 492024.
Artículo en Inglés | MEDLINE | ID: mdl-38920106

RESUMEN

Noradrenaline (NA) and serotonin (5-HT) induce nociception and antinociception. This antagonistic effect can be explained by the dose and type of activated receptors. We investigated the existence of synergism between the noradrenergic and serotonergic systems during peripheral antinociception. The paw pressure test was performed in mice that had increased sensitivity by intraplantar injection of prostaglandin E2 (PGE2). Noradrenaline (80 ng) administered intraplantarly induced an antinociceptive effect, that was reversed by the administration of selective antagonists of serotoninergic receptors 5-HT1B isamoltan, 5-HT1D BRL15572, 5-HT2A ketanserin, 5-HT3 ondansetron, but not by selective receptor antagonist 5-HT7 SB-269970. The administration of escitalopram, a serotonin reuptake inhibitor, potentiated the antinociceptive effect at a submaximal dose of NA. These results, indicate the existence of synergism between the noradrenergic and serotonergic systems in peripheral antinociception in mice.


Asunto(s)
Norepinefrina , Receptores de Serotonina , Antagonistas de la Serotonina , Serotonina , Animales , Ratones , Norepinefrina/metabolismo , Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Masculino , Receptores de Serotonina/metabolismo , Dinoprostona/metabolismo , Citalopram/farmacología , Nocicepción/efectos de los fármacos , Analgésicos/farmacología , Ondansetrón/farmacología , Ketanserina/farmacología , Dolor/tratamiento farmacológico , Dolor/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología
4.
Acta Cir Bras ; 39: e392324, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38629654

RESUMEN

PURPOSE: Patients have been severely suffered from cancer associated pain, and pancreatic cancer is the most severe form of cancer associated with pain. There are very few options available to manage it. The present report evaluated the effect of 5HT2A on pancreatic cancer associated pain. METHODS: Pancreatic cancer was induced by injecting SW 1,990 cells (~3×106 in a 20 µL suspension) into the pancreas and formed a 2-3-mm vesicle using an inoculator fitted with a 26-gauge needle in BALB/c-nu mice. Survival rate and body weight of the mice were observed. Pain behaviour testing was performed at the end of each week (third and fourth week) after surgery. Inflammatory mediators and HDAC 2 proteins were determined in the spinal tissue using quantitative real-time polymerase chain reaction. RESULTS: There was improvement in the survival rate and body weight in 5HT2A antagonist treated group than pancreatic cancer group of mice. Moreover, 5HT2A antagonist ameliorated the alteration in pain behaviour of pancreatic cancer mice. mRNA expression of HDAC2 and level of inflammatory cytokines were reduced in the spinal tissue of 5HT 2A antagonist treated group than pancreatic cancer group of mice. CONCLUSIONS: Data revealed that 5HT2A antagonist ameliorates pain associated with pancreatic cancer mice by HDAC inhibition and inflammatory cytokines. The result of investigation supports that modulation of 5HT2A receptor could be used clinically to protects neuropathic pain in pancreatic cancer.


Asunto(s)
Dolor en Cáncer , Neuralgia , Neoplasias Pancreáticas , Animales , Humanos , Ratones , Peso Corporal , Dolor en Cáncer/tratamiento farmacológico , Dolor en Cáncer/prevención & control , Citocinas , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Neuralgia/tratamiento farmacológico , Neoplasias Pancreáticas/complicaciones , Receptores de Serotonina/metabolismo
5.
Neuroscience ; 532: 65-78, 2023 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-37776946

