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1.
Molecules ; 26(4)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673167

RESUMO

The leaves of Homalomena aromatica are traditionally used in Bangladesh for the treatment of different chronic ailments. The purpose of this study was to explore in vitro antioxidant, thrombolytic activities, and in vivo neuropharmacological effects of methanolic extract of Homalomena aromatica (MEHA) leaves. Antioxidant activity of MEHA was assessed by a DPPH free radical scavenging assay and total phenolics content, total flavonoids content were also measured. The thrombolytic activity was determined by percentage of clot lysis and neuropharmacological activities by hole board, tail suspension, forced swimming and elevated plus maze tests. The results showed that the IC50 value of the extract against DPPH was 199.51 µg/mL. Quantitative analysis displayed higher contents of phenolics and flavonoids (147.71 mg gallic acid equivalent/g & 66.65 mg quercetin equivalent/g dried extract, respectively). The extract also showed a significant clot lysis (33.31%) activity. In case of anxiolytic activity, the elevate plus maze (EPM) test demonstrated an increase in time spent in open arms, and in case of hole board test, the number of head dipping was also significantly increased (p < 0.05). All the test compared with control (1% Tween in water) and standard (diazepam 1 mg/kg), significant dose (200 & 400 mg/kg) dependent anxiolytic activity was found. In antidepressant activity, there was a significant decrease in period of immobility in both test models (tail suspension and forced swimming) (p < 0.05). Moreover, 13 compounds were identified as bioactive, showed good binding affinities to xanthine oxidoreductase, tissue plasminogen activator receptor, potassium channel receptor, human serotonin receptor targets in molecular docking experiments. Furthermore, ADME/T analysis revealed their drug-likeness, likely pharmacological actions and non-toxic upon consumption. Taken together, our finding support the traditional medicinal use of this plant, which may provide a potential source for future drug discovery.


Assuntos
Antioxidantes/química , Araceae/química , Fibrinolíticos/química , Extratos Vegetais/química , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Antioxidantes/farmacologia , Compostos de Bifenilo/química , Simulação por Computador , Tempo de Lise do Coágulo de Fibrina , Fibrinolíticos/farmacologia , Flavonoides/química , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Humanos , Camundongos , Simulação de Acoplamento Molecular , Neurofarmacologia , Fenóis/química , Picratos/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Receptores de Serotonina/química , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Natação
2.
Eur J Med Chem ; 214: 113243, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33582388

RESUMO

We have previously reported that dual 5-HT1A and 5-HT7 receptor ligands might find utility as treatment options for various CNS related conditions including cognitive and anxiolytic impairments. We have also more recently reported that SYA16263 has antipsychotic-like properties with an absence of catalepsy in animal models ascribed to its ability to recruit ß-arrestin to the D2 receptor. However, SYA16263 also binds with very high affinity to 5-HT1AR (Ki = 1.1 nM) and a moderate affinity at 5-HT7R (Ki = 90 nM). Thus, it was of interest to exploit its pharmacophore elements in designing new dual receptor ligands. Using SYA16263 as the lead molecule, we have conducted a limited structure-affinity relationship (SAFIR) study by modifying various structural elements in the arylalkyl moiety, resulting in the identification of a new dual 5-HT1AR and 5-HT7R ligand, 6-chloro-2-methyl-2-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-2,3-dihydro-1H-inden-1-one (21), which unlike SYA16263, has a sub-nanomolar (5-HT1AR, Ki = 0.74 nM) and a low nanomolar (5-HT7R, Ki = 8.4 nM) affinity for these receptors. Interestingly, 21 is a full agonist at 5-HT1AR and antagonist at the 5-HT7R, functional characteristics which point to its potential as an antidepressant agent.


Assuntos
Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Agonistas do Receptor 5-HT1 de Serotonina/síntese química , Agonistas do Receptor 5-HT1 de Serotonina/química , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Relação Estrutura-Atividade
3.
Parasit Vectors ; 14(1): 14, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407815

