RESUMO
Several pathophysiological processes involve Hypoxia conditions, where the nervous system is affected as well. We postulate that the GABAergic system is especially sensitive. Furthermore, drugs improving the resistance to hypoxia have been investigated, such as the neurosteroid dehydroepiandrosterone sulfate (DHEAS) which has shown beneficial effects in hypoxic processes in mammals; however, at the cellular level, its exact mechanism of action has yet to be fully elucidated. Here, we used a chemical hypoxia model through sodium sulfite (SS) exposure in Caenorhabditis elegans (C. elegans), a nematode whose response to hypoxia involves pathways and cellular processes conserved in mammals, and that allows study the direct effect of DHEAS without its conversion to sex hormones. This work aimed to determine the effect of DHEAS on damage to the GABAergic system associated with SS exposure in C. elegans. Worms were subjected to nose touch response (Not Assay) and observed in epifluorescence microscopy. DHEAS decreased the shrinkage response of Not Assay and the level of damage in GABAergic neurons on SS-exposed worms. Also, the enhanced nuclear localization of DAF-16 and consequently the overexpression of chaperone HSP-16.2 by hypoxia were significantly reduced in SS + DHEAS exposed worms. As well, DHEAS increased the survival rate of worms exposed to hydrogen peroxide. These results suggest that hypoxia-caused damage over the GABAergic system was prevented at least partially by DHEAS, probably through non-genomic mechanisms that involve its antioxidant properties related to its chemical structure.
Assuntos
Antioxidantes/farmacologia , Proteínas de Caenorhabditis elegans/efeitos dos fármacos , Sulfato de Desidroepiandrosterona/farmacologia , Fatores de Transcrição Forkhead/efeitos dos fármacos , Neurônios GABAérgicos/efeitos dos fármacos , Proteínas de Choque Térmico/efeitos dos fármacos , Hipóxia/metabolismo , Sulfitos/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Proteínas de Choque Térmico/metabolismo , Peróxido de Hidrogênio/toxicidade , Hipóxia/patologia , Microscopia de Fluorescência , Oxidantes/toxicidade , Transdução de Sinais , Taxa de SobrevidaRESUMO
Baicalein (BA), one of the main flavonoids obtained from the Chinese medicinal herb Scutellaria baicalensis, usually exerts several pharmacological effects. In the central nervous system (CNS), BA exerts a protective effect on neurons against several neuronal insults among other effects, but it is not clear if this effect is due to its metabolite, baicalin. The purpose of the present study was to assess the anxiolytic-like and related properties of BA following its central administration (i.c.v.) in mice. BA (0.02, 0.2pmol) exerted an anxiolytic-like effect at low doses, increasing the time spent in open arms and the head-dipping whereas reducing the stretched-attend postures in the elevated plus-maze. BA also increased the duration of ether-induced sleep without affecting the pentylenetetrazol (PTZ)-induced convulsions. In addition, pretreatment with flumazenil (FMZ), PTZ, dehydroepiandrosterone sulfate (DHEAS), and dl-p-chlorophenilalanine ethyl ester (PCPA) were conducted in order to investigate its mechanism of action. PTZ and DHEAS, but not FMZ or PCPA, antagonized the BA's anxiolytic-like effect. Taken together our results showed that BA, when directly injected into the CNS, promotes anxiolytic-like and sedative effects, pharmacological activities dependent on GABAergic non-benzodiazepine sites but not on the 5-HT system.
Assuntos
Flavanonas/farmacologia , Agonistas GABAérgicos/farmacologia , Agonistas GABAérgicos/uso terapêutico , Antagonistas GABAérgicos/farmacologia , Convulsões/tratamento farmacológico , Sono/efeitos dos fármacos , Sono/fisiologia , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Sulfato de Desidroepiandrosterona/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Éter/farmacologia , Feminino , Fenclonina/análogos & derivados , Fenclonina/farmacologia , Flavanonas/administração & dosagem , Flavanonas/antagonistas & inibidores , Flavanonas/uso terapêutico , Flumazenil/farmacologia , Injeções Intraventriculares , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Pentilenotetrazol/farmacologia , Convulsões/induzido quimicamenteRESUMO
A significant role for hormones in regulating the balance of Th1- and Th2-associated cytokines with a role in modulating diseases has been accumulating. Previously, we reported that dehydroepiandrosterone (DHEA), the most abundant steroid hormone synthesized by the adrenal cortex, markedly reduced the blood and tissue parasites in experimentally Trypanosoma cruzi-infected rats. Based on these findings, the main purpose of this study was to investigate the effect of dehydroepiandrosterone-sulfate ester (DHEA-S) therapy alone or in combination with benznidazole (BNZ) (recommended in Brazil for the treatment of T. cruzi infection) will be effective during the acute phase of two different lineages of T. cruzi strains: type I (Y strain) and type II (Bolivia strain) of T. cruzi. Administration of either DHEA-S or BNZ alone or in combination significantly reduced the Y strain parasite load as compared with untreated. Furthermore treatment with DHEA-S resulted in Bolivia strain clearance. This protective effect of DHEA-S was associated with the host's immune response, as evidence by enhanced levels of interferon-gamma and interleukin-2. DHEA-S treatment also increased peritoneal macrophages levels and nitrite production. DHEA-S treatment was effective in reducing the mortality rate as compared to BNZ alone or to combiner DHEA-S+BNZ treatment of T. cruzi Bolivia strain infected animals. These findings suggest that hormonal therapy may have a protective effect in the treatment of T. cruzi infection.