RESUMEN

The blockade of 5-HT6 receptors represents an experimental approach that might ameliorate the memory deficits associated with brain disorders, including Alzheimer's disease and schizophrenia. However, the synaptic mechanism by which 5-HT6 receptors control the GABAergic and glutamatergic synaptic transmission is barely understood. In this study, we demonstrate that pharmacological manipulation of 5-HT6 receptors with the specific agonist EMD 386088 (7.4 nM) or the antagonist SB-399885 (300 nM) modulates the field inhibitory postsynaptic potentials of the dorsal hippocampus and controls the strength of the population spike of pyramidal cells. Likewise, pharmacological modulation of 5-HT6 controls the magnitude of paired-pulse inhibition, a phenomenon mediated by GABAergic interneurons acting via GABAA receptors of pyramidal cells. The effects of pharmacological manipulation of the 5-HT6 receptor were limited to GABAergic transmission and did not affect the strength of field excitatory postsynaptic potentials mediated by the Schaffer collaterals axons. Lastly, in a modified version of the Pavlovian autoshaping task that requires the activation of the hippocampal formation, we demonstrated that the anti-amnesic effect induced by the blockade of the 5-HT6 receptor is prevented when the GAT1 transporter is blocked, suggesting that modulation of GABAergic transmission is required for the anti-amnesic properties of 5-HT6 receptor antagonists.


Asunto(s)
Hipocampo , Receptores de Serotonina , Ratas , Animales , Ratas Wistar , Receptores de Serotonina/metabolismo , Células Piramidales/fisiología , Transmisión Sináptica/fisiología , Receptores de GABA-A
6.
J Ethnopharmacol ; 306: 116142, 2023 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-36638856

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: The seeds of Cajanus cajan (L) Millsp, are used in Traditional medicine for the treatment of anxiety and other neurological disorders. Hence, this study is designed to investigate the antidepressant- and anxiolytic-like properties of ethanol seed extract of Cajanus cajan (CC) in mice. MATERIALS AND METHODS: CC (50, 100 or 200 mg/kg, p.o.) was administered 1h before subjecting the animals to different behavioral models: forced swim test (FST) and tail suspension test (TST) (depressive-like behaviour), open field test (OFT), elevated plus maze (EPM), light-dark test (LDT) and hole-board test (HBT) for anxiety-like behaviour. To ascertain the pharmacodynamic of CC mice were pretreated with monoaminergic, nitrergic and GABAergic receptors antagonists. As well as molecular docking analysis of about 19 flavonoids present in CC on GABAA, α2 adrenoceptors and 5-HT2A receptors. RESULTS: CC (50, 100 or 200 mg/kg, p.o.) treatment significantly reduced immobile time in both FST and TST when compared with vehicle-treated control. However, the pretreatment of mice with prazosin/yohimbine (α1/2 adrenoceptor antagonists, respectively), WAY100635 (5-HT1A receptor antagonist), ketanserin (5-HT2A receptor antagonist), sulpiride (dopamine D2 receptor antagonist), L-NG-Nitro arginine methyl ester (L-NAME), or methylene blue reversed the antidepressant-like effect of CC. In anxiety model, CC produced significant (p < 0.05) increase in open arms exploration and head dipping behavior which was reversed by flumazenil (benzodiazepine receptor antagonist) in the EPM. Docking analysis showed significant binding affinity of orientin, vitexin, pinostrobin and quercetin with 5HT2A, α2-adrenoceptor and GABAA receptors. CONCLUSION: Findings from this study showed that C.cajan seeds extract exerts antidepressant-like effect through participation of monoaminergic systems (5-HT2 receptor, α1/α2-adrenoceptors, and dopamine D2-receptors), nitric oxide-cyclic GMP pathway and anxiolytic-like effect via GABAA benzodiazepine receptors. Moreso, presence of flavonoids with significant binding energies with monoaminergic and GABAergic systems support the potential of the extract in the management of mixed anxiety-depressive illness.


Asunto(s)
Ansiolíticos , Animales , Ratones , Ansiolíticos/farmacología , Óxido Nítrico , Dopamina , Simulación del Acoplamiento Molecular , Serotonina , Antidepresivos/farmacología , Extractos Vegetales/farmacología , Receptores de Serotonina , Ácido gamma-Aminobutírico/farmacología , Flavonoides/farmacología , Receptores Adrenérgicos , Depresión/tratamiento farmacológico , Conducta Animal , Suspensión Trasera
7.
Sci Rep ; 12(1): 21015, 2022 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-36470912

