RESUMO
In women of fertile age with functional disorders of the autonomic nervous system (ANS), a complex of indicators of the immune and neurohumoral profile associated with polymorphic variants of the HTR2A (rs7997012) and TP53 (rs1042522) genes was revealed. In patients with the diagnosis "G90.8. Other disorders of the autonomic nervous system", the neurohumoral profile is characterized by excessive content of cortisol and serotonin (p<0.05), which indicates the development of the hypersympathicotonic variant of autonomic regulation disorders. The cellular immune profile in the examined individuals was characterized by a significant decrease in the content of CD3+CD4+ and CD3+CD8+ lymphocytes (p<0.05). At the same time hyperactivation of the humoral immune response was observed. In particular, we revealed enhanced production of IgG and IgM antibodies accompanied by increased count of CD19+ lymphocytes (p<0.05), which characterized clinical and laboratory manifestations of the asthenic syndrome. The women with ANS disorders had increased frequency of the G allele (OR=3.00; 95%CI 1.20-7.47) and GG genotype (OR=3.91; 95%CI 1.00-15.24) of the HTR2A (rs7997012) serotonin receptor gene, as well as the G allele (OR=1.93; 95%CI 1.04-3.57), CG genotype (OR=2.38; 95%CI 1.02-5.53) and the GG genotype (OR=1.48; 95%CI 0.42-5.24) of the TP53 (rs1042522) oncosuppressor protein gene (p<0.05). The polymorphic G allele and GG genotype variants of candidate genes (HTR2A (rs7997012) and TP53 (rs1042522) genes) in women with ANS pathology are associated with an imbalance of the neurohumoral (excess of cortisol and serotonin) and immune regulation (deficiency of the CD3+CD4+ and CD3+CD8+, excess of CD19+, IgG and IgM). These parameters form a complex of the immune, neurohumoral, and genetic profile indicators in women of fertile age that characterize functional disorders of ANS manifestations by hypersympathicotonic type with an asthenic component.
Assuntos
Doenças do Sistema Nervoso Autônomo , Polimorfismo de Nucleotídeo Único , Receptor 5-HT2A de Serotonina , Proteína Supressora de Tumor p53 , Doenças do Sistema Nervoso Autônomo/genética , Doenças do Sistema Nervoso Autônomo/imunologia , Feminino , Genótipo , Humanos , Hidrocortisona , Imunoglobulina G/genética , Imunoglobulina M/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/imunologia , Serotonina/metabolismo , Proteína Supressora de Tumor p53/genéticaRESUMO
Fine particulate matter (PM2.5 ) is an important environmental risk factor for cardiovascular diseases. However, little is known about the effects of PM2.5 on arteries. The present study investigated whether PM2.5 alters 5-hydroxytryptamine (5-HT) receptor expression and inflammatory mediators on rat mesenteric arteries, and examined the underlying mechanisms. Isolated rat mesenteric arteries segments were cultured with PM2.5 in the presence or absence of ERK1/2, JNK, and p38 pathway inhibitors. Contractile reactivity was monitored by a sensitive myograph. The expression of 5-HT2A/1B receptors and inflammatory mediators were studied by a real-time polymerase chain reaction and/or by immunohistochemistry. The phosphorylation of mitogen-activated protein kinases (MAPK) pathway was detected by Western blot. Compared with the fresh or culture alone groups, 1.0 µg/mL PM2.5 cultured for 16 hours significantly enhanced contractile response induced by 5-HT and increased 5-HT2A receptor mRNA and protein expressions, indicating PM2.5 upregulates 5-HT2A receptor. SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor) significantly decreased PM2.5 -induced elevated contraction and mRNA and protein expression of 5-HT2A receptor. Cultured with PM2.5 significantly increased the mRNA expression of inflammatory mediators (NOS2, IL-1ß, and TNF-α), while SB203580 decreased mRNA expression level of NOS2, IL-1ß, and TNF-α. SP600125 (JNK inhibitor) decreased mRNA expression level of TNF-α and IL-1ß. After PM2.5 exposure, the phosphorylation of p38 and ERK1/2 protein were increased. SB203580 and U0126 inhibited the PM2.5 caused increased phosphorylation protein of p38 and ERK1/2. In conclusion, PM2.5 induces inflammatory-mediated MAPK pathway in artery which subsequently results in enhanced vascular contraction responding to 5-HT via the upregulated 5-HT2A receptors.
