RESUMO
An exceptionally high mortality rate is observed in sepsis and septic shock. Systemic administration of lipopolysaccharide (LPS) has been used as an experimental model for sepsis resulting in an exacerbated immune response, brain neurochemistry adjustments, hypotension, and hypothermia followed by fever. Central serotonergic pathways not only modulate systemic inflammation (SI) but also are affected by SI, including in the anteroventral region of the hypothalamus (AVPO), which is the hierarchically most important region for body temperature (Tb) control. In this study, we sought to determine if central serotonin (5-HT) plays a role in SI induced by intravenous administration of LPS (1.5â¯mg/kg) in male Wistar rats (280-350â¯g) by assessing 5-HT levels in the AVPO, mean arterial pressure, heart rate, and Tb up to 300â¯min after LPS administration, as well as assessing plasma and spleen cytokine levels, nitric oxide (NO) plasma levels, and prostaglandin (PG) E2 levels in the AVPO at 75â¯min and 300â¯min after LPS administration. We observed reduced AVPO 5-HT levels, hypotension, tachycardia, hypothermia followed by fever, as well as observing increased plasma NO, plasma and spleen cytokines and AVPO PGE2 levels in SI. Intracerebroventricular (icv) administration of 5-HT 30â¯min before LPS administration prevented hypotension and hypothermia, which were accompanied by reduced plasma NO, as well as plasma TNF-α, IL-1ß, IL-6, and IL-10 and spleen TNF-α and IL-10 levels. We suggest that SI reduced 5-HT levels in the AVPO favor an increased pro-inflammatory status both centrally and peripherally that converge to hypotension and hypothermia. Moreover, our results are consistent with the notion that exogenous 5-HT given icv prevents hypotension and hypothermia probably activating the splenic anti-inflammatory pathway.
Assuntos
Citocinas/sangue , Hipotensão/metabolismo , Hipotermia/metabolismo , Inflamação/metabolismo , Serotonina/metabolismo , Baço/metabolismo , Animais , Dopamina/metabolismo , Hipotensão/complicações , Hipotálamo Anterior/metabolismo , Hipotermia/complicações , Inflamação/induzido quimicamente , Inflamação/complicações , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Óxido Nítrico/sangue , Norepinefrina/metabolismo , Ratos Wistar , Serotonina/administração & dosagemRESUMO
Serotonin (5-HT) is a neuromodulator involved in several central-mediated mechanisms, such as endocrine processes, behavior, and sleep. Dysfunction of the serotonergic system is mainly linked to psychiatric disorders, but emerging evidence suggests that immune system activation may also alter brain 5-HT signaling. However, whether central 5-HT modulates systemic inflammation (SI) remains unknown. For this purpose, male Wistar rats (280-350g, 8-9weeks) were submitted to the experimental protocols beginning between 9 and 10AM with the performance of injections. The animals were housed at controlled conditions [temperature (25±1°C), light (06:00-18:00) and humidity (60-65%)]. Thus, we measured 5-HT and its metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) in the anteroventral preoptic region [(AVPO) - the hierarchically most important region for body temperature (Tb) control] during lipopolysaccharide (LPS)-induced SI. We also combined LPS (100µg/kg) treatment with intracerebroventricular (icv) injection of 5-HT (5, 10 and 40µg/µL) and measured Tb ("hallmark" of SI), AVPO prostaglandin E2 [(PGE2) - an essential mediator of fever] and prostaglandin D2 [(PGD2) - a cryogenic mediator], plasma corticosterone [(CORT) - a stress marker with an endogenous anti-inflammatory effect] and interleukin-6 [(IL-6) - an immune mediator] levels. Detection limits of PGE2, PGD2, CORT and IL-6 assays were 39.1-2500pg/mL, 19.5-2500pg/mL, 0.12-2000µg/dL, and 0.125-8ng/mL, respectively. We also assessed tail skin temperature [used to calculate heat loss index (HLI)] to assess a key thermoeffector mechanism. As expected we observed LPS-induced increases in Tb, AVPO PGE2 (whereas PGD2 remained unchanged), plasma CORT and IL-6 levels, as well as a decrease in HLI. These changes were accompanied by reduced levels of AVPO 5-HT and 5-HIAA. Furthermore, we also observed a negative correlation between 5-HT and plasma CORT levels. Moreover, icv 5-HT (5, 10 and 40µg/µL) microinjection caused a U-shaped dose-response curve in LPS fever, in which the intermediate dose reduced the febrile response. Icv 5-HT (10µg/µL) microinjection prevented the LPS-induced increases in AVPO PGE2 (whereas not altering PGD2), plasma CORT and IL-6 levels, as well as preventing reduced HLI. Our data are consistent with the notion that AVPO 5-HT synthesis is down-regulated during SI, favoring AVPO PGE2 synthesis and consequently potentiating the immune response. These results reveal a novel effect of central 5-HT as an anti-inflammatory neuromodulator that may take place during psychiatric disorder treatment with 5-HT reuptake inhibitors as well as suggesting that 5-HT modulation per se is a potential therapeutic approach for inflammatory diseases.