RESUMEN

Important functions of the prefrontal cortex (PFC) are established during early life, when neurons exhibit enhanced synaptic plasticity and synaptogenesis. This developmental stage drives the organization of cortical connectivity, responsible for establishing behavioral patterns. Serotonin (5-HT) emerges among the most significant factors that modulate brain activity during postnatal development. In the PFC, activated 5-HT receptors modify neuronal excitability and interact with intracellular signaling involved in synaptic modifications, thus suggesting that 5-HT might participate in early postnatal plasticity. To test this hypothesis, we employed intracellular electrophysiological recordings of PFC layer 5 neurons to study the modulatory effects of 5-HT on plasticity induced by theta-burst stimulation (TBS) in two postnatal periods of rats. Our results indicate that 5-HT is essential for TBS to result in synaptic changes during the third postnatal week, but not later. TBS coupled with 5-HT2A or 5-HT1A and 5-HT7 receptors stimulation leads to long-term depression (LTD). On the other hand, TBS and synergic activation of 5-HT1A, 5-HT2A, and 5-HT7 receptors lead to long-term potentiation (LTP). Finally, we also show that 5-HT dependent synaptic plasticity of the PFC is impaired in animals that are exposed to early-life chronic stress.


Asunto(s)
Plasticidad Neuronal , Corteza Prefrontal , Serotonina , Animales , Ratas , Potenciación a Largo Plazo/fisiología , Plasticidad Neuronal/fisiología , Corteza Prefrontal/crecimiento & desarrollo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Ritmo Teta
8.
Eur J Clin Pharmacol ; 78(10): 1601-1611, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35943535

RESUMEN

PURPOSE: The absence of specific treatments for COVID-19 leads to an intense global effort in the search for new therapeutic interventions and better clinical outcomes for patients. This review aimed to present a selection of accepted studies that reported the activity of antidepressant drugs belonging to the selective serotonin receptor inhibitor (SSRI) class for treating the novel coronavirus. METHODS: A search was performed in PubMed and SciELO databases using the following search strategies: [(coronavirus) OR (COVID) OR (SARS-CoV-2) AND (antidepressant) OR (serotonin) OR (selective serotonin receptor inhibitors)]. In the end, eleven articles were included. We also covered information obtained from ClinicalTrials.gov in our research. RESULTS: Although several clinical trials are ongoing, only a few drugs have been officially approved to treat the infection. Remdesivir, an antiviral drug, despite favorable preliminary results, has restricted the use due to the risk of toxicity and methodological flaws. Antidepressant drugs were able to reduce the risk of intubation or death related to COVID-19, decrease the need for intensive medical care, and severely inhibit viral titers by up to 99%. Among the SSRIs studied so far, fluoxetine and fluvoxamine have shown to be the most promising against SARS-CoV-2. CONCLUSION: If successful, these drugs can substantially reduce hospitalization and mortality rates, as well as allow for fully outpatient treatment for mild-to-moderate infections. Thus, repositioning SSRIs can provide benefits when faced with a rapidly evolving pandemic such as COVID-19.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Inhibidores Selectivos de la Recaptación de Serotonina , Antidepresivos/uso terapéutico , Antivirales/uso terapéutico , Fluoxetina , Fluvoxamina , Humanos , Receptores de Serotonina , SARS-CoV-2 , Serotonina , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico
9.
Mol Med ; 28(1): 70, 2022 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-35725396

RESUMEN

5-HT7 receptors (5-HT7R) are the most recently identified among the family of serotonin receptors. Their role in health and disease, particularly as mediators of, and druggable targets for, neurodegenerative diseases, is incompletely understood. Unlike other serotonin receptors, for which abundant preclinical and clinical data evaluating their effect on neurodegenerative conditions exist, the available information on the role of the 5-HT7R receptor is limited. In this review, we describe the signaling pathways and cellular mechanisms implicated in the activation of the 5-HT7R; also, we analyze different mechanisms of neurodegeneration and the potential therapeutic implications of pharmacological interventions for 5-HT7R signaling.