Assuntos
Doença de Chagas/tratamento farmacológico , Sulfato de Desidroepiandrosterona/farmacologia , Nitroimidazóis/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Doença Aguda , Animais , Doença de Chagas/sangue , Doença de Chagas/mortalidade , Sulfato de Desidroepiandrosterona/uso terapêutico , Quimioterapia Combinada , Interferon gama/metabolismo , Interleucina-2/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Nitritos/metabolismo , Nitroimidazóis/uso terapêutico , Parasitemia/sangue , Parasitemia/prevenção & controle , Ratos , Ratos Wistar , Especificidade da Espécie , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/classificaçãoRESUMO
We investigated the effect of dehydroepiandrosterone sulfate (DHEAS) and 17beta-estradiol on NTPDase activity in fresh clinical (VP60) and long-term-grown (30236 ATCC) isolates of Trichomonas vaginalis followed by NTPDase gene transcriptional analysis. ATP hydrolysis was activated in vitro by 17beta-estradiol (0.01-1.0microM) in the VP60 isolate. Treatment for 2h with 17beta-estradiol (0.01-1microM) promoted an inhibition in nucleotide hydrolysis in the 30236 isolate whereas the 12h-treatment promoted an activation of nucleotide hydrolysis in both isolates. ADP hydrolysis was inhibited in vitro by 1.0-5.0microM DHEAS in the ATCC isolate. The treatment with DHEAS (0.01-1.0microM) for 2h inhibited ATP and ADP hydrolysis in VP60; however, during a 12h-treatment with DHEAS, nucleotide hydrolysis was inhibited in both isolates. Two NTPDase orthologous (NTPDaseA and NTPDaseB) were identified and the treatment with DHEAS for 12h was able to inhibit mRNA NTPDaseA transcript levels from the VP60. These findings demonstrate that NTPDase activity and gene expression pattern are modulated by exposure to steroids in T. vaginalis.
Assuntos
Sulfato de Desidroepiandrosterona/farmacologia , Estradiol/farmacologia , Estrogênios/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Nucleosídeo-Trifosfatase/metabolismo , Trichomonas vaginalis/efeitos dos fármacos , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Sequência de Aminoácidos , Análise de Variância , Animais , Humanos , Hidrólise/efeitos dos fármacos , Cinética , Camundongos , Dados de Sequência Molecular , Nucleosídeo-Trifosfatase/química , Nucleosídeo-Trifosfatase/efeitos dos fármacos , Nucleosídeo-Trifosfatase/genética , Filogenia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alinhamento de Sequência , Trichomonas vaginalis/enzimologia , Trichomonas vaginalis/genética , Trichomonas vaginalis/crescimento & desenvolvimentoRESUMO
Dehydroepiandrosterone (DHEA) is an endogenous steroid synthesized mainly in the adrenal cortex. It is known that DHEA is a precursor of sex steroids and that part of its effects depends on its conversion to estrogens and androgens. Sex steroids exert profound and controversial effects on cardiovascular function. Exogenous DHEA can exert a dual effect, antioxidant or prooxidant, depending on the dose and on the tissue specificity [1,2] (F. Celebi, I. Yilmaz, H. Aksoy, M. Gümüs, S. Taysi, D. Oren, Dehydroepiandrosterone prevents oxidative injury in obstructive jaundice in rats, J. Int. Med. Res. 32 (4) (2004) 400-405; S.K. Kim, R.F. Novak, The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression, Pharmacol. Ther. 113 (1) (2007) 88-120). Akt signaling pathway is one of the anti-proliferative mechanisms of DHEA (Y. Jiang, T. Miyazaki, A. Honda, T. Hirayama, S. Yoshida, N. Tanaka, Y. Matsuzaki, Apoptosis and inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway in the anti-proliferative actions of dehydroepiandrosterone, J. Gastroenterol. 40 (5) (2005) 490-497). Heart homogenates were prepared to quantify lipid peroxidation (LPO), concentration of superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), 4-hydroxy-2-nonenal (HNE) and p-Akt/Akt ratio, and the activities of those antioxidant enzymes. When administrated to male Wistar rats in short-term (6 or 24h) intraperitoneally, DHEA produced significant differences in some parameters of oxidative stress in rat hearts among the distinct doses (1, 10, and 50mg/kg) used. The results here presented, regarding 6 and 24h oxidative stress status, have shown that DHEA injections promoted a prooxidant answer in healthy Wistar rat hearts.
