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1.
Cell Mol Life Sci ; 79(1): 24, 2021 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-34966948

RESUMEN

Protecting neurons from death during oxidative and neuroexcitotoxic stress is key for preventing cognitive dysfunction. We uncovered a novel neuroprotective mechanism involving interaction between neurotrophic factor-α1 (NF-α1/carboxypeptidase E, CPE) and human 5-HTR1E, a G protein-coupled serotonin receptor with no previously known neurological function. Co-immunoprecipitation and pull-down assays confirmed interaction between NFα1/CPE and 5-HTR1E and 125I NF-α1/CPE-binding studies demonstrated saturable, high-affinity binding to 5-HTR1E in stably transfected HEK293 cells (Kd = 13.82 nM). Treatment of 5-HTR1E stable cells with NF-α1/CPE increased pERK 1/2 and pCREB levels which prevented a decrease in pro-survival protein, BCL2, during H2O2-induced oxidative stress. Cell survival assay in ß-arrestin Knockout HEK293 cells showed that the NF-α1/CPE-5-HTR1E-mediated protection against oxidative stress was ß-arrestin-dependent. Molecular dynamics studies revealed that NF-α1/CPE interacts with 5-HTR1E via 3 salt bridges, stabilized by several hydrogen bonds, independent of the serotonin pocket. Furthermore, after phosphorylating the C-terminal tail and intracellular loop 3 (ICL3) of NF-α1/CPE-5-HTR1E, it recruited ß-arrestin1 by forming numerous salt bridges and hydrogen bonds to ICL2 and ICL3, leading to activation of ß-arrestin1. Immunofluorescence studies showed 5-HTR1E and NF-α1/CPE are highly expressed and co-localized on cell surface of human hippocampal neurons. Importantly, knock-down of 5-HTR1E in human primary neurons diminished the NF-α1/CPE-mediated protection of these neurons against oxidative stress and glutamate neurotoxicity-induced cell death. Thus, NF-α1/CPE uniquely interacts with serotonin receptor 5-HTR1E to activate the ß-arrestin/ERK/CREB/BCL2 pathway to mediate stress-induced neuroprotection.


Asunto(s)
Carboxipeptidasa H/metabolismo , Sistema de Señalización de MAP Quinasas , Factores de Crecimiento Nervioso/metabolismo , Neuronas/metabolismo , Neurotoxinas/toxicidad , Estrés Oxidativo , Receptores de Serotonina/metabolismo , beta-Arrestinas/metabolismo , Animales , Carboxipeptidasa H/química , Supervivencia Celular/efectos de los fármacos , AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Células HEK293 , Hipocampo/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Neuronas/efectos de los fármacos , Neuronas/patología , Fármacos Neuroprotectores/metabolismo , Fosforilación/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Dominios Proteicos , Receptores de Serotonina/química
2.
Biomolecules ; 11(12)2021 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-34944557

RESUMEN

The present review summarizes the data concerning the influence of serotonin (5-HT) receptors on body temperature in warm-blooded animals and on processes associated with its maintenance. This review includes the most important part of investigations from the first studies to the latest ones. The established results on the pharmacological activation of 5-HT1A, 5-HT3, 5-HT7 and 5-HT2 receptor types are discussed. Such activation of the first 3 type of receptors causes a decrease in body temperature, whereas the 5-HT2 activation causes its increase. Physiological mechanisms leading to changes in body temperature as a result of 5-HT receptors' activation are discussed. In case of 5-HT1A receptor, they include an inhibition of shivering and non-shivering thermogenesis, as well simultaneous increase of peripheral blood flow, i.e., the processes of heat production and heat loss. The physiological processes mediated by 5-HT2 receptor are opposite to those of the 5-HT1A receptor. Mechanisms of 5-HT3 and 5-HT7 receptor participation in these processes are yet to be studied in more detail. Some facts indicating that in natural conditions, without pharmacological impact, these 5-HT receptors are important links in the system of temperature homeostasis, are also discussed.


Asunto(s)
Temperatura Corporal , Receptores de Serotonina/metabolismo , Animales , Circulación Sanguínea , Homeostasis , Receptores de Serotonina/clasificación , Termogénesis
3.
Int J Mol Sci ; 22(19)2021 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-34639113

RESUMEN

Among the serotonin receptors, one of the most recently discovered 5-HT6 subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT6 receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT6 receptor. Thus, a broader pharmacological profile for 1-3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT6 receptor target.


Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Demencia/tratamiento farmacológico , Receptores de Serotonina/química , Antagonistas de la Serotonina/farmacología , Triazinas/farmacología , Animales , Células CACO-2 , Humanos , Masculino , Estructura Molecular , Ratas , Ratas Wistar , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/química , Relación Estructura-Actividad , Triazinas/química
4.
Int J Mol Sci ; 22(18)2021 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-34576176

RESUMEN

It has been established that enhancement of serotonergic transmission contributes to improvement of major depression; however, several post-mortem studies and experimental depression rodent models suggest that functional abnormalities of astrocytes play important roles in the pathomechanisms/pathophysiology of mood disorders. Direct effects of serotonin (5-HT) transporter inhibiting antidepressants on astroglial transmission systems has never been assessed in this context. Therefore, to explore the effects of antidepressants on transmission associated with astrocytes, the present study determined the effects of the selective 5-HT transporter inhibitor, escitalopram, and the 5-HT partial agonist reuptake inhibitor, vortioxetine, on astroglial L-glutamate release through activated hemichannels, and the expression of connexin43 (Cx43), type 1A (5-HT1AR) and type 7 (5-HT7R) 5-HT receptor subtypes, and extracellular signal-regulated kinase (ERK) in astrocytes using primary cultured rat cortical astrocytes in a 5-HT-free environment. Both escitalopram and 5-HT1AR antagonist (WAY100635) did not affect basal astroglial L-glutamate release or L-glutamate release through activated hemichannels. Subchronic (for seven days) administrations of vortioxetine and the 5-HT7R inverse agonist (SB269970) suppressed both basal L-glutamate release and L-glutamate release through activated hemichannels, whereas 5-HT1AR agonist (BP554) inhibited L-glutamate release through activated hemichannels, but did not affect basal L-glutamate release. In particular, WAY100635 did not affect the inhibitory effects of vortioxetine on L-glutamate release. Subchronic administration of vortioxetine, BP554 and SB269970 downregulated 5-HT1AR, 5-HT7R and phosphorylated ERK in the plasma membrane fraction, but escitalopram and WAY100635 did not affect them. Subchronic administration of SB269970 decreased Cx43 expression in the plasma membrane but did not affect the cytosol; however, subchronic administration of BP554 increased Cx43 expression in the cytosol but did not affect the plasma membrane. Subchronic vortioxetine administration increased Cx43 expression in the cytosol and decreased it in the plasma membrane. WAY100635 prevented an increased Cx43 expression in the cytosol induced by vortioxetine without affecting the reduced Cx43 expression in the plasma membrane. These results suggest that 5-HT1AR downregulation probably increases Cx43 synthesis, but 5-HT7R downregulation suppresses Cx43 trafficking to the plasma membrane. These results also suggest that the subchronic administration of therapeutic-relevant concentrations of vortioxetine inhibits both astroglial L-glutamate and Cx43 expression in the plasma membrane via 5-HT7R downregulation but enhances Cx43 synthesis in the cytosol via 5-HT1AR downregulation. This combination of the downregulation of 5-HT1AR, 5-HT7R and Cx43 in the astroglial plasma membrane induced by subchronic vortioxetine administration suggest that astrocytes is possibly involved in the pathophysiology of depression.


Asunto(s)
Conexina 43/metabolismo , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Cromatografía Líquida de Alta Presión , Citalopram/farmacología , Conexina 43/genética , Depresión/genética , Depresión/metabolismo , Femenino , Immunoblotting , Ratas , Receptores de Serotonina/metabolismo , Vortioxetina/farmacología
5.
Int J Mol Sci ; 22(18)2021 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-34576341

RESUMEN

Neurofibromatosis type 1 (NF1) is a common inherited disorder caused by mutations of the NF1 gene that encodes the Ras-GTPase activating protein neurofibromin, leading to overactivation of Ras-dependent signaling pathways such as the mTOR pathway. It is often characterized by a broad range of cognitive symptoms that are currently untreated. The serotonin 5-HT6 receptor is a potentially relevant target in view of its ability to associate with neurofibromin and to engage the mTOR pathway to compromise cognition in several cognitive impairment paradigms. Here, we show that constitutively active 5-HT6 receptors contribute to increased mTOR activity in the brain of Nf1+/- mice, a preclinical model recapitulating some behavioral alterations of NF1. Correspondingly, peripheral administration of SB258585, a 5-HT6 receptor inverse agonist, or rapamycin, abolished deficits in long-term social and associative memories in Nf1+/- mice, whereas administration of CPPQ, a neutral antagonist, did not produce cognitive improvement. These results show a key influence of mTOR activation by constitutively active 5-HT6 receptors in NF1 cognitive symptoms. They provide a proof of concept that 5-HT6 receptor inverse agonists already in clinical development as symptomatic treatments to reduce cognitive decline in dementia and psychoses, might be repurposed as therapies alleviating cognitive deficits in NF1 patients.