Asunto(s)
Enfermedades Neurodegenerativas , Receptores de Serotonina , Sistema Nervioso Central/metabolismo , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Receptores de Serotonina/metabolismo , Transducción de Señal
10.
Braz. J. Pharm. Sci. (Online) ; 58: e18578, 2022. tab, graf
Artículo en Inglés | LILACS | ID: biblio-1360165

RESUMEN

Moringa stenopetala (Baker f.) Cufod., is an endemic species growing in the south of Ethiopia. M. stenopetala is often consumed as food and used in traditional medicine and it has also been traditionally used for relieving of pain in Ethiopia. This study aimed to investigate the antinociceptive effect and mechanisms of action of M. stenopetala leaves methanol extract in mice. The per-oral doses of 50, 100, and 200 mg/kg of M. stenopetala extract were tested for antinociceptive action by using hot-plate, tail-immersion, and writhing tests. The possible mechanisms of in the antinociceptive action were investigated by pre-treatment with 5 mg/kg naloxone (non-selective opioid antagonist), 1 mg/kg ketanserin (5-HT2A/2C receptor antagonist), and 1 mg/kg yohimbine (α2 adrenoceptor antagonist). The methanol extract of M. stenopetala showed antinociceptive effect in all tests. The significant involvement of 5-HT2A/2C receptors and α2 adrenoceptors in antinociception induced by M. stenopetala extract in the hot-plate and tail-immersion tests, as well as significant contribution of opioid receptors and α2 adrenoceptors in writhing test, were identified. In conclusion, these findings demonstrate that the methanol extract of M. stenopetala has potential in pain management. Thisstudywillcontributetonewtherapeuticapproachesandprovideguidancefornewdrug development studies.


Asunto(s)
Animales , Masculino , Femenino , Ratones , Extractos Vegetales/agonistas , Moringa oleifera/efectos adversos , Dolor , Receptores Adrenérgicos/administración & dosificación , Receptores de Serotonina/administración & dosificación , Inmersión , Antagonistas de Narcóticos
11.
Pharmacol Biochem Behav ; 210: 173276, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34555392

RESUMEN

Serotonin (5-HT) receptors have been implicated in responses to aversive stimuli in mammals and fish, but its precise role is still unknown. Moreover, since at least seven families of 5-HT receptors exist in vertebrates, the role of specific receptors is still debated. Aversive stimuli can be classified as indicators of proximal, distal, or potential threat, initiating responses that are appropriate for each of these threat levels. Responses to potential threat usually involve cautious exploration and increased alertness, while responses to distal and proximal threat involve a fight-flight-freeze reaction. We exposed adult zebrafish to a conspecific alarm substance (CAS) and observed behavior during (distal threat) and after (potential threat) exposure, and treated with the 5-HT2C receptor agonists MK-212 or WAY-161503 or with the antagonist RS-102221. The agonists blocked CAS-elicited defensive behavior (distal threat), but not post-exposure increases in defensive behavior (potential threat), suggesting inhibition of responses to distal threat. MK-212 blocked changes in freezing elicited by acute restraint stress, a model of proximal threat, while RS-102221 blocked changes in geotaxis elicited this stressor. We also found that RS-102221, a 5-HT2C receptor antagonist, produced small effect on behavior during and after exposure to CAS. Preprint: https://www.biorxiv.org/content/10.1101/2020.10.04.324202; Data and scripts: https://github.com/lanec-unifesspa/5-HT-CAS/tree/master/data/5HT2C.


Asunto(s)
Conducta Animal/efectos de los fármacos , Reacción de Fuga/efectos de los fármacos , Miedo/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Pez Cebra
12.
Naunyn Schmiedebergs Arch Pharmacol ; 394(10): 2023-2032, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34251503