Assuntos
Artérias Mesentéricas/imunologia , Proteínas Quinases Ativadas por Mitógeno/imunologia , Material Particulado/toxicidade , Receptor 5-HT2A de Serotonina/imunologia , Animais , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Artérias Mesentéricas/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Proteínas Quinases Ativadas por Mitógeno/genética , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/genética , Transdução de Sinais/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologiaRESUMO
Chronic methamphetamine (meth) abuse often turns into a compulsive drug-taking disorder accompanied by persistent cognitive deficits and re-occurring psychosis. Possible common neurobiological substrates underlying meth-induced deficits and schizophrenia remain poorly understood. Serotonin 2A (5-HT2A) and metabotropic glutamate 2 (mGlu2) receptors co-regulate psychosis-like behaviors and cognitive function in animals. Therefore, in the present study we examined the effects of chronic exposure to three different drugs known to produce persistent deficits in sensorimotor gating and cognition [meth, phencyclidine (PCP) and MK-801] on the expression of 5-HT2A and mGlu2 within the rat medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC) and perirhinal cortex (PRh). Adult male rats underwent 14â¯days of: (a) meth self-administration (6â¯h/day), (b) phencyclidine (PCP; 5â¯mg/kg, twice/day) administration, or (c) MK-801 (0.3â¯mg/kg, twice/day) administration. Seven days after the discontinuation of drug administration, tissues of interest were collected for protein expression analysis. We found that despite different pharmacological mechanism of action, chronic meth, PCP, and MK-801 similarly dysregulated 5-HT2A and mGlu2, as indicated by an increase in the 5-HT2A/mGlu2 expression ratio in the mPFC (all three tested drugs), PRh (meth and PCP), and dHPC (MK-801 only). Complementary changes in G-protein expression (increase in Gαq and decrease in Gαi) were also observed in the mPFC of meth animals. Finally, we found that 5-HT2A/mGlu2 cooperation can be mediated in part by the formation of the receptor heteromer in some, but not all cortical regions. In summary, these data suggest that a shift towards increased availability (and G-protein coupling) of cortical 5-HT2A vs. mGlu2 receptors may represent a common neurobiological mechanism underlying the emergence of psychosis and cognitive deficits observed in subjects with meth use disorder and schizophrenia.
Assuntos
Maleato de Dizocilpina/farmacologia , Metanfetamina/administração & dosagem , Córtex Perirrinal/efeitos dos fármacos , Fenciclidina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Anticorpos/imunologia , Imunoprecipitação , Masculino , Metanfetamina/farmacologia , Córtex Perirrinal/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Long-Evans , Ratos Wistar , Receptor 5-HT2A de Serotonina/imunologia , Reprodutibilidade dos TestesRESUMO
Experiments on CBA mice showed that selective stimulation of 2A serotonin receptors with DOI agonist (1 mg/kg) led to suppression of the immune response and reduction of the spleen and peripheral blood CD8(+)T cell counts with the cytotoxic/suppressor function. Selective blockade of these receptors with ketanserin (1 mg/kg) had an opposite effect: immunostimulation with an increase in CD8(+)T cell count in the spleen. These data indicate the involvement of 2A serotonin receptors in immunosuppressive mechanisms of serotoninergic system.
Assuntos
Anfetaminas/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Tolerância Imunológica/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/imunologia , Receptor 5-HT2A de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Análise de Variância , Animais , Citometria de Fluxo , Ketanserina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos CBA , Antagonistas da Serotonina/farmacologia , Baço/efeitos dos fármacos , Baço/imunologiaRESUMO
We studied the susceptibility of human embryonic stem cell-derived oligodendrocyte progenitor cells to infection with JC virus, the causative agent of progressive multifocal leukoencephalopathy (PML). A human embryonic stem cell line, H7, was used to derive an enriched population of cells expressing the oligodendrocyte progenitor cell-specific marker NG2. These cells expressed the 5HT2a receptor (5HT2aR) for JC virus and were highly susceptible to infection. Infection was reduced by treatment with anti-5HT2aR antibodies and by the 5HT2aR antagonists ritanserin and ketanserin. This is the first demonstration that human embryonic stem cell-derived oligodendrocyte progenitor cells are susceptible to JC virus infection and indicates that cells poised to replenish mature oligodendrocytes in PML lesions may also be a target of viral infection.
