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1.
Life Sci ; 285: 120002, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34599937

RESUMO

AIMS: To explore the relationship between renal ischemia/reperfusion injury (RIRI) and the activation of the renal 5-HT degradation system, including 5-HT2A receptor (5-HT2AR), 5-HT synthases and monoamine oxidase-A (MAO-A). MAIN METHODS: Rat RIRI was induced by removing the right kidney, causing ischemia of the left kidney for 45 min and reperfusion for different times. RIRI model (ischemia for 45 min and reperfusion for 24 h) was pretreated with 5-HT2AR antagonist sarpogrelate hydrochloride (SH) and the 5-HT synthase inhibitor carbidopa. In HK-2 cells, cellular damage was induced by hypoxia (24 h)/reoxygenation (12 h) (H/R) and treated with SH, carbidopa or the MAO-A inhibitor clorgyline. Hematoxylin-eosin, immunohistochemistry, TUNEL and fluorescent probe staining, RT-qPCR, western blotting, ELISA, etc. were used in the tests. KEY FINDINGS: The development of RIRI and the emergence of the RIRI peak were consistent with renal 5-HT degradation system activation. The highest expression regions of the 5-HT degradation system overlapped with those of the most severe lesions in the kidney, which were in proximal renal tubules. Rat RIRI and HK-2 cell damage, including oxidative stress, inflammation and apoptosis, could be almost abolished by synergistic inhibition of SH and carbidopa. Clorgyline also abolished the cellular damage induced by H/R. H/R-induced production of mitochondrial ROS in HK-2 cells was due to MAO-A-catalyzed 5-HT degradation, and 5-HT2AR was involved by mediating the expression of 5-HT synthases and MAO-A. SIGNIFICANCE: These findings revealed a close association between RIRI and activation of the renal 5-HT degradation system.


Assuntos
Túbulos Renais/irrigação sanguínea , Túbulos Renais/metabolismo , Traumatismo por Reperfusão/metabolismo , Serotonina/metabolismo , Animais , Apoptose , Células Epiteliais/metabolismo , Inflamação/metabolismo , Túbulos Renais/patologia , Masculino , Mitocôndrias/metabolismo , Monoaminoxidase/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Traumatismo por Reperfusão/patologia , Fatores de Tempo
2.
Cells ; 10(8)2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34440670

RESUMO

The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor-receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1-15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor-receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Neurônios Dopaminérgicos/metabolismo , Transtornos Mentais/metabolismo , Receptor Cross-Talk , Receptor 5-HT2A de Serotonina/metabolismo , Receptores 5-HT1 de Serotonina/metabolismo , Neurônios Serotoninérgicos/metabolismo , Animais , Antidepressivos/uso terapêutico , Antipsicóticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 1 de Galanina/metabolismo , Receptor Tipo 2 de Galanina/metabolismo , Receptor 5-HT2A de Serotonina/genética , Receptores de Dopamina D2/metabolismo , Receptores 5-HT1 de Serotonina/genética , Transdução de Sinais
3.
Sci Rep ; 11(1): 15437, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34326453

RESUMO

The serotonin 5-HT2A receptor (5-HT2AR) has been receiving increasing attention because its genetic variants have been associated with a variety of neurological diseases. To elucidate the pathogenesis of the neurological diseases associated with 5-HT2AR gene (HTR2A) variants, we have previously established a protocol to induce HTR2A-expressing neurons from human-induced pluripotent stem cells (hiPSCs). Here, we investigated the maturation stages and electrophysiological properties of HTR2A-positive neurons induced from hiPSCs and constructed an HTR2A promoter-specific reporter lentivirus to label the neurons. We found that neuronal maturity increased over time and that HTR2A expression was induced at the late stage of neuronal maturation. Furthermore, we demonstrated successful labelling of the HTR2A-positive neurons, which had fluorescence and generated repetitive action potentials in response to depolarizing currents and an inward current during the application of TCB-2, a selective agonist of 5-HT2ARs, respectively. These results indicated that our in vitro model mimicked the in vivo dynamics of 5-HT2AR. Therefore, in vitro monitoring of the function of HTR2A-positive neurons induced from hiPSCs could help elucidate the pathophysiological mechanisms of neurological diseases associated with genetic variations of the HTR2A gene.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Neurogênese/genética , Neurônios/citologia , Neurônios/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Transdução de Sinais/genética , Potenciais de Ação/genética , Adulto , Doadores de Sangue , Células Cultivadas , Voluntários Saudáveis , Humanos , Técnicas de Patch-Clamp/métodos , Regiões Promotoras Genéticas , Receptor 5-HT2A de Serotonina/genética , Transfecção
4.
Commun Biol ; 4(1): 740, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131274