RESUMEN

Benzodiazepines are highly effective in combating anxiety; however, they have considerable adverse effects, so it is important to discover new safe anxiolytic agents. This study was designed to investigate the effect of the natural product 2-hydroxy-3,4,6-trimethoxyacetophenone (HTMCX) on anxiety and seizure behavior in adult zebrafish and its possible mechanisms of action. The acute toxicity of 96 h of HTMCX was analyzed, and the open and light/dark field tests (n = 6 animals/group) were used to assess the anxiety behavior of animals treated with HTMCX. In addition, the mechanisms of action were investigated with antagonists of the GABAA, 5-HT receptors, and molecular anchorage study. Pentylenetetrazole (PTZ) was used to induce seizure by immersion. As a result, acetophenone HTMCX (1, 3 and 10 mg/kg; v.o.) was non-toxic and affected locomotor activity. The higher doses (3 and 10 mg/kg; v.o.) produced signs of anxiolytic action in the light/dark test, and this effect was reversed by the pizotifen (antagonist 5HTR1 and 5HTR2A/2C), having the potential to form a complex with 5HTR1B. However, the anxiolytic effect of HTMCX has not been abolished by flumazenil (antagonist GABAA), cyproheptadine (antagonist 5HTR2A), and granisetron (antagonist 5HTR3A/3B). Therefore, HTMCX demonstrated an anxiolytic effect, suggesting that the 5HTR1 and 5HTR2C receptors may be involved in the pharmacological performance of this acetophenone in the central nervous system.


Asunto(s)
Acetofenonas/uso terapéutico , Ansiolíticos/uso terapéutico , Ansiedad/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Croton , Neurotransmisores/uso terapéutico , Acetofenonas/farmacología , Acetofenonas/toxicidad , Animales , Ansiolíticos/farmacología , Ansiolíticos/toxicidad , Ansiedad/metabolismo , Productos Biológicos/farmacología , Productos Biológicos/toxicidad , Femenino , Masculino , Simulación del Acoplamiento Molecular , Neurotransmisores/farmacología , Neurotransmisores/toxicidad , Pentilenotetrazol , Receptores de Serotonina/metabolismo , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Convulsiones/metabolismo , Serotonina/metabolismo , Pez Cebra
13.
Eur J Pharmacol ; 908: 174339, 2021 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-34265293

RESUMEN

This study tested the effects of ß-methylphenylethylamine (ß-MPEA) and octopamine on contractile parameters of the gastrointestinal tract in rats. We hypothesized that some of their effects result from interactions with trace amine (TA)-associated receptors or serotoninergic 5-hydroxytryptamine (5-HT) receptors. ß-MPEA-induced contractions in rat gastric fundus strips under resting tonus conditions, but induced relaxation in preparations that were previously contracted with carbachol. Octopamine relaxed gastric fundus strips maintained at resting tonus or contracted with carbachol. The contractile effect of ß-MPEA was reduced by cyproheptadine and methiothepin, antagonists of excitatory 5-HT receptors. The relaxing effect of ß-MPEA on gastric fundus was insensitive to pretreatment with N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide (EPPTB) and tropisetron, antagonists of TA1 and 5-HT4 receptors, respectively. Both EPPTB and tropisetron inhibited the relaxant effects of octopamine on carbachol-contracted preparations. Contrarily, EPPTB did not reduce the relaxant effects of RO5263397 (TA1 agonist) or zacopride (5-HT4 agonist). Octopamine, but not ß-MPEA, delayed the gastrointestinal transit of a liquid test meal in awaken rats. In isolated preparations of the small intestine under resting conditions, ß-MPEA did not alter the basal tonus, but octopamine relaxed it. Intestinal preparations previously contracted with carbachol relaxed after the addition of octopamine and decreased the magnitude of their spontaneous rhythmic contractions in a tropisetron-dependent manner. Thus, ß-MPEA and octopamine exerted pharmacological actions on the rat gastrointestinal tract. The excitatory effects of ß-MPEA involved 5-HT receptors. Octopamine inhibited the rat gut contractility through the likely involvement of 5-HT4 and TA receptors. Overall, octopamine effectively inhibited rat gastrointestinal transit.