RESUMO

BACKGROUND: Serotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms. In addition to its role as a neurotransmitter, serotonin acts as a morphogen and regulates developmental processes. Although several studies have focused on the serotonergic nervous system in parasitic flatworms, little is known on the role of serotonin in flatworm development. METHODS: To study the effects of serotonin on proliferation and development of the cestode Echinococcus multilocularis, we cloned the genes encoding the E. multilocularis serotonin transporter (SERT) and tryptophan hydroxylase (TPH), analyzed gene expression by transcriptome analysis and whole mount in situ hybridization (WMISH) and performed cell culture experiments. RESULTS: We first characterized orthologues encoding the SERT and TPH, the rate-limiting enzyme in serotonin biosynthesis. WMISH and transcriptomic analyses indicated that the genes for both SERT and TPH are expressed in the parasite nervous system. Long-term treatment of parasite stem cell cultures with serotonin stimulated development towards the parasite metacestode stage. Mature metacestode vesicles treated with serotonin showed increased rates of incorporation of the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU), indicating stimulated cell proliferation. In contrast, treatment with the selective serotonin reuptake inhibitor paroxetine strongly affected the viability of parasite cells. Paroxetine also caused structural damage in metacestode vesicles, suggesting that serotonin transport is crucial for the integrity of parasite vesicles. CONCLUSIONS: Our results indicate that serotonin plays an important role in E. multilocularis development and proliferation, providing evidence that the E. multilocularis SERT and TPH are expressed in the nervous system of the protoscolex. Our results further suggest that the E. multilocularis SERT has a secondary role outside the nervous system that is essential for parasite integrity and survival. Since serotonin stimulated E. multilocularis metacestode development and proliferation, serotonin might also contribute to the formation and growth of the parasite in the liver.


Assuntos
Echinococcus multilocularis , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Triptofano Hidroxilase/metabolismo , Animais , Proliferação de Células , Echinococcus multilocularis/efeitos dos fármacos , Echinococcus multilocularis/crescimento & desenvolvimento , Echinococcus multilocularis/metabolismo , Expressão Gênica , Perfilação da Expressão Gênica , Proteínas de Helminto/genética , Proteínas de Helminto/metabolismo , Hibridização In Situ , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Larva/metabolismo , Sistema Nervoso/metabolismo , Paroxetina/farmacologia , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Triptofano Hidroxilase/genética
4.
J Med Chem ; 64(2): 1180-1196, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33439019

RESUMO

G-protein coupled receptors (GPCRs) exist in an equilibrium of multiple conformational states, including different active states, which depend on the nature of the bound ligand. In consequence, different conformational states can initiate specific signal transduction pathways. The study identified compound 7e, which acts as a potent 5-hydroxytryptamine type 6 receptor (5-HT6R) neutral antagonist at Gs and does not impact neurite growth (process controlled by Cdk5). MD simulations highlighted receptor conformational changes for 7e and inverse agonist PZ-1444. In cell-based assays, neutral antagonists of the 5-HT6R (7e and CPPQ), but not inverse agonists (SB-258585, intepirdine, PZ-1444), displayed glioprotective properties against 6-hydroxydopamine-induced and doxorubicin-induced cytotoxicity. These suggest that targeting the activated conformational state of the 5-HT6R with neutral antagonists implicates the protecting properties of astrocytes. Additionally, 7e prevented scopolamine-induced learning deficits in the novel object recognition test in rats. We propose 7e as a probe for further understanding of the functional outcomes of different states of the 5-HT6R.


Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Humanos , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/prevenção & controle , Masculino , Conformação Molecular , Neuritos/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade
5.
Int J Mol Sci ; 21(24)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33348850

RESUMO

Mitochondria in neurons contribute to energy supply, the regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability, and stress adaptation. In recent years, several studies have highlighted that the neurotransmitter serotonin (5-HT) plays an important role in mitochondrial biogenesis in cortical neurons, and regulates mitochondrial activity and cellular function in cardiomyocytes. 5-HT exerts its diverse actions by binding to cell surface receptors that are classified into seven distinct families (5-HT1 to 5-HT7). Recently, it was shown that 5-HT3 and 5-HT4 receptors are located on the mitochondrial membrane and participate in the regulation of mitochondrial function. Furthermore, it was observed that activation of brain 5-HT7 receptors rescued mitochondrial dysfunction in female mice from two models of Rett syndrome, a rare neurodevelopmental disorder characterized by severe behavioral and physiological symptoms. Our Western blot analyses performed on cell-lysate and purified mitochondria isolated from neuronal cell line SH-SY5Y showed that 5-HT7 receptors are also expressed into mitochondria. Maximal binding capacity (Bmax) obtained by Scatchard analysis on purified mitochondrial membranes was 0.081 pmol/mg of 5-HT7 receptor protein. Lastly, we evaluated the effect of selective 5-HT7 receptor agonist LP-211 and antagonist (inverse agonist) SB-269970 on mitochondrial respiratory chain (MRC) cytochrome c oxidase activity on mitochondria from SH-SY5Y cells. Our findings provide the first evidence that 5-HT7 receptor is also expressed in mitochondria.