Assuntos
Catalase/metabolismo , Sulfato de Desidroepiandrosterona/metabolismo , Miocárdio/metabolismo , Proteínas Proto-Oncogênicas c-akt/fisiologia , Superóxido Dismutase/metabolismo , Animais , Sulfato de Desidroepiandrosterona/farmacologia , Ativação Enzimática , Peroxidação de Lipídeos , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Transdução de SinaisRESUMO
Dehydroepiandrosterone (DHEA) is synthesized in the brain and several studies have shown that this steroid is a modulator of synaptic transmission. The effect of DHEA, and its sulfate ester DHEAS, on glutamate and GABA neurotransmission has been extensively studied but some effects on other neurotransmitter systems, such as dopamine, serotonin and nitric oxide, have also been reported. This review summarizes studies showing the effect of DHEA and DHEAS on neurotransmitter systems at different levels (metabolism, release, reuptake, receptor activation), as well as the activation of voltage-gated ion channels and calcium homeostasis, showing the variety of effects that these steroids exert on those systems, allowing the discussion of its mechanisms of action and its relevance to psychiatric disorders.
Assuntos
Adjuvantes Imunológicos/farmacologia , Sulfato de Desidroepiandrosterona/farmacologia , Desidroepiandrosterona/farmacologia , Transtornos Mentais/metabolismo , Neurotransmissores/metabolismo , Adjuvantes Imunológicos/uso terapêutico , Animais , Desidroepiandrosterona/química , Desidroepiandrosterona/uso terapêutico , Sulfato de Desidroepiandrosterona/química , Sulfato de Desidroepiandrosterona/uso terapêutico , Humanos , Transtornos Mentais/tratamento farmacológico , Modelos BiológicosRESUMO
Ageing of the endocrine system (endocrinosenescence) has been closely related to immunosenescence. Dehydroepiandrosterone sulphate (DHEAS), a steroid hormone produced by the adrenals with reported enhancing immunomodulatory properties, consistently decline during ageing in parallel to detrimental increase in peripheral glucocorticoids. We investigated here the adjuvant effects of DHEAS during intraperitoneal immunization to Mycobacterium tuberculosis heat shock protein 70 (mycHSP70) in old (24 months) as well as young (3 months) BALB/c mice. Both young and old mice had significantly higher Immunoglobulin G (IgG) levels following immunization. Young mice co-immunized with mycHSP70-DHEAS presented an early increase in specific IgG levels and showed increased Interferon-gamma production compared to old mice. Also, T cells of immunized young animals were consistently more resistant to the immunosuppressive effects of glucocorticoids and to DHEAS. DHEAS was not effective in modulating antigen-specific T-cell proliferation, Interleukin-2 production or percentage of recent activated T-cell subsets (CD4 + CD69 + and CD8 + CD69 +). Our data further indicate mycHSP70 as a putative good antigen in vaccine to tuberculosis. Our data also suggest that DHEAS produced adjuvant effects upon humoral and some cellular immune responses of young, but not old mice and indicate that immunization with DHEAS is capable of changing T-cell responses to steroids.
Assuntos
Adjuvantes Imunológicos , Envelhecimento/imunologia , Proteínas de Bactérias/imunologia , Sulfato de Desidroepiandrosterona/imunologia , Proteínas de Choque Térmico HSP70/imunologia , Imunoglobulina G/sangue , Interferon gama/metabolismo , Linfócitos T/imunologia , Vacinas contra a Tuberculose/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Formação de Anticorpos , Antígenos CD/análise , Células Cultivadas , Corticosterona/imunologia , Sulfato de Desidroepiandrosterona/farmacologia , Dexametasona/imunologia , Relação Dose-Resposta a Droga , Feminino , Imunidade Celular , Interleucina-2/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Fatores de Tempo , VacinaçãoRESUMO
BACKGROUND: Pregnancy is a condition that favors oxidative stress by reactive oxygen species. Oxidative stress is involved in the etiopathogenesis of disorders of pregnancy such as pre-eclampsia. An antioxidant effect of estrogens has been described and a putative role of them as antioxidants has been proposed. The aim of this work was to evaluate in vitro the antioxidant properties of dehydroepiandrosterone sulfate, estradiol, estriol, progesterone, and testosterone, five steroid hormones present in the maternofetal circulation. METHODS: The antioxidant properties of the hormones were evaluated by two methods: 1. their antioxidant effect on the auto-oxidation of linoleic acid, a hydrogen atom transfer reaction; 2. diphenylpicrylhydrazyl-scavenging capacity, a single electron transfer reaction. RESULTS: Of the five hormones tested, only estradiol and estriol at 10 microM concentration exerted a strong antioxidant effect of 81.73 and 70.97% respectively on linoleic acid auto-oxidation, at the end-point of the reaction. Likewise, only these two hormones showed radical-scavenging activity on diphenylpicrylhydrazyl, noticeable only at supraphysiological concentrations of 1 mM. CONCLUSIONS: Estradiol and estriol could play a role as antioxidants for maternofetal autoprotection in addition to their hormonal activity, but this role could be preferentially exerted by estriol due to its higher concentrations exhibited during pregnancy. In vivo studies are necessary to shed light on this issue.