RESUMO

Aging arises from complex interactions among multiple biochemical products. Systems-level analyses of biological networks may provide insights into the causes and consequences of aging that evade single-gene studies. We have previously found that dietary choice is sufficient to modulate aging in the vinegar fly, Drosophila melanogaster. Here we show that nutrient choice influenced several measures of metabolic network integrity, including connectivity, community structure, and robustness. Importantly, these effects are mediated by serotonin signaling, as a mutation in serotonin receptor 2A (5-HT2A) eliminated the effects of nutrient choice. Changes in network structure were associated with organism resilience and increased susceptibility to genetic perturbation. Our data suggest that the behavioral or perceptual consequences of exposure to individual macronutrients, involving serotonin signaling through 5-HT2A, qualitatively change the state of metabolic networks throughout the organism from one that is highly connected and robust to one that is fragmented, fragile, and vulnerable to perturbations.


Assuntos
Envelhecimento/fisiologia , Drosophila melanogaster/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo , Animais , Comportamento Alimentar/fisiologia , Longevidade/fisiologia , Masculino , Redes e Vias Metabólicas/fisiologia , Metabolômica , Nutrientes , Receptor 5-HT2A de Serotonina/genética , Transdução de Sinais/fisiologia
5.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067933

RESUMO

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.


Assuntos
Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/fisiologia , Imagem Individual de Molécula/métodos , Proteínas de Transporte/metabolismo , Cristalografia por Raios X/métodos , Ouro , Células HEK293 , Humanos , Íons/metabolismo , Ligantes , Nanotecnologia/métodos , Receptores de Serotonina/metabolismo , Receptores de Serotonina/fisiologia , Difração de Raios X/métodos , Raios X
6.
Exp Neurol ; 343: 113778, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34090893

RESUMO

New psychoactive stimulants and psychedelics continue to play an important role on the illicit new psychoactive substance (NPS) market. Designer stimulants and psychedelics both affect monoaminergic systems, although by different mechanisms. Stimulant NPS primarily interact with monoamine transporters, either as inhibitors or as substrates. Psychedelic NPS most potently interact with serotonergic receptors and mediate their mind-altering effects mainly through agonism at serotonin 5-hydroxytryptamine-2A (5-HT2A) receptors. Rarely, designer stimulants and psychedelics are associated with potentially severe adverse effects. However, due to the high number of emerging NPS, it is not possible to investigate the toxicity of each individual substance in detail. The brain is an organ particularly sensitive to substance-induced toxicity due to its high metabolic activity. In fact, stimulant and psychedelic NPS have been linked to neurological and cognitive impairments. Furthermore, studies using in vitro cell models or rodents indicate a variety of mechanisms that could potentially lead to neurotoxic damage in NPS users. Cytotoxicity, mitochondrial dysfunction, and oxidative stress may potentially contribute to neurotoxicity of stimulant NPS in addition to altered neurochemistry. Serotonin 5-HT2A receptor-mediated toxicity, oxidative stress, and activation of mitochondrial apoptosis pathways could contribute to neurotoxicity of some psychedelic NPS. However, it remains unclear how well the current preclinical data of NPS-induced neurotoxicity translate to humans.


Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Alucinógenos/toxicidade , Síndromes Neurotóxicas/patologia , Psicotrópicos/toxicidade , Animais , Estimulantes do Sistema Nervoso Central/metabolismo , Alucinógenos/metabolismo , Humanos , Síndromes Neurotóxicas/metabolismo , Psicotrópicos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/toxicidade
7.
Int J Mol Sci ; 22(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064332

RESUMO

Spinal cord injury (SCI) leads to numerous chronic and debilitating functional deficits that greatly affect quality of life. While many pharmacological interventions have been explored, the current unsurpassed therapy for most SCI sequalae is exercise. Exercise has an expansive influence on peripheral health and function, and by activating the relevant neural pathways, exercise also ameliorates numerous disorders of the central nervous system (CNS). While the exact mechanisms by which this occurs are still being delineated, major strides have been made in the past decade to understand the molecular underpinnings of this essential treatment. Exercise rapidly and prominently affects dendritic sprouting, synaptic connections, neurotransmitter production and regulation, and ionic homeostasis, with recent literature implicating an exercise-induced increase in neurotrophins as the cornerstone that binds many of these effects together. The field encompasses vast complexity, and as the data accumulate, disentangling these molecular pathways and how they interact will facilitate the optimization of intervention strategies and improve quality of life for individuals affected by SCI. This review describes the known molecular effects of exercise and how they alter the CNS to pacify the injury environment, increase neuronal survival and regeneration, restore normal neural excitability, create new functional circuits, and ultimately improve motor function following SCI.