Assuntos
Membranas Mitocondriais/metabolismo , Neuroblastoma/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Humanos , Membranas Mitocondriais/efeitos dos fármacos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Receptores de Serotonina/química , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Células Tumorais Cultivadas
6.
Artigo em Inglês | MEDLINE | ID: mdl-32479008

RESUMO

Glutamatergic N-methyl-D-aspartate (NMDA) receptors have critical roles in several neurological and psychiatric diseases. Dizocilpine (MK-801) is a ligand at phencyclidine recognition sites that is associated with NMDA receptor-coupled cation channels, where it acts as a potent noncompetitive antagonist of central glutamate receptors. In this study, we investigate the effect of clozapine on MK-801-induced neurochemical and neurobehavioral alterations in the prefrontal cortex of mice. Acute administration of NMDA noncompetitive antagonist MK-801 impairs motor coordination, grip strength, and locomotor activity. Clozapine is the only medication that is indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents; however, its mechanism is not well understood. To understand its mechanism, we investigated the effects of clozapine on motor coordination, locomotor activity, and grip strength in mice against the NMDA receptor antagonist MK-801. MK-801 induced elevations in acetylcholinesterase (AChE) activity, monoamine oxidase (MAO) activity, and c-fos expression. The administration of clozapine inhibited the effects caused by MK-801 (0.2 mg/kg body weight). Motor coordination and grip strength paradigms that had been altered by MK-801 were restored by clozapine. Moreover, clozapine also ameliorated MK-801-induced elevation in AChE and MAO activity. Our immunostaining results demonstrated that clozapine treatment reduced overexpression of the neuronal activity marker c-fos in cortices of the brain. Results of the current study determine that clozapine ameliorated cognition in MK-801-treated mice via cholinergic and neural mechanisms. These findings show that clozapine possesses the potential to augment cognition in diseases such as schizophrenia.


Assuntos
Clozapina/farmacologia , Maleato de Dizocilpina/toxicidade , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Antagonistas da Serotonina/farmacologia , Animais , Antipsicóticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/toxicidade , Masculino , Camundongos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/induzido quimicamente
7.
Psychopharmacology (Berl) ; 237(8): 2469-2483, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32445054

RESUMO

RATIONALE: MK801, like other NMDA receptor open-channel blockers (e.g., ketamine and phencyclidine), increases the locomotor activity of rats and mice. Whether this behavioral effect ultimately relies on monoamine neurotransmission is of dispute. OBJECTIVE: The purpose of this study was to determine whether these psychopharmacological effects and underlying neural mechanisms vary according to sex and age. METHODS: Across four experiments, male and female preweanling and adolescent rats were pretreated with vehicle, the monoamine-depleting agent reserpine (1 or 5 mg/kg), the dopamine (DA) synthesis inhibitor ∝-methyl-DL-p-tyrosine (AMPT), the serotonin (5-HT) synthesis inhibitor 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), or both AMPT and PCPA. The locomotor activity of preweanling and adolescent rats was then measured after saline or MK801 (0.3 mg/kg) treatment. RESULTS: As expected, MK801 increased the locomotor activity of all age groups and both sexes, but the stimulatory effects were significantly less pronounced in male adolescent rats. Preweanling rats and adolescent female rats were more sensitive to the effects of DA and 5-HT synthesis inhibitors, as AMPT and PCPA caused only small reductions in the MK801-induced locomotor activity of male adolescent rats. Co-administration of AMPT+PCPA or high-dose reserpine (5 mg/kg) treatment substantially reduced MK801-induced locomotor activity in both age groups and across both sexes. CONCLUSIONS: These results, when combined with other recent studies, show that NMDA receptor open-channel blockers cause pronounced age-dependent behavioral effects that can vary according to sex. The neural changes underlying these sex and age differences appear to involve monoamine neurotransmission.


Assuntos
Maleato de Dizocilpina/farmacologia , Dopamina/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Locomoção/fisiologia , Serotonina/fisiologia , Maturidade Sexual/fisiologia , Inibidores da Captação Adrenérgica/farmacologia , Fatores Etários , Animais , Animais Recém-Nascidos , Antagonistas de Dopamina/farmacologia , Feminino , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/farmacologia , Fatores Sexuais , Maturidade Sexual/efeitos dos fármacos
8.
J Nutr ; 150(7): 1966-1976, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32386234