Assuntos
Células-Tronco Embrionárias/citologia , Vírus JC/fisiologia , Leucoencefalopatia Multifocal Progressiva/patologia , Leucoencefalopatia Multifocal Progressiva/virologia , Oligodendroglia/virologia , Receptor 5-HT2A de Serotonina/fisiologia , Anticorpos Monoclonais , Antígenos/metabolismo , Biomarcadores/metabolismo , Linhagem Celular , Feto/citologia , Humanos , Ketanserina/farmacologia , Leucoencefalopatia Multifocal Progressiva/genética , Proteoglicanas/metabolismo , Receptor 5-HT2A de Serotonina/imunologia , Ritanserina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina , Antagonistas da Serotonina/farmacologiaRESUMO
3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") is a psychoactive and hallucinogenic drug of abuse. MDMA has been shown to produce neurotoxicity both in animals and humans. MDMA and other amphetamines induce serotonergic and dopaminergic terminal neurotoxicity and also neurodegeneration in areas including the cortex, hippocampus, striatum and thalamus. Herein, we investigated the mechanisms involved in MDMA-induced neurotoxicity to neuronal serum free cultures from rat cortex. The hyperthermic effect produced by MDMA has been shown to be a clinically relevant aspect for the neurotoxic events. Thus, MDMA-induced toxicity to cortical neurons was evaluated both under normothermic (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Our findings showed that MDMA produced neuronal apoptosis, accompanied by activation of caspase 3, in a concentration dependent manner. MDMA neurotoxicity was completely prevented by pre-treatment with a 5-HT(2A)-receptor antibody, which acted as an "irreversible non-competitive antagonist" of this receptor. Furthermore, MDMA depleted intracellular glutathione (GSH) levels in a concentration dependent manner, an effect that was attenuated by Ketanserin, a competitive 5-HT(2A)-receptor antagonist. Accordingly, N-acetylcysteine, an antioxidant and GSH precursor, also reduced MDMA-induced toxicity. Specific inhibitors of the inducible and neuronal nitric oxide synthase (NOS) partially prevented MDMA neurotoxicity, ascertaining the involvement of reactive nitrogen species, in the toxic effect. In conclusion, direct MDMA 5-HT(2A)-receptor stimulation produces intracellular oxidative stress that leads to neuronal apoptosis accompanied by caspase 3 activation.
Assuntos
Apoptose/efeitos dos fármacos , Córtex Cerebral/citologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Neurônios/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/fisiologia , Serotoninérgicos/farmacologia , Animais , Anticorpos/farmacologia , Caspase 3/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Receptor 5-HT2A de Serotonina/imunologiaRESUMO
Atypical antipsychotics such as olanzapine have high affinity for multiple monoamine neurotransmitter receptors and are the mainstay of pharmacological therapy for treatment of schizophrenia. In addition to blocking monoamine receptors, these drugs also affect intracellular signaling cascades. We now report that 24-h treatment with 300 nM olanzapine causes desensitization of serotonin (5-HT)(2A) receptors in A1A1v cells, a rat cortical cell line, as indicated by a reduction in inositol phosphate accumulation following stimulation with a 5-HT(2A/2C) receptor agonist (-)-1-(2,5-dimethoxy-4-lodophenyl)-2-aminopropane HCl. Olanzapine treatment for 24 h increased the levels of 5-HT(2A) receptors in both cytosol (234 +/- 34% of control level) and membrane fractions (206 +/- 14% of control levels) and RGS7 proteins in both cytosol (193 +/- 32% of control levels) and membrane fractions (160 +/- 18% of control levels) as measured on Western blots. Increased phosphorylation of Janus tyrosine kinase (JAK) 2 and increased phosphorylation and nuclear translocation of signal transducer and activator of transcription (STAT) 3 with 24-h olanzapine treatment demonstrate activation of the JAK-STAT signaling cascade. Pretreatment with a JAK inhibitor, AG490 [alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide], prevented the olanzapine-induced increase in membrane RGS7 protein levels; AG490 alone had no effect on RGS7 protein levels. We verified that treatment with AG490 reduced phosphorylation of JAK2 and inhibited the nuclear localization of phospho-STAT3. Interestingly, treatment with the JAK inhibitor had no effect on 5-HT(2A) receptor protein levels. These data suggest that olanzapine-induced activation of the JAK-STAT signaling cascade causes increased expression of RGS7 protein, which in turn could mediate desensitization of 5-HT(2A) receptor signaling caused by olanzapine because RGS7 binds to Galpha(q) protein and accelerates GTP hydrolysis.