Assuntos
Exercício Físico , Regulação da Expressão Gênica , Regeneração Nervosa/genética , Plasticidade Neuronal/genética , Recuperação de Função Fisiológica/genética , Traumatismos da Medula Espinal/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Humanos , Neurotrofina 3/genética , Neurotrofina 3/metabolismo , Qualidade de Vida , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo , Transdução de Sinais , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/reabilitação , Simportadores/genética , Simportadores/metabolismo
8.
J Med Chem ; 64(10): 6937-6948, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33887904

RESUMO

The activation of cannabinoid CB1 receptors (CB1R) by Δ9-tetrahydrocannabinol (THC), the main component of Cannabis sativa, induces analgesia. CB1R activation, however, also causes cognitive impairment via the serotonin 5HT2A receptor (5HT2AR), a component of a CB1R-5HT2AR heteromer, posing a serious drawback for cannabinoid therapeutic use. We have shown that peptides reproducing CB1R transmembrane (TM) helices 5 and 6, fused to a cell-penetrating sequence (CPP), can alter the structure of the CB1R-5HT2AR heteromer and avert THC cognitive impairment while preserving analgesia. Here, we report the optimization of these prototypes into drug-like leads by (i) shortening the TM5, TM6, and CPP sequences, without losing the ability to disturb the CB1R-5HT2AR heteromer, and (ii) extensive sequence remodeling to achieve protease resistance and blood-brain barrier penetration. Our efforts have culminated in the identification of an ideal candidate for cannabis-based pain management, an orally active 16-residue peptide preserving THC-induced analgesia.


Assuntos
Analgésicos/química , Cannabis/química , Peptídeos/química , Administração Oral , Sequência de Aminoácidos , Analgésicos/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Canabinoides/química , Canabinoides/farmacologia , Cannabis/metabolismo , Dimerização , Camundongos , Camundongos Endogâmicos ICR , Simulação de Dinâmica Molecular , Dor/tratamento farmacológico , Dor/patologia , Peptídeos/metabolismo , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2A de Serotonina/metabolismo
9.
Acta Pharmacol Sin ; 42(6): 885-897, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33782540

RESUMO

Hypertension is a serious public health problem worldwide. MT-1207, chemically named 3-(4-(4-(1H-benzotriazole-1-yl)butyl)piperazine-1-yl) benzisothiazole hydrochloride, is a new chemical entity that has entered into clinical trial as antihypertensive agent in China. In this paper we report the pharmacological profile of MT-1207 regarding its acute, subacute, and long-term effects on hypertensive animal models, and its actions on isolated organs in vitro as well as its molecular targets. Blood pressure (BP) was measured in conscious animals; amlodipine was taken as a positive control drug. We showed that both single dose of MT-1207 (1.25-20 mg/kg, ig) in spontaneously hypertensive rats (SHR) and MT-1207 (0.25-6 mg/kg, ig) in two-kidney one-clip (2K1C) dogs dose-dependently decreased BP. MT-1207 quickly decreased BP within 5 min after administration; the hypotensive effect lasted for 8 and 12 h, respectively, in SHR and 2K1C dogs without reflex increase in heart rate. Multiple doses of MT-1207 (5 mg · kg-1 · d-1 in SHR; 2 mg · kg-1 · d-1 in 2K1C dogs, for 7 days) significantly decreased BP, slightly reduced heart rate, and both of them recovered after withdrawal. Long-term administration of MT-1207 (10 mg · kg-1 · d-1 for 4 months or more time) produced a stable BP reduction, improved baroreflex sensitivity, reduced renal and cardiovascular damage in SHR, and delayed stroke occurrence and death in stroke-prone SHR. In isolated rat aortic rings precontracted by adrenaline, KCl, noradrenaline or 5-hydroxytryptamine (5-HT), MT-1207 (10-9-10-4 M) caused concentration-dependent relaxation. In a panel of enzyme activity or radioligand binding assays of 87 molecular targets, MT-1207 potently inhibited adrenergic α1A, α1B, α1D, and 5-HT2A receptors with Ki < 1 nM. The antagonism of MT-1207 against these receptors was confirmed in isolated rabbit arteries. We conclude that MT-1207 is a novel and promising single-molecule multitarget agent for hypertension treatment to reduce hypertensive organ damage and stroke mortality.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Tiazóis/uso terapêutico , Triazóis/uso terapêutico , Animais , Anti-Hipertensivos/metabolismo , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cães , Eletrocardiografia/efeitos dos fármacos , Feminino , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/mortalidade , Masculino , Simulação de Acoplamento Molecular , Coelhos , Ratos Endogâmicos SHR , Receptor 5-HT2A de Serotonina/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Acidente Vascular Cerebral/mortalidade , Tiazóis/metabolismo , Triazóis/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatadores/metabolismo , Vasodilatadores/uso terapêutico
10.
Elife ; 102021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33789079