RESUMO

BACKGROUND: L-tryptophan (Trp) has been reported to regulate gut immune responses during inflammation. However, the underlying mechanisms are largely unknown. OBJECTIVE: We investigated the role of Trp supplementation on the serotonin receptor (HTR)-mediated immune response in the colon of mice with dextran sodium sulfate (DSS)-induced colitis. METHODS: In Experiment 1, male C57BL/6 mice were randomly assigned to 1 of 4 groups: Control (Con) or L-Trp supplementation [0.1 mg/(g body weight·d) in drinking water] (Trp) with (+DSS) or without 2% DSS in drinking water from days 8 to 14 of the 17-d study. In Experiments 2 and 3, Trp + DSS (Expt. 2) or DSS (Expt. 3) mice were treated as described above and subcutaneously administered with HTR1A or HTR4 antagonists (or their combination) or an HTR2 agonist from days 8 to 14 of the 15-d study. Changes in immune cell phenotypes, inflammatory mediators, and related cell signaling molecules were assessed by flow cytometry, real-time PCR, or Western blot. The mRNA abundances of Trp hydroxylase (Tph1), serotonin reuptake transporter (Slc6a4), and Htr in the colon were also assessed. RESULTS: Trp supplementation before DSS treatment upregulated the expression of colonic Slc6a4 (0.49 compared with 0.30), Htr1a (1.14 compared with 0.65), and Htr4 (1.08 compared with 0.70), downregulated the expression of Htr2a (1.54 compared with 1.89), and decreased the colonic serotonin concentration (11.5 compared with 14.8 nmol/g tissue) (P < 0.01). Trp regulated the DSS-induced immune response partly through attenuating the activation of toll-like receptor 4 (TLR4)-STAT3 signaling and nucleus p-65. Either an HTR2 agonist or HTR1A and HTR4 antagonists reversed the effects of Trp. CONCLUSIONS: In mice treated with DSS, Trp supplementation before DSS administration improved colonic immune responses partly by reducing colonic serotonin and subsequent interactions with HTR1A and HTR4, which are known to be present on neutrophils and macrophages.


Assuntos
Colite/metabolismo , Colo/metabolismo , Sulfato de Dextrana/toxicidade , Suplementos Nutricionais , Homeostase/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Serotonina/metabolismo , Triptofano/farmacologia , Animais , Colite/induzido quimicamente , Dieta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piperazinas/farmacologia , Distribuição Aleatória , Antagonistas da Serotonina/administração & dosagem , Triptofano/administração & dosagem
9.
Poult Sci ; 99(5): 2708-2717, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32359608

RESUMO

Brooding behavior, a common characteristic of native breeds of the domestic chicken, is marked by elevated prolactin (PRL) levels, which is necessary for incubation and connected with changes in hypothalamic-pituitary-gonadal axis activity. Evidence indicates the serotoninergic system is a potent modulator of PRL secretion. The objective of this study is to investigate whether blocking serotonin synthesis with parachlorophenylalanine (PCPA) prevents incubation behavior in native Polish crested chickens. In addition, we examined the effect of PCPA on the gene expression of the gonadal and lactotrophic axes. Birds were stimulated to broodiness by artificial eggs in nests. At 34 wk of age (April: spring period), the hens were divided into 2 groups (14 hens in each group): control and PCPA-treated (50 mg/kg BW) group. After 5 wk of treatment, the artificial eggs were removed from the nests. Egg production, incubation activity, and levels of plasma ovarian steroids progesterone (P4), testosterone (T), estradiol (E2), and PRL were examined. At the end of the experiment (45 wk of age, June: summer period), ovarian characteristics and mRNA gene expression of gonadal (gonadotropin-releasing hormone [GnRH] I, luteinizing hormone [LH] ß, follicle-stimulating hormone [FSH] ß) and lactotrophic (vasoactive intestinal peptide [VIP], PRL) axes were measured by quantitative real-time PCR. Incubation activity was observed in the hens of both groups but with lower frequency in PCPA-treated birds. Moreover, the PCPA group had a higher cumulative egg production than the controls. During the first six and 8 wk of the experiment, levels of P4 and E2, respectively, were similar in both groups, but all concentrations increased in the PCPA-treated hens after this period. In addition, increased GnRH-I, LHß, and FSHß and decreased VIP mRNA expression was observed in the PCPA group compared with the controls. There were no differences in PRL mRNA expression, the PRL level, and ovarian morphometry between the 2 groups. These results indicate that blockage of serotonin synthesis by PCPA does not effectively prevent incubation in native Polish crested chickens. However, treatment with PCPA increased gonadal axis activity and improved reproductive performance.


Assuntos
Galinhas/fisiologia , Fenclonina/farmacologia , Lactotrofos/efeitos dos fármacos , Comportamento de Nidação/efeitos dos fármacos , Ovário/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Animais , Feminino , Lactotrofos/fisiologia , Ovário/fisiologia , Polônia , Serotonina/metabolismo
10.
Eur J Med Chem ; 193: 112214, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32182489

RESUMO

Schizophrenia is a chronic, disabling mental disorder that affects about one percent of world's population. Drugs acting on multiple targets have been demonstrated to provide superior efficacy in schizophrenia than agents acting on single target. In this study, based on FW01, a selective potent 5-HT1A receptor agonist discovered via dynamic pharmacophore-based virtual screening, molecular hybridization strategy was employed to optimize its in vitro activity over D2 and 5-HT2A receptors. The optimized compound 9f was found to show dual potent D2 and 5-HT2A receptors antagonistic activity. In addition, compound 9f showed good in vivo metabolic stability with t1/2 of 2 h in ICR mice and good capability to penetrate the blood-brain barrier with Kp value of 4.03. These results demonstrated that the dual D2 and 5-HT1A receptor antagonist 9f could serve as a promising lead compound to discover potent antipsychotic agents.