Asunto(s)
Anfetaminas , Octopamina , Animales , Fundus Gástrico , Contracción Muscular , Relajación Muscular , Músculo Liso , Ratas , Receptores de Serotonina
14.
Pharmacology ; 106(5-6): 305-315, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33756489

RESUMEN

BACKGROUND: Piperidines are biogenic amines studied mainly in toxicology because they were initially found as alkaloids from peppers and insect venoms. Piperidines are also produced in the human body, and their actions seem to be related to wakefulness/sleep and other cognitive phenomena. Piperidines have been minimally characterized for therapeutic applications. In this context, 1-Boc-piperidine-4-carboxaldehyde (1-Boc-piperidine) is a piperidine-derivative molecule with no mechanism of action reported, although its uses include the synthesis of GPR119 selective agonists that have been patented as anti-obesity drugs. OBJECTIVES: The aim of this work was to study the effects of 1-Boc-piperidine on binge-eating behaviour and anxiety in Wistar rats. METHODS: In experimental protocol 1, binge-eating behaviour was induced in animals that received pre-treatment (i.p.) with (i) vehicle (methanol 10%; 1 mL/kg), (ii) 1-Boc-piperidine (1 µmol kg-1), or (iii) 1-Boc-piperidine (10 µmol kg-1). In experimental protocol 2, mildly stressed animals were evaluated in the elevated plus maze under the acute effects of the pre-treatments applied in experimental protocol 1. RESULTS AND CONCLUSIONS: 1-Boc-piperidine decreased, in a dose-dependent manner, the intake of calories from a succulent hyper-caloric food in a binge-eating protocol in female rats, whereas the acute exposition to this piperidine exerted an anxiolytic effect in the male rat. In both effects, the mechanism of action remains to be characterized.


Asunto(s)
Ansiedad/tratamiento farmacológico , Trastorno por Atracón/tratamiento farmacológico , Animales , Ansiedad/etiología , Conducta Animal/efectos de los fármacos , Trastorno por Atracón/etiología , Relación Dosis-Respuesta a Droga , Ingestión de Energía/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Inyecciones Intraperitoneales , Ligandos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Dolor/complicaciones , Unión Proteica , Ratas Wistar , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Estrés Psicológico/complicaciones , Aumento de Peso/efectos de los fármacos
15.
Neurosci Biobehav Rev ; 124: 78-88, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33524415

RESUMEN

Chronic-stress-induced depression is recognized as a widespread public health concern. Selective serotonin reuptake inhibitors (SSRIs) have been the most common treatment for this illness. However, the role of 5-hydroxytryptamine (5-HT) receptor subtypes in stress-induced depression remains unclear. Evidence from Animal studies has reported a variety of results regarding the effects of chronic unpredictable mild stress (CUMS) on serotonin signaling pathways and 5-HT receptor subtypes. This divergence may rely on differences in protocols, methods, and studied pathways. Thus, the aim of this systematic review was to weigh the currently available findings regarding serotonin receptor changes in animal models of CUMS. Overall, our meta-analysis results showed the association of altered expression of 5-HT1A receptors in the frontal cortex and 5-HT2A receptors both in the whole cortex and the hypothalamus of rats following CUMS. Moreover, by using a qualitative-structured analysis and the application of risk-of-bias tools, we identified possible sources of data variation between the studied literature, which should be taken into account in future animal studies of chronic-stress induced depression.


Asunto(s)
Hipocampo , Estrés Psicológico , Animales , Depresión , Modelos Animales de Enfermedad , Ratones , Ratas , Receptores de Serotonina , Inhibidores Selectivos de la Recaptación de Serotonina
16.
J Mol Graph Model ; 104: 107844, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33529936

RESUMEN

Alzheimer's Disease (AD) is the most frequent illness and cause of death amongst the age related-neurodegenerative disorders. The Alzheimer's Disease International (ADI) reported in 2019 that over 50 million people were living with dementia in the world and this number could potentially be around 152 million by 2050.5-hydroxtryptamine subtype 6 receptor (5-HT6R) has been identified as a potential anti-amnesic drug target and therefore, the administration of 5-HT6R antagonists can likely mitigate the memory loss and intellectual deterioration associated with AD. Herein, computational tools were applied to design new 5-HT6 antagonists and their biological activity values were predicted by our QSAR model obtained from Artificial Neural Networks (ANN). The proposed compounds here from the QSAR-ANN model presented significant biological activity values and some of them have achieved pKi above 9.00. Furthermore, our results suggest that the presence of halogen atoms (especially bromine) linked to the aromatic ring at para-position (HYD) contribute considerably to the increase of the biological activity values while bulky groups in the PI position do not culminate with the increase antagonist activity of compounds here analyzed. Finally, the ADME/Tox profile as well as the synthetic accessibility of new proposed compounds qualify them to go on further with experimental procedures and thenceforward their antagonist effects can be confirmed.