RESUMO

Serotonin (5-HT) is one of the major neuromodulators present in the mammalian brain and has been shown to play a role in multiple physiological processes. The mechanisms by which 5-HT modulates cortical network activity, however, are not yet fully understood. We investigated the effects of 5-HT on slow oscillations (SOs), a synchronized cortical network activity universally present across species. SOs are observed during anesthesia and are considered to be the default cortical activity pattern. We discovered that (±)3,4-methylenedioxymethamphetamine (MDMA) and fenfluramine, two potent 5-HT releasers, inhibit SOs within the entorhinal cortex (EC) in anesthetized mice. Combining opto- and pharmacogenetic manipulations with in vitro electrophysiological recordings, we uncovered that somatostatin-expressing (Sst) interneurons activated by the 5-HT2A receptor (5-HT2AR) play an important role in the suppression of SOs. Since 5-HT2AR signaling is involved in the etiology of different psychiatric disorders and mediates the psychological effects of many psychoactive serotonergic drugs, we propose that the newly discovered link between Sst interneurons and 5-HT will contribute to our understanding of these complex topics.


Assuntos
Córtex Entorrinal/fisiologia , Interneurônios/fisiologia , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo , Animais , Camundongos
11.
Int J Mol Sci ; 22(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33672070

RESUMO

Serotonin communication operates mainly in the extracellular space and cerebrospinal fluid (CSF), using volume transmission with serotonin moving from source to target cells (neurons and astroglia) via energy gradients, leading to the diffusion and convection (flow) of serotonin. One emerging concept in depression is that disturbances in the integrative allosteric receptor-receptor interactions in highly vulnerable 5-HT1A heteroreceptor complexes can contribute to causing major depression and become novel targets for the treatment of major depression (MD) and anxiety. For instance, a disruption and/or dysfunction in the 5-HT1A-FGFR1 heteroreceptor complexes in the raphe-hippocampal serotonin neuron systems can contribute to the development of MD. It leads inter alia to reduced neuroplasticity and potential atrophy in the raphe-cortical and raphe-striatal 5-HT pathways and in all its forebrain networks. Reduced 5-HT1A auto-receptor function, increased plasticity and trophic activity in the midbrain raphe 5-HT neurons can develop via agonist activation of allosteric receptor-receptor interactions in the 5-HT1A-FGFR1 heterocomplex. Additionally, the inhibitory allosteric receptor-receptor interactions in the 5-HT1AR-5-HT2AR isoreceptor complex therefore likely have a significant role in modulating mood, involving a reduction of postjunctional 5-HT1AR protomer signaling in the forebrain upon activation of the 5-HT2AR protomer. In addition, oxytocin receptors (OXTRs) play a significant and impressive role in modulating social and cognitive related behaviors like bonding and attachment, reward and motivation. Pathological blunting of the OXTR protomers in 5-HT2AR and especially in 5-HT2CR heteroreceptor complexes can contribute to the development of depression and other types of psychiatric diseases involving disturbances in social behaviors. The 5-HTR heterocomplexes are novel targets for the treatment of MD.