Assuntos
Antipsicóticos/farmacologia , Descoberta de Drogas , Piperidinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Antagonistas da Serotonina/farmacologia , Animais , Antipsicóticos/síntese química , Antipsicóticos/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Relação Estrutura-Atividade
11.
J Neuroinflammation ; 17(1): 53, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32050980

RESUMO

BACKGROUND: Atypical antipsychotic agents, such as clozapine, are used to treat schizophrenia and other psychiatric disorders by a mechanism that is believed to involve modulating the immune system. Multiple sclerosis is an immune-mediated neurological disease, and recently, clozapine was shown to reduce disease severity in an animal model of MS, experimental autoimmune encephalomyelitis (EAE). However, the mode of action by which clozapine reduces disease in this model is poorly understood. METHODS: Because the mode of action by which clozapine reduces neuroinflammation is poorly understood, we used the EAE model to elucidate the in vivo and in vitro effects of clozapine. RESULTS: In this study, we report that clozapine treatment reduced the infiltration of peripheral immune cells into the central nervous system (CNS) and that this correlated with reduced expression of the chemokines CCL2 and CCL5 transcripts in the brain and spinal cord. We assessed to what extent immune cell populations were affected by clozapine treatment and we found that clozapine targets the expression of chemokines by macrophages and primary microglia. Furthermore, in addition to decreasing CNS infiltration by reducing chemokine expression, we found that clozapine directly inhibits chemokine-induced migration of immune cells. This direct target on the immune cells was not mediated by a change in receptor expression on the immune cell surface but by decreasing downstream signaling via these receptors leading to a reduced migration. CONCLUSIONS: Taken together, our study indicates that clozapine protects against EAE by two different mechanisms; first, by reducing the chemoattractant proteins in the CNS; and second, by direct targeting the migration potential of peripheral immune cells.


Assuntos
Encéfalo/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Clozapina/farmacologia , Encefalomielite Autoimune Experimental/metabolismo , Medula Espinal/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CCL5/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Antagonistas da Serotonina/farmacologia , Medula Espinal/metabolismo
12.
Eur J Pharmacol ; 874: 173029, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32084419

RESUMO

Central post-stroke pain (CPSP) is a type of neuropathic pain for which the mechanism and relevant drug pathways remain unknown. Recently, it was reported that intracerebroventricular (ICV) administration of orexin-A suppresses pain and ischemia. In this study, we tested the role of orexin-A in CPSP induction in mice. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). CPSP was assessed by von Frey test. Colocalization of orexin 1 receptor (OX1R) with various neuron markers were determined by double-immunofluorescence. The hindpaw withdrawal responses to mechanical stimuli were significantly increased 3 days post-BCAO compared with those of sham groups. ICV injection of orexin-A dose-dependently suppressed BCAO-induced mechanical allodynia. These effects were inhibited by pre-treatment with SB334867 (an OX1R antagonist; ICV injection), yohimbine (a noradrenaline α2 receptor antagonist; intrathecal (IT) injection), and WAY100635 (a serotonin 5-HT1A receptor antagonist; IT injection), but not TCS OX2 29 (an OX2R antagonist; ICV injection). OX1R colocalized with TH (a noradrenergic neuron marker) and TPH (a serotonergic neuron marker) in the locus ceruleus (LC) and the rostral ventromedial medulla (RVM), respectively. The number of c-Fos positive cells in the LC and the RVM of BCAO mice was increased at 90 min after ICV injection of orexin-A compared to saline group. These results indicate that orexin-A/OX1R signaling plays an important role through activation of the descending pain control system in the induction of CPSP in mice.


Assuntos
Isquemia Encefálica/metabolismo , Hiperalgesia/metabolismo , Proteínas Mitocondriais/metabolismo , Neuralgia/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Benzoxazóis/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Isoquinolinas/farmacologia , Masculino , Camundongos , Proteínas Mitocondriais/antagonistas & inibidores , Naftiridinas/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Orexinas/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Antagonistas da Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ureia/análogos & derivados , Ureia/farmacologia , Ioimbina/farmacologia
13.
Psychopharmacology (Berl) ; 237(4): 957-966, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31897573