Asunto(s)
Diseño de Fármacos , Serotonina , Humanos , Redes Neurales de la Computación , Receptores de Serotonina , Antagonistas de la Serotonina/farmacología
17.
Mol Neurobiol ; 58(6): 2692-2703, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33492645

RESUMEN

Since Ginkgo biloba extract (GbE) was reported to improve the hypothalamic serotonergic system of ovariectomized (OVX) rats, the present study aimed to verify the GbE effects on hippocampal oxidative stress, inflammation, and levels of the serotonin transporter (5-HTT), and both the serotonin (5-HT1A, 5-HT1B) and leptin receptors of OVX rats. Two-month-old female Wistar rats had their ovaries surgically removed (OVX) or not (SHAM). After 60 days, OVX rats were gavaged daily with GbE 500 mg kg-1 (OVX+GbE), while SHAM and OVX groups received saline 0.9% (vehicle) for 14 days. Rats were then euthanized, and hippocampi were collected. Both 5-HT1A and 5-HT1B levels were significantly reduced in OVX rats compared to SHAM rats, while 5-HT1A was higher in OVX+GbE rats in comparison to OVX rats. Similarly, LepR levels were increased in OVX+GbE rats compared to OVX rats, reaching similar levels to SHAM rats. Superoxide dismutase activity increased in OVX rats in relation to SHAM rats, which was restored to SHAM levels by GbE treatment. Additionally, GbE significantly increased the glutathione peroxidase activity in comparison to the SHAM group. No differences were observed either in catalase activity or in the levels of 5-HTT, PKCα, TLR-4, NF-κBp50, ERK, and CREB. In summary, our results show a potential effect of GbE on hippocampal pathways involved in feeding behavior, and thus, they suggest that GbE activity might improve menopausal-related hippocampal disorders, offering an alternative therapeutic tool particularly for women to whom hormone replacement therapy may be contraindicated.


Asunto(s)
Antioxidantes/farmacología , Hipocampo/metabolismo , Ovariectomía , Extractos Vegetales/farmacología , Receptores de Leptina/metabolismo , Receptores de Serotonina/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Femenino , Flavonoides/análisis , Ginkgo biloba , Inflamación/patología , Ratas Wistar , Serotonina/metabolismo , Terpenos/análisis
18.
J Smooth Muscle Res ; 57(0): 79-93, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34980821

RESUMEN

BACKGROUND: Serotonin (5-hydroxytryptamine; 5-HT) performs a variety of functions in the body including the modulation of muscle tone in respiratory airways. Several studies indicate a possible role of 5-HT in the pathophysiology of bronchial hyperresponsiveness. However, the receptors and the molecular mechanisms by which 5-HT acts on airway smooth muscle (ASM) continue to be controversial. Most of the evidence suggests the participation of different subtypes of receptors in an indirect response. This study supports the proposal that 5-HT directly contracts ASM and characterizes pharmacologically the subtypes of serotonergic receptors involved. The characterization was carried out by using selective antagonists in an organ bath model allowing study of the smooth muscle of segments of bovine trachea. RESULTS: The results obtained show that 5-HT2A receptors are the main mediators of the direct contractile response of bovine ASM, with the cooperation of the 5-HT7, 5-HT3 and 5-HT1B/D receptors. Also, it was observed that the muscle response to serotonin is developed more slowly and to a lesser extent in comparison with the response to cholinergic stimulation. CONCLUSION: Overall, the receptors that mediate the direct serotonergic contraction of the smooth muscle of the bovine trachea are 5-HT2A, 5-HT7, 5-HT3 and 5-HT1B/D receptors.