Assuntos
Depressão/metabolismo , Transtorno Depressivo Maior/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Serotonina/metabolismo , Transdução de Sinais , Animais , Humanos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Receptores de Ocitocina/metabolismo
12.
Biol Pharm Bull ; 44(2): 238-244, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33518675

RESUMO

Mirtazapine (MTZ) is a noradrenergic and specific serotonergic antidepressant. MTZ is reportedly associated with an increased risk of bleeding. However, the underlying mechanism remains unclear. In this study, we investigated the antiplatelet effect of MTZ in mice via light transmission aggregometry to elucidate the mechanism of MTZ-induced bleeding. The results of the ex vivo study showed that the oral administration of MTZ (20 or 100 mg/kg) significantly suppressed platelet aggregation mediated by the synergic interaction of 5-hydroxytryptamine (5-HT) and adrenaline. Additionally, MTZ significantly suppressed platelet aggregation, mediated by the synergic interaction of ADP and 5-HT or adrenaline. Similar results were obtained in vitro, under the condition of 5-HT- and adrenaline-induced platelet aggregation. Overall, the results suggest that MTZ exerts antiplatelet effect by co-blocking 5-HT2A and α2-adrenergic receptors on platelets and suppresses platelet aggregation mediated by ADP, increased by either 5-HT or adrenaline. Thus, a detailed monitoring of bleeding is recommended for patients taking MTZ.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Mirtazapina/efeitos adversos , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor 5-HT2 de Serotonina/efeitos adversos , Administração Oral , Antagonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Epinefrina/metabolismo , Masculino , Camundongos , Mirtazapina/administração & dosagem , Modelos Animais , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Succinatos/administração & dosagem , Ioimbina/administração & dosagem
13.
J Pharmacol Sci ; 145(3): 289-295, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33602510

RESUMO

Gastrodin (Gas) represents the major active component of Gastrodia elata, a Chinese herb. Clinically, Gas is widely used for its sedative, anticonvulsive and neuroprotective properties. This work aimed to assess Gas for its efficacy in Tourette Syndrome (TS) treatment. Twenty-four rats were randomized to the blank control (n = 6) and experimental (n = 18) groups. The experimental group was administered continuous injection of 3, 3'-iminodipropionitrile (IDPN) intraperitoneally for 7 days, and subdivided into the IDPN + NS, IDPN + Hal, and IDPN + Gas groups (n = 6). The control and IDPN + NS groups received saline intragastrically, while the IDPN + Hal and IDPN + Gas groups were administered Gas and Haloperidol, respectively, for 8 weeks. Then, micro-positron emission tomography (PET) was performed for measuring the density and brain distribution of dopamine D2 receptors (D2Rs), dopamine transporters (DATs), 5-HT2A receptors (5-HT2ARs) and 5-HT transporters (SERTs). According to stereotypical behavior experiments, IDPN significantly induced abnormal stereotypical behaviors in rats in comparison with control animals. In addition, micro-PET revealed that by reducing the amounts of D2Rs and increasing those of DATs, Gas could significantly reduce stereotypical TS-like behaviors in this rat model system. Furthermore, Gas treatment reduced the density of SERTs, which could indirectly decrease DA release. The current study demonstrated that Gas could be effective in treating TS.


Assuntos
Álcoois Benzílicos/administração & dosagem , Álcoois Benzílicos/farmacologia , Dopamina/metabolismo , Glucosídeos/administração & dosagem , Glucosídeos/farmacologia , Fitoterapia , Serotonina/metabolismo , Síndrome de Tourette/tratamento farmacológico , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Gastrodia/química , Masculino , Imagem Molecular , Tomografia por Emissão de Pósitrons , Ratos Wistar , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Síndrome de Tourette/diagnóstico por imagem , Síndrome de Tourette/metabolismo
14.
Biochem Pharmacol ; 185: 114440, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33539816