RESUMO

RATIONALE AND OBJECTIVES: Although clozapine is effective in treating schizophrenia, it is associated with adverse side effects including weight gain and metabolic syndrome. Despite this, the role of clozapine on feeding behaviour and food intake has not been thoroughly characterised. Clozapine has a broad pharmacological profile, with affinities for several neurotransmitter receptors, including serotonin (5-hydroxytriptamine, 5-HT) and histamine. Given that the serotonin 5-HT2C receptor and histaminergic H1 receptor are involved in aspects of feeding behaviour, the effect of clozapine on feeding may be linked to its action at these receptors. METHODS: We assessed, in rats, the effect of acute and subchronic administration of clozapine on responding for food under a progressive ratio (PR) schedule under conditions of food restriction and satiety. We also examined the effect of antagonists of the serotonin 5-HT2C and histaminergic H1 receptors on the same schedule. Clozapine reliably increased responding for food, even when rats had ad libitum access to food. The effect of clozapine on responding for food was reproduced by combined (but not individual) antagonism of the serotonin 5-HT2C and histaminergic H1 receptors. CONCLUSION: These findings show that clozapine enhances the motivation to work for food, that this effect is stable over repeated testing, and is independent of hunger state of the animal. This effect may relate to a combined action of clozapine at the serotonin 5-HT2C and histaminergic H1 receptors.


Assuntos
Antipsicóticos/farmacologia , Clozapina/farmacologia , Comportamento Alimentar/fisiologia , Motivação/fisiologia , Receptor 5-HT2C de Serotonina/fisiologia , Receptores 5-HT1 de Serotonina/fisiologia , Animais , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Ingestão de Alimentos/psicologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/psicologia , Masculino , Motivação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Esquema de Reforço , Antagonistas da Serotonina/farmacologia , Ganho de Peso/efeitos dos fármacos , Ganho de Peso/fisiologia
14.
J Pharmacol Sci ; 142(1): 26-33, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31786058

RESUMO

Cedrol, mainly derived from Juniperus virginiana L. essential oil, has been demonstrated the anxiolytic effect, although its mechanism of action is still not fully established. In the present study, male ICR mice were submitted to the elevated plus maze (EPM) and light-dark box (LDB) tests to investigate the putative mechanism of anxiolytic effect. WAY100635 (5-HT1A receptor antagonist), flumazenil (benzodiazepine receptor antagonist), SCH23390 (dopamine D1 receptor antagonist) or sulpiride (dopamine D2/D3 receptor antagonist) were used in the behavioral experiment to determine the mechanism of action of cedrol. Subsequently, the monoamine neurotransmitter levels were evaluated after behavioral tests. The data suggest that no significant effect in behavioral parameters were observed after sole intraperitoneal (i.p.) injection of antagonists compared to saline group. The anxiolytic effect of cedrol in behavioral procedures was blocked by either WAY100635 or flumazenil. The anxiolytic effect of cedrol (1200 mg/kg) was effectively antagonized by SCH23390 (0.125 mg/kg). Furthermore, cedrol decreased the DA and NE levels in hippocampus, striatum and hypothalamus. The present findings suggest that the dopaminergic system (D1 receptor) rather than serotoninergic or GABAergic system may potentially be involved in the modulation of cedrol-induced anxiolytic-like behaviors in mice.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Sesquiterpenos Policíclicos/farmacologia , Receptores Dopaminérgicos/metabolismo , Animais , Benzazepinas/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Flumazenil/farmacologia , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos ICR , Norepinefrina/metabolismo , Piperazinas/farmacologia , Piridinas/farmacologia , Antagonistas da Serotonina/farmacologia , Sulpirida/farmacologia
15.
Sci Rep ; 9(1): 18451, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804595

RESUMO

The ventral tegmental area (VTA) projection to the nucleus accumbens shell (NAcSh) regulates NAcSh-mediated motivated behaviors in part by modulating the glutamatergic inputs. This modulation is likely to be mediated by multiple substances released from VTA axons, whose phenotypic diversity is illustrated here by ultrastructural examination. Furthermore, we show in mouse brain slices that a brief optogenetic stimulation of VTA-to-NAc projection induced a transient inhibition of excitatory postsynaptic currents (EPSCs) in NAcSh principal medium spiny neurons (MSNs). This inhibition was not accompanied by detectable alterations in presynaptic release properties of electrically-evoked EPSCs, suggesting a postsynaptic mechanism. The VTA projection to the NAcSh releases dopamine, GABA and glutamate, and induces the release of other neuronal substrates that are capable of regulating synaptic transmission. However, pharmacological inhibition of dopamine D1 or D2 receptors, GABAA or GABAB receptors, NMDA receptors, P2Y1 ATP receptors, metabotropic glutamate receptor 5, and TRP channels did not prevent this short-term inhibition. These results suggest that an unknown mechanism mediates this form of short-term plasticity induced by the VTA-to-NAc projection.