Asunto(s)
Neurofibromatosis 1/metabolismo , Receptores de Serotonina/metabolismo , Animales , Humanos , Serotonina/metabolismo , Tiofenos/metabolismo
6.
Molecules ; 26(15)2021 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-34361754

RESUMEN

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous-in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.


Asunto(s)
Antipsicóticos/farmacología , Inhibidores de Captación de Dopamina/farmacología , Indoles/farmacología , Nootrópicos/farmacología , Inhibidores de la Captación de Serotonina/farmacología , Triptaminas/farmacología , Animales , Antipsicóticos/síntesis química , Familia 2 del Citocromo P450/metabolismo , Modelos Animales de Enfermedad , Inhibidores de Captación de Dopamina/síntesis química , Células Hep G2 , Humanos , Indoles/síntesis química , Ligandos , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Ratones , Modelos Moleculares , Estructura Molecular , Nootrópicos/síntesis química , Unión Proteica , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/metabolismo , Trastornos Psicóticos/fisiopatología , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Inhibidores de la Captación de Serotonina/síntesis química , Relación Estructura-Actividad , Triptaminas/síntesis química
7.
Mol Pharmacol ; 100(5): 470-479, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34393108

RESUMEN

We compared monotherapies and combinations of therapies that regulate G-protein-coupled receptors (GPCRs) with respect to their abilities to inhibit early stages of diabetic retinopathy (DR) in streptozotocin-diabetic mice. Metoprolol (MTP; 0.04-1.0 mg/kg b.wt./day), bromocriptine (BRM; 0.01-0.1 mg/kg b.wt./day), doxazosin (DOX; 0.01-1.0 mg/kg b.wt./day), or tamsulosin (TAM; 0.05-0.25 mg/kg b.wt./day) were injected individually daily for 2 months in dose-response studies to assess their effects on the diabetes-induced increases in retinal superoxide and leukocyte-mediated cytotoxicity against vascular endothelial cells, both of which abnormalities have been implicated in the development of DR. Each of the individual drugs inhibited the diabetes-induced increase in retinal superoxide at the higher concentrations tested, but the inhibition was lost at lower doses. To determine whether combination therapies had superior effects over individual drugs, we intentionally selected for each drug a low dose that had little or no effect on the diabetes-induced retinal superoxide for use separately or in combinations in 8-month studies of retinal function, vascular permeability, and capillary degeneration in diabetes. At the low doses used, combinations of the drugs generally were more effective than individual drugs, but the low-dose MTP alone totally inhibited diabetes-induced reduction in a vision task, BRM or DOX alone totally inhibited the vascular permeability defect, and DOX alone totally inhibited diabetes-induced degeneration of retinal capillaries. Although low-dose MTP, BRM, DOX, or TAM individually had beneficial effects on some endpoints, combination of the therapies better inhibited the spectrum of DR lesions evaluated. SIGNIFICANCE STATEMENT: The pathogenesis of early stages of diabetic retinopathy remains incompletely understood, but multiple different cell types are believed to be involved in the pathogenic process. We have compared the effects of monotherapies to those of combinations of drugs that regulate GPCR signaling pathways with respect to their relative abilities to inhibit the development of early diabetic retinopathy.


Asunto(s)
Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/metabolismo , Hipoglucemiantes/administración & dosificación , Receptores Adrenérgicos/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/metabolismo , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Retinopatía Diabética/patología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Masculino , Ratones , Ratones Endogámicos C57BL , Vasos Retinianos/efectos de los fármacos , Vasos Retinianos/metabolismo , Vasos Retinianos/patología
8.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-34445318

RESUMEN

Recent studies revealed that the activation of serotonergic 5-HT1A and muscarinic M1, M4, or M5 receptors prevent MK-801-induced cognitive impairments in animal models. In the present study, the effectiveness of the simultaneous activation of 5-HT1A and muscarinic receptors at preventing MK-801-induced cognitive deficits in novel object recognition (NOR) or Y-maze tests was investigated. Activators of 5-HT1A (F15599), M1 (VU0357017), M4 (VU0152100), or M5 (VU0238429) receptors administered at top doses for seven days reversed MK-801-induced deficits in the NOR test, similar to the simultaneous administration of subeffective doses of F15599 (0.05 mg/kg) with VU0357017 (0.15 mg/kg), VU0152100 (0.05 mg/kg), or VU0238429 (1 mg/kg). The compounds did not prevent the MK-801-induced impairment when administered acutely. Their activity was less evident in the Y-maze. Pharmacokinetic studies revealed high brain penetration of F15599 (brain/plasma ratio 620%), which was detected in the frontal cortex (FC) up to 2 h after administration. Decreases in the brain penetration properties of the compounds were observed after acute administration of the combinations, which might have influenced behavioral responses. This negative effect on brain penetration was not observed when the compounds were administered repeatedly. Based on our results, prolonged administration of a 5-HT1A activator with muscarinic receptor ligands may be effective at reversing cognitive decline related to schizophrenia, and the FC may play a critical role in this interaction.