RESUMO

Antipsychotic drugs remain the current standard for schizophrenia treatment. Although they directly recognize the orthosteric binding site of numerous monoaminergic G protein-coupled receptors (GPCRs), these drugs, and particularly second-generation antipsychotics such as clozapine, all have in common a very high affinity for the serotonin 5-HT2A receptor (5-HT2AR). Using classical pharmacology and targeted signaling pathway assays, previous findings suggest that clozapine and other atypical antipsychotics behave principally as 5-HT2AR neutral antagonists and/or inverse agonists. However, more recent findings showed that antipsychotics may also behave as pathway-specific agonists. Reversible phosphorylation is a common element in multiple signaling networks. Combining a quantitative phosphoproteomic method with signaling network analysis, we tested the effect of clozapine treatment on the overall level of protein phosphorylation and signal transduction cascades in vitro in mammalian cell lines induced to express either the human 5-HT2AR or the H452Y variant of the gene encoding the 5-HT2AR receptor. This naturally occurring variation within the 5-HT2AR gene was selected because it has been repeatedly associated with schizophrenia patients who do not respond to clozapine treatment. Our data show that short time exposure (5 or 10 min) to clozapine (10-5 M) led to phosphorylation of numerous signaling components of pathways involved in processes such as endocytosis, ErbB signaling, insulin signaling or estrogen signaling. Cells induced to express the H452Y variant showed a different basal phosphoproteome, with increases in the phosphorylation of mTOR signaling components as a translationally relevant example. However, the effect of clozapine on the functional landscape of the phosphoproteome was significantly reduced in cells expressing the 5-HT2AR-H452Y construct. Together, these findings suggest that clozapine behaves as an agonist inducing phosphorylation of numerous pathways downstream of the 5-HT2AR, and that the single nucleotide polymorphism encoding 5-HT2AR-H452Y affects these clozapine-induced phosphorylation-dependent signaling networks.


Assuntos
Clozapina/metabolismo , Histamina/genética , Polimorfismo de Nucleotídeo Único/genética , Proteômica/métodos , Receptor 5-HT2A de Serotonina/genética , Tirosina/genética , Membrana Celular/efeitos dos fármacos , Membrana Celular/genética , Membrana Celular/metabolismo , Clozapina/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Histamina/metabolismo , Humanos , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Tirosina/metabolismo
15.
Neuropharmacology ; 186: 108465, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33485945

RESUMO

Antagonising the serotonin 2A (5-HT2A) receptor is an efficacious way to alleviate dyskinesia and psychosis in Parkinson's disease (PD). However, previous research indicates that there might be a limit to the effects conferred by this approach. 5-HT2A receptors were shown to form hetero-dimers with metabotropic glutamate 2 (mGlu2) receptors, in which 5-HT2A blockade and mGlu2 activation elicit equivalent effects at the downstream signalling level. We have previously shown that mGlu2 activation reduces both dyskinesia and psychosis-like behaviours (PLBs) induced by L-3,4-dihydroxyphenylalanine (l-DOPA), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Here, we hypothesised that concurrent 5-HT2A antagonism and mGlu2 activation would provide greater anti-dyskinetic and anti-psychotic benefits than either approach alone. We conducted 3 series of experiments in the MPTP-lesioned marmoset. In the first series of experiments, the mGlu2 positive allosteric modulator LY-487,379 and the 5-HT2A antagonist EMD-281,014, either alone or in combination, were added to l-DOPA. In the second series of experiments, the mGlu2/3 orthosteric agonist LY-354,740 and EMD-281,014, either alone or in combination, were added to l-DOPA. In the last series of experiments, we investigated whether mGlu2 blockade would diminish the effects of antagonising 5-HT2A receptors. To this end, the mGlu2/3 orthosteric antagonist LY-341,495 and EMD-281,014, either alone or in combination, were added to l-DOPA. We found that the anti-dyskinetic effect of the combination LY-487,379/EMD-281,014 was greater than the ones conferred by LY-487,379 (by 35%, P < 0.05) and EMD-281,014 (by 38%, P < 0.01). The anti-dyskinetic and anti-psychotic effects of the combination LY-354,740/EMD-281,014 were also greater than the ones conferred by LY-354,740 (by 57% for dyskinesia and 54% for PLBs, both P < 0.001) and EMD-281,014 (by 61% for dyskinesia and 53% for PLBs, both P < 0.001). The anti-parkinsonian action of l-DOPA was maintained with all treatments. Lastly, the addition of LY-341,495 abolished the therapeutic effects of EMD-281,014 on dyskinesia and PLBs. Our results suggest that mGlu2 activation may enhance the anti-dyskinetic and anti-psychotic effects of 5-HT2A blockade and could provide relief to PD patients with dyskinesia and psychotic symptoms beyond what can be achieved with current therapies.