Assuntos
Antioxidantes/metabolismo , Estrogênios/farmacologia , Ácido Linoleico/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Gravidez/sangue , Adulto , Antioxidantes/farmacologia , Compostos de Bifenilo/metabolismo , Sulfato de Desidroepiandrosterona/metabolismo , Sulfato de Desidroepiandrosterona/farmacologia , Relação Dose-Resposta a Droga , Estradiol/metabolismo , Estradiol/farmacologia , Estriol/metabolismo , Estriol/farmacologia , Estrogênios/metabolismo , Feminino , Humanos , Hidrazinas/metabolismo , Técnicas In Vitro , Oxirredução , Estresse Oxidativo , Picratos , Progesterona/metabolismo , Progesterona/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Testosterona/metabolismo , Testosterona/farmacologiaRESUMO
The low prevalence of coronary heart disease in premenopausal women and its increase after menopause are well established. Many studies have suggested that steroid hormones can inhibit platelet aggregation, reducing the cardiovascular risk. In addition, a number of studies have shown an effect of estrogen on vascular function. The process of haemostasis and thrombus formation can be also affected by adenine nucleotides and adenosine. Consequently, the regulation of enzymes that hydrolyze these nucleotides in the bloodstream is essential in the modulation of the processes of platelet aggregation, vasodilatation and coronary flow. Thus, in this study, we examined the effect of ovariectomy (OVX), estradiol replacement therapy and the in vitro administration of 17beta-estradiol, dehydroisoandrosterone 3-sulfate (DHEAS) and pregnenolone (PREG) on the activity of the enzymes that degrade adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP) in the blood serum of female rats. OVX significantly increased the hydrolysis of ATP, ADP and AMP, whilst phosphodiesterase activity was unchanged. Estradiol replacement therapy significantly decreased the hydrolysis of the adenine nucleotides and of the substrate marker of phosphodiesterase. In vitro, the addition of steroid hormones did not have any effect on the nucleotide hydrolysis by rat serum. These results suggest the presence of a strong relation between these enzymes and the hormonal system. In addition, the alterations observed are important, because these enzymes control the nucleotides/nucleosides ratio in the circulation and thus the events related to haemostasis.
Assuntos
Nucleotídeos de Adenina/metabolismo , Terapia de Reposição Hormonal , Ovariectomia , 5'-Nucleotidase/metabolismo , Nucleotídeos de Adenina/sangue , Difosfato de Adenosina/metabolismo , Monofosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Apirase/metabolismo , Sulfato de Desidroepiandrosterona/farmacologia , Estradiol/farmacologia , Feminino , Hormônios Esteroides Gonadais/farmacologia , Hidrólise , Pregnanolona/farmacologia , Ratos , Ratos WistarRESUMO
Our previous study showed that the neurosteroids pregnenolone sulfate (PS) and epipregnanolone stimulated and blocked, respectively, the demonstration of chronic tolerance to the incoordinating effect of ethanol. The aim of the present study was to investigate the influence of three neurosteroids on the demonstration of tolerance to ethanol-induced hypothermia in mice using the rapid tolerance paradigm. The first experiment defined the doses of ethanol that did or did not induce rapid tolerance to ethanol-induced hypothermia. In the second, the influence of pretreatment of mice with PS (0.08 or 0.15 mg/kg, i.p.) or dehydroepiandrosterone sulfate (DHEAS; 0.15 or 0.20 mg/kg, i.p.) before ethanol (4.0 g/kg, i.p.) on rapid tolerance was studied. The third experiment examined the effect of allotetrahydrodeoxicorticosterone (ALLOT; 0.10 or 0.20 mg/kg, i.p.) before ethanol (4.0 g/kg, i.p.) on rapid tolerance. Results showed that pretreatment with PS or with DHEAS significantly facilitated the demonstration of rapid tolerance, whereas pretreatment with ALLOT interfered with the demonstration of tolerance to the hypothermic effect.