Asunto(s)
Colinérgicos/farmacología , Disfunción Cognitiva/tratamiento farmacológico , Corteza Prefrontal/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Agonistas de Receptores de Serotonina/farmacología , Animales , Benzamidas/farmacocinética , Benzamidas/farmacología , Benzamidas/uso terapéutico , Barrera Hematoencefálica/metabolismo , Colinérgicos/farmacocinética , Colinérgicos/uso terapéutico , Disfunción Cognitiva/etiología , Maleato de Dizocilpina/toxicidad , Masculino , Aprendizaje por Laberinto , Ratones , Piperidinas/farmacocinética , Piperidinas/farmacología , Piperidinas/uso terapéutico , Corteza Prefrontal/metabolismo , Piridinas/farmacocinética , Piridinas/farmacología , Piridinas/uso terapéutico , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Esquizofrenia/complicaciones , Agonistas de Receptores de Serotonina/farmacocinética , Agonistas de Receptores de Serotonina/uso terapéutico , Tiofenos/farmacocinética , Tiofenos/farmacología , Tiofenos/uso terapéutico
9.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-34445721

RESUMEN

Serotonin modulates several physiological and cognitive pathways throughout the human body that affect emotions, memory, sleep, and thermal regulation. The complex nature of the serotonergic system and interactions with other neurochemical systems indicate that the development of depression may be mediated by various pathomechanisms, the common denominator of which is undoubtedly the disturbed transmission in central 5-HT synapses. Therefore, the deliberate pharmacological modulation of serotonergic transmission in the brain seems to be one of the most appropriate strategies for the search for new antidepressants. As discussed in this review, the serotonergic system offers great potential for the development of new antidepressant therapies based on the combination of SERT inhibition with different pharmacological activity towards the 5-HT system. The aim of this article is to summarize the search for new antidepressants in recent years, focusing primarily on the possibility of benefiting from interactions with various 5-HT receptors in the pharmacotherapy of depression.


Asunto(s)
Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Receptores de Serotonina/metabolismo , Encéfalo/metabolismo , Desarrollo de Medicamentos/tendencias , Humanos , Receptores de Serotonina/efectos de los fármacos , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/metabolismo , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo
10.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-34298938

RESUMEN

The expression of 5-HT (serotonin) receptors (sr) was analyzed in the spinal cord and ganglia of 15 human conceptuses (5-10-weeks), and in the 9-week fetus with spina bifida. We used immunohistochemical method to detect sr-positive, apoptotic (caspase-3) and proliferating (Ki-67) cells, double immunofluorescence for co-localization with protein gene peptide (pgp) 9.5 and GFAP, as well as semiquantification and statistical measurements. Following the neurulation process, moderate (sr1 and sr2) and mild (sr3) expression characterized neuroblasts in the spinal cord and ganglia. During further development, sr1 expression gradually increased in the motoneurons, autonomic and sensory neurons, while sr2 and sr3 increased strongly in floor and roof plates. In the ganglia, sr3 expression increased during limited developmental period, while sr1 and sr2 increased throughout the investigated period. Co-expression of sr/pgp 9.5 characterized developing neurons, while sr/GFAP co-localized in the roof plate. In the spinal cord and ganglia of malformed fetus, weaker sr1 and sr2 and stronger sr3 expression accompanied morphological abnormalities. Anomalous roof plate morphology showed an excess of apoptotic and proliferating cells and increased sr3 expression. Our results indicate a human-species specific sr expression pattern, and the importance of sr1 in neuronal differentiation, and sr2 and sr3 in the control of the roof plate morphogenesis in normal and disturbed development.


Asunto(s)
Feto/metabolismo , Ganglios Espinales/metabolismo , Ganglios/metabolismo , Receptores de Serotonina/metabolismo , Médula Espinal/metabolismo , Disrafia Espinal/metabolismo , Apoptosis/fisiología , Caspasa 3/metabolismo , Diferenciación Celular/fisiología , Proliferación Celular/fisiología , Humanos , Antígeno Ki-67/metabolismo , Células Receptoras Sensoriales/metabolismo , Serotonina/metabolismo
11.
Molecules ; 26(11)2021 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-34199418