Assuntos
Discinesia Induzida por Medicamentos/tratamento farmacológico , Indóis/administração & dosagem , Transtornos Parkinsonianos/tratamento farmacológico , Piperazinas/administração & dosagem , Psicoses Induzidas por Substâncias/tratamento farmacológico , Piridinas/administração & dosagem , Receptores de Glutamato Metabotrópico/agonistas , Sulfonamidas/administração & dosagem , Animais , Callithrix , Quimioterapia Combinada , Discinesia Induzida por Medicamentos/metabolismo , Feminino , Masculino , Transtornos Parkinsonianos/metabolismo , Psicoses Induzidas por Substâncias/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Resultado do Tratamento
16.
Sci Rep ; 11(1): 1670, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462318

RESUMO

The serotonin transporter (SLC6A4), 5-HT2A (HTR2A) and 5-HT2B (HTR2B) recepter genes, express proteins that are important regulators of serotonin reuptake and signaling, and thereby may contribute to the pathogenesis of aggressive criminal behavior. 370 sentenced murderers in Pakistani prisons and 359 men without any history of violence or criminal delinquency were genotyped for six candidate polymorphisms in SLC6A4, HTR2A and HTR2B genes. An association of higher expressing L/L and LA/LA variants of the 5-HTTLPR polymorphism was observed with homicidal behavior (bi-allelic: OR = 1.29, p = 0.016, tri-allelic: OR = 1.32, p = 0.015) and in the murderer group only with response to verbal abuse (OR = 2.11, p = 0.015), but not with other measures of self-reported aggression. L/L and LA/LA genotypes of the 5-HTTLPR polymorphism were associated with higher aggression scores on STAX1 scale of aggression compared to lower expressing genotypes (S/S, S/LG, LG/LG) in prison inmates. No associations were apparent for other serotonergic gene polymorphisms analyzed. Using the Braineac and GTEx databases, we demonstrated significant eQTL based functional effects for rs25531 in HTTLPR and other serotonergic polymorphisms analyzed in different brain regions and peripheral tissues. In conclusion, these findings implicate SLC6A4* HTTLPR as a major genetic determinant associated with criminal aggression. Future studies are needed to replicate this finding and establish the biologic intermediate phenotypes mediating this relationship.


Assuntos
Agressão/fisiologia , Comportamento Criminoso/fisiologia , Homicídio/estatística & dados numéricos , Prisioneiros/estatística & dados numéricos , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Serotonina/metabolismo , Adulto , Agressão/psicologia , Homicídio/psicologia , Humanos , Masculino , Paquistão , Polimorfismo de Nucleotídeo Único , Prisioneiros/psicologia , Prisões , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/genética , Receptor 5-HT2B de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
17.
Sci Rep ; 11(1): 1149, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441874

RESUMO

Bladder and bowel dysfunction (BBD) is a common yet underdiagnosed paediatric entity that describes lower urinary tract symptoms (LUTS) accompanied by abnormal bowel patterns manifested as constipation and/or encopresis. LUTS usually manifest as urgency, urinary frequency, incontinence, and urinary tract infections (UTI). Despite increasing recognition of BBD as a risk factor for long-term urinary tract problems including recurrent UTI, vesicoureteral reflux, and renal scarring, the mechanisms underlying BBD have been unclear, and treatment remains empirical. We investigated how constipation affects the lower urinary tract function using a juvenile murine model of functional constipation. Following four days of functional constipation, animals developed LUTS including urinary frequency and detrusor overactivity evaluated by awake cystometry. Physiological examination of detrusor function in vitro using isolated bladder strips, demonstrated a significant increase in spontaneous contractions without affecting contractile force in response to electrical field stimulation, carbachol, and KCl. A significant upregulation of serotonin receptors, Htr2a and Htr2c, was observed in the bladders from mice with constipation, paralleled with augmented spontaneous contractions after pre-incubation of the bladder strips with 0.5 µM of serotonin. These results suggest that constipation induced detrusor overactivity and increased excitatory serotonin receptor activation in the urinary bladder, which contributes to the development of BBD.


Assuntos
Canais de Cálcio/metabolismo , Constipação Intestinal/complicações , Receptor 5-HT2A de Serotonina/metabolismo , Transdução de Sinais , Canais de Cátion TRPV/metabolismo , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária/fisiopatologia , Animais , Constipação Intestinal/metabolismo , Constipação Intestinal/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Bexiga Urinária/metabolismo , Bexiga Urinária Hiperativa/metabolismo , Bexiga Urinária Hiperativa/fisiopatologia
18.
Int J Mol Sci ; 22(2)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467676

RESUMO

A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n = 6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n = 6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [3H]UCB-J (SV2A), [3H]MDL100907 (5-HT2AR antagonist) and [3H]Cimbi-36 (5-HT2AR agonist). One day post psilocybin injection, we observed 4.42% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (-15.21% to -50.19%). These differences were statistically significant in the hippocampus for all radioligands and in the PFC for [3H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in the hippocampus (+9.24%) and the PFC (+6.10%), whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin causes increased persistent synaptogenesis and an acute decrease in 5-HT2AR density, which may play a role in psilocybin's antidepressive effects.