Assuntos
Antipsicóticos/farmacologia , Janus Quinases/fisiologia , Proteínas RGS/análise , Fatores de Transcrição STAT/fisiologia , Transdução de Sinais/fisiologia , Transporte Ativo do Núcleo Celular , Sequência de Aminoácidos , Animais , Benzodiazepinas/farmacologia , Linhagem Celular , Humanos , Fosfatos de Inositol/metabolismo , Janus Quinases/antagonistas & inibidores , Dados de Sequência Molecular , Olanzapina , Fosforilação , Proteínas RGS/genética , RNA Mensageiro/análise , Ratos , Receptor 5-HT2A de Serotonina/análise , Receptor 5-HT2A de Serotonina/imunologia , Tirfostinas/farmacologiaRESUMO
Psoriasis appears to be influenced by stress, which causes release of adrenal hormones. Serotonin, or hormonal actions on serotonin and serotonin receptors, may have a role in psoriasis. Distribution of serotonin receptors was studied in involved and noninvolved skin in patients with psoriasis and compared to normal skin, by using immunohistochemistry and antibodies to 5-HT1A, 5-HT2A and 5-HT3 receptors (R). There was a decreased (P<0.001) number of 5-HT1AR positive cells, the majority being tryptase positive, in involved and noninvolved psoriatic papillary dermis, compared to normal skin. 5-HTlAR expression was also found in the upper part of the epidermis, on vessel walls and on melanocytes. 5-HT2AR expressing papillary mononuclear cells, CD3 positive, were increased (P<0.001 and P<0.01, respectively) in involved and noninvolved psoriatic skin, compared to normal skin, an increase (P<0.01) also being found in the involved compared to noninvolved skin. Expression of 5-HT3R could be found in the basal epidermal layer of noninvolved but not in the involved skin of psoriasis, where it was only found in the acrosyringium. The present findings are compatible with the 5-HT1A and 5-HT2A receptors having antagonistic functions, and raise the possibility of using receptor specific drugs in the treatment of psoriasis.
Assuntos
Psoríase/metabolismo , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT2A de Serotonina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Receptor 5-HT1A de Serotonina/biossíntese , Receptor 5-HT1A de Serotonina/imunologia , Receptor 5-HT2A de Serotonina/biossíntese , Receptor 5-HT2A de Serotonina/imunologiaRESUMO
The human polyomavirus, JCV, causes the fatal demyelinating disease progressive multifocal leukoencephalopathy in immunocompromised patients. We found that the serotonergic receptor 5HT2AR could act as the cellular receptor for JCV on human glial cells. The 5HT2A receptor antagonists inhibited JCV infection, and monoclonal antibodies directed at 5HT2A receptors blocked infection of glial cells by JCV, but not by SV40. Transfection of 5HT2A receptor-negative HeLa cells with a 5HT2A receptor rescued virus infection, and this infection was blocked by antibody to the 5HT2A receptor. A tagged 5HT2A receptor colocalized with labeled JCV in an endosomal compartment following internalization. Serotonin receptor antagonists may thus be useful in the treatment of progressive multifocal leukoencephalopathy.
Assuntos
Vírus JC/fisiologia , Neuroglia/virologia , Receptor 5-HT2A de Serotonina/fisiologia , Receptores Virais/fisiologia , Anticorpos Monoclonais , Linhagem Celular Transformada , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Endossomos/metabolismo , Endossomos/virologia , Citometria de Fluxo , Técnica Indireta de Fluorescência para Anticorpo , Células HeLa , Humanos , Microscopia Confocal , Neuroglia/fisiologia , Receptor 5-HT2A de Serotonina/imunologia , Receptores Dopaminérgicos/imunologia , Receptores Dopaminérgicos/fisiologia , Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina , Antagonistas da Serotonina/farmacologia , Ácidos Siálicos/fisiologia , TransfecçãoRESUMO
An imbalance between serotonin-2A (5-HT2A) and 5-HT1A receptors may underlie several mood disorders. The present studies determined whether 5-HT2A receptors interact with 5-HT1A receptors in the rat hypothalamic paraventricular nucleus (PVN). The sensitivity of the hypothalamic 5-HT1A receptors was measured as oxytocin and adrenocorticotropic hormone (ACTH) responses to the 5-HT1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide [(+)8-OH-DPAT] (40 microg/kg s.c.). The 5-HT(2A/2C) receptor agonist (-)DOI [(-)-1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane HCl] (1 mg/kg s.c.) injected 2 h prior to (+)8-OH-DPAT significantly reduced the oxytocin and ACTH responses to (+)8-OH-DPAT, producing a heterologous desensitization of the 5-HT1A receptors. Microinjection of the 5-HT2A receptor antagonist MDL100,907 [(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol; 0, 10, or 20 nmol, 15 min prior to (-)DOI] into the PVN dose-dependently prevented the desensitization of 5-HT1A receptors induced by the 5-HT2A receptor agonist (-)DOI. Double-label immunocytochemistry revealed a high degree of colocalization of 5-HT1A and 5-HT2A receptors in the oxytocin and corticotropin-releasing factor neurons of the PVN. Thus, activation of 5-HT2A receptors in the PVN may directly induce a heterologous desensitization of 5-HT1A receptors within individual neuroendocrine cells. These findings may provide insight into the long-term adaptation of 5-HT1A receptor signaling after changes in function of 5-HT2A receptors; for example, during pharmacotherapy of mood disorders.