RESUMEN

Since neurodevelopmental disorders (NDDs) influence more than 3% of children worldwide, there has been intense investigation to understand the etiology of disorders and develop treatments. Although there are drugs such as aripiprazole, risperidone, and lurasidone, these medications are not cures for the disorders and can only help people feel better or alleviate their symptoms. Thus, it is required to discover therapeutic targets in order to find the ultimate treatments of neurodevelopmental disorders. It is suggested that abnormal neuronal morphology in the neurodevelopment process is a main cause of NDDs, in which the serotonergic system is emerging as playing a crucial role. From this point of view, we noticed the correlation between serotonin receptor subtype 7 (5-HT7R) and NDDs including autism spectrum disorder (ASD), fragile X syndrome (FXS), and Rett syndrome (RTT). 5-HT7R modulators improved altered behaviors in animal models and also affected neuronal morphology via the 5-HT7R/G12 signaling pathway. Through the investigation of recent studies, it is suggested that 5-HT7R could be a potential therapeutic target for the treatment of NDDs.


Asunto(s)
Terapia Molecular Dirigida/métodos , Trastornos del Neurodesarrollo/metabolismo , Receptores de Serotonina/metabolismo , Animales , Humanos , Trastornos del Neurodesarrollo/tratamiento farmacológico , Antagonistas de la Serotonina/farmacología , Antagonistas de la Serotonina/uso terapéutico , Agonistas de Receptores de Serotonina/farmacología , Agonistas de Receptores de Serotonina/uso terapéutico , Transducción de Señal/efectos de los fármacos
12.
Molecules ; 26(13)2021 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-34201675

RESUMEN

The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α2-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α2-adrenoceptors and 5-HT7 receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α2A/5-HT7 receptor antagonist and displayed moderate-to-high selectivity over α1-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.


Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2/química , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Actividad Motora/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/síntesis química , Antagonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Animales , Antidepresivos/uso terapéutico , Escala de Evaluación de la Conducta , Depresión/fisiopatología , Células HEK293 , Humanos , Ligandos , Masculino , Ratones , Mirtazapina/farmacología , Mirtazapina/uso terapéutico , Norepinefrina/metabolismo , Piperidinas/química , Ratas , Receptores de Serotonina/genética , Serotonina/metabolismo , Natación
13.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-34202161

RESUMEN

The autonomic nervous system derives from the neural crest (NC) and supplies motor innervation to the smooth muscle of visceral organs, including the lower urinary tract (LUT). During fetal development, sacral NC cells colonize the urogenital sinus to form pelvic ganglia (PG) flanking the bladder neck. The coordinated activity of PG neurons is required for normal urination; however, little is known about the development of PG neuronal diversity. To discover candidate genes involved in PG neurogenesis, the transcriptome profiling of sacral NC and developing PG was performed, and we identified the enrichment of the type 3 serotonin receptor (5-HT3, encoded by Htr3a and Htr3b). We determined that Htr3a is one of the first serotonin receptor genes that is up-regulated in sacral NC progenitors and is maintained in differentiating PG neurons. In vitro cultures showed that the disruption of 5-HT3 signaling alters the differentiation outcomes of sacral NC cells, while the stimulation of 5-HT3 in explanted fetal pelvic ganglia severely diminished neurite arbor outgrowth. Overall, this study provides a valuable resource for the analysis of signaling pathways in PG development, identifies 5-HT3 as a novel regulator of NC lineage diversification and neuronal maturation in the peripheral nervous system, and indicates that the perturbation of 5-HT3 signaling in gestation has the potential to alter bladder function later in life.


Asunto(s)
Cresta Neural/metabolismo , Receptores de Serotonina 5-HT3/metabolismo , Transducción de Señal , Sistema Urinario/inervación , Sistema Urinario/metabolismo , Animales , Sistema Nervioso Autónomo , Diferenciación Celular , Biología Computacional/métodos , Perfilación de la Expresión Génica , Ratones , Cresta Neural/embriología , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Neuritas/metabolismo , Neurogénesis , Proyección Neuronal , Neuronas/metabolismo , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT3/genética , Transcriptoma , Sistema Urinario/embriología
14.
Theranostics ; 11(14): 6950-6965, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34093864