Assuntos
Encéfalo/efeitos dos fármacos , Psilocibina/administração & dosagem , Receptor 5-HT2A de Serotonina/metabolismo , Sinapses/efeitos dos fármacos , Animais , Antidepressivos/administração & dosagem , Autorradiografia , Feminino , Alucinógenos/administração & dosagem , Hipocampo/efeitos dos fármacos , Ligantes , Córtex Pré-Frontal/efeitos dos fármacos , Suínos
19.
Nature ; 589(7842): 474-479, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33299186

RESUMO

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.


Assuntos
Comportamento Aditivo/tratamento farmacológico , Desenho de Fármacos , Ibogaína/análogos & derivados , Ibogaína/efeitos adversos , Alcoolismo/tratamento farmacológico , Animais , Antidepressivos/farmacologia , Arritmias Cardíacas/induzido quimicamente , Técnicas de Química Sintética , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Alucinógenos/efeitos adversos , Dependência de Heroína/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Segurança do Paciente , Receptor 5-HT2A de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Natação , Tabernaemontana/química
20.
J Ethnopharmacol ; 267: 113619, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33248185

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The aerial parts of Tilia americana var. mexicana (Malvaceae, formerly Tiliaceae) or "sirimo" are used in Mexican traditional medicine for the relief of mild symptoms of mental stress, commonly referred to as "nerve diseases". Individuals use this plant to fall asleep, to calm states of nervous excitement, headaches, mood disorders, and general discomfort. Recent studies indicated that fractions standardized in their flavonoid content possess antidepressant activity in behavioral assays in mice. The present study aims to focus on the evaluation of the antidepressant effect of the mixture of two flavonoids (FMix), and its interaction with serotonergic drugs. Also, the pharmacological effect of the products of the metabolism of aglycone, quercetin, was evaluated in mice subjected to forced swimming test (FST) and open field test (OFT). MATERIALS AND METHODS: A methanol-soluble extract obtained from leaves of Tilia americana was fractionated in an open column chromatographic separation. One of the fractions contained FMix wich is constituted of the mixture of quercetin 4'-O-rhamnoside (1, 47%) y isoquercitrin (2, 53%). The mice were divided into the several following groups: FMix (0.01, 0.1, 0.5, 1.0, and 2 mg/kg); FMix (1.0 mg/kg) and agonist DOI (2.0 mg/kg); FMix (1.0 mg/kg) and antagonist ketanserin (KET, 0.03 mg/kg) of 5-HT2A receptors; FMix (1.0 mg/kg) and selective agonist 8-OH-DPAT (8-OH, 0.01 mg/kg); FMix (1.0 mg/kg) and antagonist WAY100635 (WAY, 0.5 mg/kg) of 5HT1 receptors; Phloroglucinol (PHL); 3,4-dihydroxy-phenyl acid (DOPAC); p-hydroxyphenyl acetic acid (p-HPAA); and m-hydroxyphenyl acetic acid (m-HPAA) were tested in FST or OFT. RESULTS: FMix induced dependent-dose antidepressant activity and, at the highest dose administered, a sedative effect was also observed. The 8-OH-DPAT, or the DOI, or the KET combination with FMix (1.0 mg/kg) induced a higher antidepressant effect than compounds alone; there was no effect exerted with WAY. The activity on OFT increased only with the FMix and KET combination. At the same time, the products of the aglycone metabolism of quercetin, that is, DOPAC and p-HPAA, decreased the immobility time of the mice in FST at 1.0 mg/kg, and a dose-curve was formed for these. CONCLUSION: The antidepressant effect of FMix could depend, at least in part, on the degradation products of quercetin and with a possible action mode through interaction with the serotoninergic system.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Depressão/prevenção & controle , Extratos Vegetais/farmacologia , Quercetina/análogos & derivados , Neurônios Serotoninérgicos/efeitos dos fármacos , Tilia , Animais , Antidepressivos/isolamento & purificação , Antidepressivos/metabolismo , Biotransformação , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Depressão/metabolismo , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Quercetina/isolamento & purificação , Quercetina/metabolismo , Quercetina/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Tilia/química
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