Assuntos
Axônios/metabolismo , Ácido Glutâmico/metabolismo , Núcleo Accumbens/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Axônios/efeitos dos fármacos , Axônios/ultraestrutura , Antagonistas de Dopamina/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Antagonistas GABAérgicos/farmacologia , Masculino , Camundongos , Microscopia Eletrônica , Vias Neurais/citologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Vias Neurais/ultraestrutura , Optogenética , Antagonistas da Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/ultraestrutura
16.
Sci Rep ; 9(1): 20358, 2019 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-31885035

RESUMO

Serotonin (5-hydroxytryptamine: 5-HT) is a biogenic monoamine that mediates immune responses and modulates nerve signal in insects. Se-5HTR, a specific receptor of serotonin, has been identified in the beet armyworm, Spodoptera exigua. It is classified into subtype 7 among known 5HTRs. Se-5HTR was expressed in all developmental stages of S. exigua. It was expressed in all tested tissues of larval stage. Its expression was up-regulated in hemocytes and fat body in response to immune challenge. RNA interference (RNAi) of Se-5HTR exhibited significant immunosuppression by preventing cellular immune responses such as phagocytosis and nodulation. Treatment with an inhibitor (SB-269970) specific to 5HTR subtype 7 resulted in significant immunosuppression. Furthermore, knockout mutant of Se-5HTR by CRISPR-Cas9 led to significant reduction of phagocytotic activity of S. exigua hemocytes. Such immunosuppression was also induced by bacterial secondary metabolites derived from Xenorhabdus and Photorhabdus. To determine specific bacterial metabolites inhibiting Se-5HTR, this study screened 37 bacterial secondary metabolites with respect to cellular immune responses associated with Se-5HTR and selected 10 potent inhibitors. These 10 selected compounds competitively inhibited cellular immune responses against 5-HT and shared phenylethylamide (PEA) chemical skeleton. Subsequently, 46 PEA derivatives were screened and resulting potent chemicals were used to design a compound to be highly inhibitory against Se-5HTR. The designed compound was chemically synthesized. It showed high immunosuppressive activities along with specific and competitive inhibition activity for Se-5HTR. This study reports the first 5HT receptor from S. exigua and provides its specific inhibitor designed from bacterial metabolites and their derivatives.


Assuntos
Proteínas de Insetos/antagonistas & inibidores , Fenetilaminas/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Sequência de Aminoácidos , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/metabolismo , Sistemas CRISPR-Cas , Expressão Gênica , Hemócitos/metabolismo , Imunidade Celular , Larva , Fagocitose/genética , Fagocitose/imunologia , Fenetilaminas/química , Filogenia , Interferência de RNA , Receptores de Serotonina/genética , Metabolismo Secundário , Antagonistas da Serotonina/química
17.
Bull Exp Biol Med ; 168(2): 193-198, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31776959

RESUMO

Stimulation of the serotoninergic system (5-hydroxytryptophan, 50 mg/kg; fluoxetine, 3 mg/kg) induced a significant increase in HR and a reduction in the amplitude of all waves of the heart rhythm variability. Stimulation of the dopaminergic system (L-DOPA and amantadine, 20 mg/kg each) resulted in a moderate increase in HR and amplitudes of low-frequency (LF) and very-low-frequency (VLF) waves of the heart rhythm variability. Successive blockade of nicotinic (hexamethonium, 7 mg/kg) and muscarinic cholinergic receptors (atropine, 1 mg/kg) leads to a significant decrease in the variability of cardiointervals (almost to complete levelling) both under control conditions and after stimulation of the neurotransmitter systems. Serotonin receptor blockade (promethazine, 2 mg/kg) did not affect HR, but reduced the amplitude of LF- and VLF-waves. Under conditions of serotoninergic system stimulation, the blockade of serotonin receptors was followed by a significant HR acceleration without changes in heart rhythm variability; blockade of dopamine receptors (sulpiride, 1 mg/kg) induced HR acceleration and increase in the amplitude of LF- and VLF-waves; blockade of dopamine receptors under conditions of dopamine system stimulation was followed by a significant increase in HR and a decrease in the amplitude of all waves of the heart rhythm variability. It can be hypothesized that serotonin- and dopaminergic systems affect the heart rhythm via cardiomyocyte receptors and via modulation of activity of the adrenergic and cholinergic systems. The effects of serotonin- and dopaminergic systems can be considered as synergic in the CNS, and antagonistic at the periphery.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Neurotransmissores/farmacologia , Receptores de Neurotransmissores/efeitos dos fármacos , Neurônios Serotoninérgicos/fisiologia , Animais , Colina/antagonistas & inibidores , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Ratos , Receptores Dopaminérgicos/metabolismo , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Neurônios Serotoninérgicos/efeitos dos fármacos , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
18.
Neuroreport ; 30(18): 1316-1322, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31714483