RESUMEN

Rationale: Psychological stress has been linked to cancer development and resistance to therapy by many epidemiological and clinical studies. Stress-induced immunosuppressive microenvironment by stress hormones, in particular glucocorticoids, has been extensively studied. However, the impacts of other stress-related neurotransmitters, such as serotonin (5-hydroxytryptamine, 5-HT), on cancer development just start to be revealed. Here, we aimed to identify novel neurotransmitters involved in stress-induced growth and dissemination of ovarian cancer (OC) and reveal the major underlying signaling pathway and the therapeutic significance. Methods: Through a genome-wide CRISPR/Cas9 knockout screen in the murine orthotopic model of ovarian carcinoma (OC), we identified candidate genes regulating the peritoneal dissemination of OC. Among them, we picked out HTR1E, one member of 5-HT receptor family specifically expressed in the ovary and endometrium in addition to brain. The correlation of HTR1E expression with OC progression was analyzed in OC patient specimen by quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry (IHC). Gain-of-function and loss-of-function analyses were performed to explore the functions of 5-HT/HTR1E signaling in OC growth and dissemination in vitro and in vivo. In addition, we investigated the therapeutic values of HTR1E specific agonist and small molecular inhibitors against HTR1E downstream factor SRC in a stressed murine OC xenograft model. Results: In OC patients, the HTR1E expression is dramatically decreased in peritoneal disseminated OC cells, which correlates with poor clinical outcome. Silence of HTR1E in OC cells greatly promotes cell proliferation and epithelial mesenchymal transition (EMT) by the activation of SRC-mediated downstream signaling pathways. Furthermore, chronic stress results in significantly decreased serotonin in the ovary and the enhanced OC growth and peritoneal dissemination in mice, which can be strongly inhibited by specific HTR1E agonist or the SRC inhibitor. Conclusions: We discovered the essential role of serotonin/HTR1E signaling in preventing the chronic psychological stress-promoted progression of OC, suggesting the potential therapeutic value of the HTR1E specific agonist and the SRC inhibitor for OC patients who are suffering from psychological stress.


Asunto(s)
Adenocarcinoma/metabolismo , Neoplasias Ováricas/metabolismo , Receptores de Serotonina 5-HT1/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/farmacología , Estrés Fisiológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Animales , Escala de Evaluación de la Conducta , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/ética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Pruebas Genéticas , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Invasividad Neoplásica/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , RNA-Seq , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Serotonina/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/genética , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Biol Pharm Bull ; 44(8): 1067-1074, 2021 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-34135207

RESUMEN

Musculoskeletal and psychological complaints have increased with the widespread use of visual display terminals, and musculoskeletal pain is known to be closely related to stress. One method of experimentally inducing persistent muscle pain is repeated cold stress (RCS), and animals exposed to such stress exhibit a dysfunction in the descending pain inhibitory system. Acetaminophen (N-acetyl-p-aminophenol; APAP) is widely used to relieve several types of pain, including musculoskeletal pain, and is available as an OTC drug. However, the mechanism underlying its analgesic action has not yet been fully elucidated. In this study, we compared the analgesic effect of APAP on RCS-induced muscular hyperalgesia with those of other analgesics to identify its mechanism of action. The daily oral administration of APAP significantly suppressed the decrease in the mechanical withdrawal threshold caused by RCS, similar to the results for neurotropin but not for the cyclooxygenase inhibitor ibuprofen (IBP). Moreover, the intrathecal administration of antagonists of the 5-hydroxytryptamine (5-HT)3 receptor or α2-adrenoceptor significantly abolished the analgesic effect of APAP but not of IBP. These results suggest that the analgesic effect of APAP on RCS-induced muscular pain might be exerted due to the activation of the descending pathways involving the spinal 5-HT3 receptor or α2-adrenoceptor.


Asunto(s)
Acetaminofén/farmacología , Respuesta al Choque por Frío , Hiperalgesia/metabolismo , Mialgia/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Serotonina/metabolismo , Médula Espinal/efectos de los fármacos , Analgésicos no Narcóticos/farmacología , Animales , Frío , Inhibidores de la Ciclooxigenasa/farmacología , Modelos Animales de Enfermedad , Miembro Posterior/patología , Hiperalgesia/prevención & control , Ibuprofeno/farmacología , Masculino , Músculo Esquelético/patología , Mialgia/prevención & control , Neuralgia/metabolismo , Neuralgia/prevención & control , Umbral del Dolor , Ratas Sprague-Dawley , Serotonina/metabolismo
16.
PLoS One ; 16(6): e0252474, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34086766