Asunto(s)
Receptores de Serotonina , Serotonina , Animales , Bovinos , Contracción Muscular , Músculo Liso , Receptores de Serotonina/fisiología , Serotonina/farmacología , Serotonina/fisiología , Antagonistas de la Serotonina/farmacología
19.
Aging Ment Health ; 25(2): 219-224, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-31603040

RESUMEN

OBJECTIVES: To evaluate whether fall risk in older adults is associated with the use of selective serotonin receptor inhibitor (SSRI) monotherapy among geriatric outpatients, and whether this association is moderated by the presence of depressive disorder and/or frailty. METHODS: Prospective cohort study with a 12-month follow-up and including 811 community-dwelling adults aged 60 or older from a university-based Geriatric Outpatient Unit. Major depressive disorder (MDD) was diagnosed according to DSM-5 criteria; subsyndromal depression as not meeting MDD criteria, but a Geriatric Depression Scale 15-item score ≥ 6 points. Frailty was evaluated with the FRAIL questionnaire. The association between SSRI use, depression, or both as well as the association between SSRI use, frailty, or both with falls were estimated through a generalized estimating equation (GEE) adjusted for relevant confounders. RESULTS: At baseline, 297 patients (36.6%) used a SSRI (82 without remitted depression) and 306 (37.7%) were classified as physically frail. Frailty was more prevalent among SSRI users (44.8% versus 33.7%, p =.004). After 12 months, 179 participants had at least one fall (22.1%). SSRI use, depression as well as frailty were all independently associated with falls during follow-up. Nonetheless, patients with concurrent of SSRI usage and non-remitted depression had no higher risk compared to either remitted SSRI users or depressed patients without SSRIs. In contrast, concurrence of SSRI use and frailty increases the risk of falling substantially above those by SSRI usage or frailty alone. CONCLUSION: SSRI usage was independently associated with falls. Especially in frail-depressed patients, treatment strategies for depression other than SSRIs should be considered.


Asunto(s)
Accidentes por Caídas , Trastorno Depresivo Mayor , Fragilidad , Antagonistas de la Serotonina/efectos adversos , Anciano , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/epidemiología , Anciano Frágil , Fragilidad/epidemiología , Evaluación Geriátrica , Humanos , Estudios Prospectivos , Receptores de Serotonina
20.
Mol Neurobiol ; 58(3): 926-943, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33063280

RESUMEN

Early life stress is considered a risk factor for the development of long-term psychiatric disorders. Maternal deprivation (MD) is a useful paradigm to understand the neurobiological underpinnings of early stress-induced changes in neurodevelopment trajectory. The goal of the present study was to examine the effects of a chronic treatment with escitalopram (ESC) on the hippocampal levels of BDNF and neuropeptide Y (NPY), expression of serotonin type 1A receptor (5-HT1A), plasma corticosterone levels and emotional behaviours in male and female adolescent rats submitted to MD at 9 days of life (group DEP9) and challenged with a brief and mild stress (saline injection (SAL)) at the end of MD. Whole litters were kept with mothers (CTL) or submitted to MD (DEP9). Within each group, pups were stress-challenged (CTL-SAL and DEP9-SAL) or not (CTL-NSAL and DEP9-NSAL). ESC or vehicle treatments began at weaning and lasted 24 days, when animals were sacrificed for determination of neurobiological variables or submitted to a battery of tests for evaluation of emotional behaviours. The results showed that BDNF levels were higher in SAL-challenged males and in DEP9-SAL females, whereas 5-HT1A receptor expression was reduced in DEP9 males and in SAL-challenged females. There were no changes in NPY or corticosterone levels. In the forced swim test, SAL-challenged males and DEP9 females displayed less immobility and ESC only increased social motivation in males. The results indicated that neonatal stress led to sex-dependent changes in neurobiology and behaviour and that chronic ESC treatment had minor effects on these parameters.


Asunto(s)
Envejecimiento/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Citalopram/farmacología , Emociones , Hipocampo/metabolismo , Serotonina/metabolismo , Estrés Psicológico/metabolismo , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Corticosterona/sangre , Prueba de Laberinto Elevado , Emociones/efectos de los fármacos , Femenino , Masculino , Neuropéptido Y/metabolismo , Ratas Wistar , Receptores de Serotonina/metabolismo , Conducta Social , Natación
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