RESUMO

Serotonin modulates cognitive processes and is related to various psychiatric disorders, including major depression. Administration of citalopram reduces the amplitude of auditory evoked potentials in depressed people and animal models, suggesting that 5-HT has an inhibitory role. Here, we characterize the modulation of excitatory post-synaptic currents by application of either 5-HT or agonists of 5-HT1A and 5-HT2 receptors, or by endogenous 5-HT evoked by citalopram on pyramidal neurons from layer II/III of rat auditory cortex. We found that application of 5-HT concentration-dependently reduces excitatory post-synaptic currents amplitude without changing the paired-pulse ratio, suggesting a post-synaptic modulation. We observed that selective agonists of 5-HT1A and 5-HT2 receptors [8-OH-DPAT (10 µM) and DOI (10 µM), respectively] mimic the effect of 5-HT on the excitatory post-synaptic currents. Effect of 5-HT was entirely blocked by co-application of the antagonists NAN-190 (1 µM) and ritanserin (200 nM). Similarly, citalopram application (1 µM) reduced the amplitude of the evoked excitatory post-synaptic currents. Reduction in the magnitude of the excitatory post-synaptic currents by endogenous 5-HT was interpolated in the dose-response curve elicited by exogenous 5-HT, yielding that citalopram raised the extracellular 5-HT concentration to 823 nM. Effect of citalopram was blocked by the previous application of NAN-190 but not ritanserin, indicating that citalopram reduces glutamatergic synaptic transmission via 5-HT1A receptors in layer II/III of the auditory cortex. These results suggest that the local activity of 5-HT contributes to decrease in the basal excitability of the auditory cortex for enhancing the detection of external relevant acoustic signals.


Assuntos
Córtex Auditivo/efeitos dos fármacos , Citalopram/farmacologia , Ácido Glutâmico/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Córtex Auditivo/metabolismo , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Masculino , Piperazinas/farmacologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Ratos , Ratos Wistar
19.
Molecules ; 24(22)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731603

RESUMO

The presence of dominant active compounds in standardised methanol extract from the leaves of Stizolophus balsamita (S. balsamita) was examined using HPLC with a diode-array detector. The extract and three dominant parthenolide derivatives were tested with Serotonin Research ELISA for their ability to inhibit the serotonin release from platelets. The antiserotonin effect of the extract was compared with that of parthenolide, a compound with proven antiserotonin and antimigraine effects. This study aimed to evaluate the ability of natural parthenolide derivatives to inhibit serotonin release from platelets. Izospiciformin, stizolin and stizolicin were analysed along with the standardised alcohol extract of S. balsamita leaves, which also contained four other parthenolide derivatives. All the analysed substances were found to inhibit serotonin release from platelets as compared with the control sample, which had 100% of serotonin released. Izospiciformin had the most significant impact (97.98% serotonin release inhibition). The effect of the methanol extract of S. balsamita on the serotonin release inhibition was also statistically significant.


Assuntos
Asteraceae/química , Plaquetas/metabolismo , Extratos Vegetais , Folhas de Planta/química , Antagonistas da Serotonina , Serotonina/metabolismo , Sesquiterpenos , Animais , Feminino , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia
20.
Eur J Pharmacol ; 864: 172718, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586629

RESUMO

Whereas the potential role of serotonin for the pathophysiology of irritable bowel syndrome (IBS) has since long been discussed, the possibility that 5-hydroxytryptamine 6 (5-HT6) receptors may serve as targets for the treatment of this condition has as yet not been explored. The aim of the current study was to assess to what extent defecation in rats is influenced by manipulation of 5-HT6 receptors. Reduced defecation following SB-399885 was observed in non-stressed animals assessed for 7 h after drug administration. While not impacting context-conditioned freezing, three 5-HT6 receptor antagonists (SB-399885, SB-271046 and SB-258585) also markedly reduced the number of faecal boli produced by rats exposed to context-conditioned fear. In contrast, a 5-HT6 receptor agonist, WAY-208466, influenced defecation neither in unstressed animals nor in rats experiencing conditioned fear stress. A clinical study on the possible effect of a 5-HT6 receptor antagonist in IBS with diarrhea appears warranted.


Assuntos
Defecação/efeitos dos fármacos , Diarreia/complicações , Diarreia/fisiopatologia , Síndrome do Intestino Irritável/complicações , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Animais , Condicionamento Psicológico/efeitos dos fármacos , Diarreia/tratamento farmacológico , Diarreia/psicologia , Medo/efeitos dos fármacos , Medo/psicologia , Masculino , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/uso terapêutico , Estresse Psicológico/psicologia
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