RESUMEN

Exposure to heat stress can alter the development and immune system function in dairy calves. Serotonin is an immunomodulatory biogenic amine that functions as a neurotransmitter and as a stress-response mediator. Our objectives were to characterize the patterns of serum serotonin concentrations and the pattern of serotonin-related genes expressed by immune cells of calves exposed to chronic heat stress or heat stress abatement during early life, and to explore whether these might relate to immune system development. Dairy calves were exposed to chronic heat stress (HS; n = 6) or heat stress abatement (cooling, CL; n = 6) across the prenatal (late gestation, last 46 d) and postnatal (from birth to weaning, 56 d) developmental windows. Blood samples were collected to harvest serum (weekly, from d 1 to 49), to isolate of circulating leukocyte mRNA (at 1, 21 and 42 d of age) and characterize immune cell populations by flow cytometry (at 21 and 47 d of age). Calves exposed to chronic heat stress pre- and postnatally had lower red blood cell counts and lower circulating serotonin, immunoglobulin G, and B-lymphocytes compared to CL calves. Circulating blood leukocyte mRNA expression of serotonin receptors -1A, -1F, -4 and -5 was greater, while heat shock protein 70 and immune-related genes (i.e., TBX21, TLR4, and TGFß) were lower in HS relative to CL calves. Peripheral blood leukocytes from all calves secreted serotonin and interleukin-6 after in-vitro lipopolysaccharide stimulation. However, the HS calves produced more serotonin and less interleukin-6 than CL calves when activated in-vitro. Together, our data suggest that providing heat stress abatement to dairy calves across prenatal and postnatal developmental windows might modulate the serotonin synthesis pathway in ways that may benefit humoral immunity against microbial pathogens.


Asunto(s)
Enfermedades de los Bovinos/metabolismo , Bovinos/metabolismo , Trastornos de Estrés por Calor/metabolismo , Linfocitos/inmunología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Receptores de Serotonina/metabolismo , Animales , Bovinos/crecimiento & desarrollo , Femenino , Trastornos de Estrés por Calor/veterinaria , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/veterinaria , Receptores de Serotonina/genética
17.
Int J Mol Sci ; 22(10)2021 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-34067933

RESUMEN

Serotonin receptors play important roles in neuronal excitation, emotion, platelet aggregation, and vasoconstriction. The serotonin receptor subtype 2A (5-HT2AR) is a Gq-coupled GPCR, which activate phospholipase C. Although the structures and functions of 5-HT2ARs have been well studied, little has been known about their real-time dynamics. In this study, we analyzed the intramolecular motion of the 5-HT2AR in living cells using the diffracted X-ray tracking (DXT) technique. The DXT is a very precise single-molecular analytical technique, which tracks diffraction spots from the gold nanocrystals labeled on the protein surface. Trajectory analysis provides insight into protein dynamics. The 5-HT2ARs were transiently expressed in HEK 293 cells, and the gold nanocrystals were attached to the N-terminal introduced FLAG-tag via anti-FLAG antibodies. The motions were recorded with a frame rate of 100 µs per frame. A lifetime filtering technique demonstrated that the unliganded receptors contain high mobility population with clockwise twisting. This rotation was, however, abolished by either a full agonist α-methylserotonin or an inverse agonist ketanserin. Mutation analysis revealed that the "ionic lock" between the DRY motif in the third transmembrane segment and a negatively charged residue of the sixth transmembrane segment is essential for the torsional motion at the N-terminus of the receptor.


Asunto(s)
Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2A/fisiología , Imagen Individual de Molécula/métodos , Proteínas Portadoras/metabolismo , Cristalografía por Rayos X/métodos , Oro , Células HEK293 , Humanos , Iones/metabolismo , Ligandos , Nanotecnología/métodos , Receptores de Serotonina/metabolismo , Receptores de Serotonina/fisiología , Difracción de Rayos X/métodos , Rayos X
18.
Molecules ; 26(11)2021 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-34073226

RESUMEN

Breast tumors were the first tumors of epithelial origin shown to follow the cancer stem cell model. The model proposes that cancer stem cells are uniquely endowed with tumorigenic capacity and that their aberrant differentiation yields non-tumorigenic progeny, which constitute the bulk of the tumor cell population. Breast cancer stem cells resist therapies and seed metastases; thus, they account for breast cancer recurrence. Hence, targeting these cells is essential to achieve durable breast cancer remissions. We identified compounds including selective antagonists of multiple serotonergic system pathway components required for serotonin biosynthesis, transport, activity via multiple 5-HT receptors (5-HTRs), and catabolism that reduce the viability of breast cancer stem cells of both mouse and human origin using multiple orthologous assays. The molecular targets of the selective antagonists are expressed in breast tumors and breast cancer cell lines, which also produce serotonin, implying that it plays a required functional role in these cells. The selective antagonists act synergistically with chemotherapy to shrink mouse mammary tumors and human breast tumor xenografts primarily by inducing programmed tumor cell death. We hypothesize those serotonergic proteins of diverse activity function by common signaling pathways to maintain cancer stem cell viability. Here, we summarize our recent findings and the relevant literature regarding the role of serotonin in breast cancer.


Asunto(s)
Neoplasias de la Mama/metabolismo , Células Madre Neoplásicas/citología , Serotonina/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Modelos Animales de Enfermedad , Docetaxel/administración & dosificación , Transición Epitelial-Mesenquimal , Femenino , Humanos , Ratones , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/metabolismo , Trasplante de Neoplasias , Fenotipo , Receptores de Serotonina/metabolismo , Inducción de Remisión , Sertralina/administración & dosificación , Transducción de Señal
19.
Clin Pharmacol Ther ; 110(3): 808-815, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33961287

RESUMEN

In contrast to the dose-occupancy relationship in the treatment of schizophrenia, the minimal effective level of dopamine receptor 2 (D2R) blockade for antipsychotics in the treatment of bipolar depression is unknown. Lower doses aimed at reducing extrapyramidal side effects must be balanced against the need to retain the therapeutic benefit of D2R blockade on emergent cycling, mixed, manic, anxiety, and/or psychotic symptoms. Dose-reductions intended to lower D2R blockade, however, could also decrease concomitant serotonin receptor antagonism and its potential benefit on depressive symptoms. Here, we uncoupled the potential antidepressant activity in amisulpride, driven by 5-HT7 receptor (5-HT7R) antagonism, from the D2R-mediated antipsychotic activity by discovering that each enantiomer favors a different receptor. Aramisulpride was more potent at 5-HT7R relative to esamisulpride (Ki 47 vs. 1,900 nM, respectively), whereas esamisulpride was more potent at D2R (4.0 vs. 140 nM). We hypothesized that a nonracemic ratio might achieve greater 5-HT7R-mediated antidepressant effects at a lower level of D2R blockade. The dose-occupancy relationship of esamisulpride at D2R was determined by positron emission tomography (PET) imaging in human volunteers. Separately the dose-relationship of aramisulpride was established in humans using suppression of rapid eye movement (REM) sleep as a marker of 5-HT7R antagonism. These results led to the discovery of an 85:15 ratio of aramisulpride to esamisulpride (SEP-4199) that maximizes the potential for antidepressant benefit of aramisulpride via 5-HT7R and reduces esamisulpride to minimize D2R-related extrapyramidal side effects while still retaining D2R-mediated effects predicted to provide benefit in bipolar depression. The antidepressant efficacy of SEP-4199 was recently confirmed in a proof-of-concept trial for the treatment of bipolar depression (NCT03543410).


Asunto(s)
Amisulprida/efectos adversos , Amisulprida/uso terapéutico , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Antagonistas de los Receptores de Dopamina D2/uso terapéutico , Trastornos del Humor/tratamiento farmacológico , Receptores de Serotonina/metabolismo , Adulto , Animales , Antidepresivos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/metabolismo , Femenino , Humanos , Masculino , Trastornos del Humor/metabolismo , Tomografía de Emisión de Positrones/métodos , Ratas , Ratas Wistar , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Sueño REM/efectos de los fármacos
20.
Pharmacopsychiatry ; 54(5): 215-223, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33957677

RESUMEN

INTRODUCTION: Depression is responsible for 800 000 deaths worldwide, a number that will rise significantly due to the COVID-19 pandemic. Affordable novel drugs with less severe side effects are urgently required. We investigated the effect of withanone (WN) from Withania somnifera on the serotonin system of wild-type and knockout Caenorhabditis elegans strains using in silico, in vitro, and in vivo methods. METHODS: WN or fluoxetine (as positive control drug) was administered to wild-type (N2) and knockout C. elegans strains (AQ866, DA1814, DA2100, DA2109, and MT9772) to determine their effect on oxidative stress (Trolox, H2DCFDA, and juglone assays) on osmotic stress and heat stress and lifespan. Quantitative real-time RT-PCR was applied to investigate the effect of WN or fluoxetine on the expression of serotonin receptors (ser-1, ser-4, ser-7) and serotonin transporter (mod-5). The binding affinity of WN to serotonin receptors and transporter was analyzed in silico using AutoDock 4.2.6. RESULTS: WN scavenged ROS in wild-type and knockout C. elegans and prolonged their lifespan. WN upregulated the expression of serotonin receptor and transporter genes. In silico analyses revealed high binding affinities of WN to Ser-1, Ser-4, Ser-7, and Mod-5. LIMITATIONS: Further studies are needed to prove whether the results from C. elegans are transferrable to mammals and human beings. CONCLUSION: WN ameliorated depressive-associated stress symptoms by activating the serotonin system. WN may serve as potential candidate in developing new drugs to treat depression.


Asunto(s)
Depresión , Receptores de Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Transmisión Sináptica/efectos de los fármacos , Witanólidos/farmacología , Animales , Animales Modificados Genéticamente , Antidepresivos/farmacología , COVID-19/psicología , Caenorhabditis elegans , Depresión/tratamiento farmacológico , Depresión/metabolismo , Fluoxetina/farmacología , Humanos , Longevidad/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , SARS-CoV-2
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