Assuntos
Inflamação/metabolismo , Área Pré-Óptica/metabolismo , Serotonina/metabolismo , Animais , Corticosterona/sangue , Dinoprostona/metabolismo , Febre/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Inflamação/induzido quimicamente , Lipopolissacarídeos/administração & dosagem , Masculino , Prostaglandina D2/metabolismo , Ratos Wistar , Serotonina/administração & dosagem , Temperatura CutâneaRESUMO
Caramboxin: Patients suffering from chronic kidney disease are frequently intoxicated after ingesting star fruit. The main symptoms of this intoxication are named in the picture. Bioguided chemical procedures resulted in the discovery of caramboxin, which is a phenylalanine-like molecule that is responsible for intoxication. Functional experiments inâ vivo and inâ vitro point towards the glutamatergic ionotropic molecular actions of caramboxin, which explains its convulsant and neurodegenerative properties.
Assuntos
Injúria Renal Aguda/etiologia , Doenças Transmitidas por Alimentos/etiologia , Frutas/química , Frutas/intoxicação , Síndromes Neurotóxicas/etiologia , Neurotoxinas/intoxicação , Neurotoxinas/toxicidade , Plantas Tóxicas/química , Plantas Tóxicas/intoxicação , Injúria Renal Aguda/terapia , Animais , Produtos Biológicos , Frutas/toxicidade , Hipocampo/efeitos dos fármacos , Humanos , Ratos , Ratos Wistar , Diálise RenalRESUMO
The transcriptional repressor REV-ERB-α, encoded by Nuclear Receptor Subfamily 1 Group D Member 1 (Nr1d1), has been considered to play an essential role in the skeletal muscle oxidative capacity adaptation and muscle mass control. Also, this molecule regulates autophagy via the repression of autophagy-related genes both in skeletal muscle and brain regions. Classically, training programs based on endurance or strength characteristics enhance skeletal muscle mass content and/or oxidative capacity, leading to autophagy activation in several tissues. Thus, it seems that REV-ERB-α regulates similar responses induced by exercise. However, how this molecule responds to different exercise models/intensities in different tissues is still unclear. Therefore, the main aim was to characterize the responses of REV-ERB-α and autophagy-related genes to different exercise protocols (endurance/interval run/strength) in distinct tissues (gastrocnemius, soleus and hippocampus). Since REV-ERB-α presents a circadian rhythm, the analyses were performed in a time-course manner. The endurance and strength groups attenuated REV-ERB-α transcriptional response during the time course in gastrocnemius and soleus. Conversely, the interval group enhanced the Nr1d1 expression in the hippocampus. All protocols downregulated the REV-ERB-α protein levels in gastrocnemius following the exercise session with concomitant nuclear exclusion. The major autophagy-related genes presented downregulation after the exercise session in all analyzed tissues. Altogether, these results highlight that REV-ERB-α is extremely sensitive to physical exercise stimuli, including different models and intensities in skeletal muscle and the hippocampus.
Assuntos
Ritmo Circadiano , Exercício Físico , Ritmo Circadiano/genética , Autofagia/genética , Músculo Esquelético , HipocampoRESUMO
Parkinson's disease results from a degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) and it is more prevalent in men than in women. Estrogen has neuroprotective action of the nigrostriatal dopaminergic (NSDA) neurons. It was investigated whether differences in plasma 17ß-estradiol (E2) levels alter the degree of neuroprotection in NSDA neurons. Ovariectomized rats, implanted with subcutaneous capsules containing 400, 800 or 1,600 µg of E2 or corn oil, were injected with 1 µg of 6-OHDA in the SNpc or the medial forebrain bundle (MFB). Striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and plasma E2 levels were measured. Only at 400 µg, E2 protected striatal DA against lesion of the MFB. In the SNpc, E2 failed to prevent DA depletion, but increased DOPAC/DA ratio in the striatum. In an NSDA moderate lesion, E2 has a neuroprotective action. In a severe lesion, E2 could stimulate DA activity in remaining neurons.
Assuntos
Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Estrogênios/farmacologia , Oxidopamina/farmacologia , Doença de Parkinson/metabolismo , Substância Negra/efeitos dos fármacos , Animais , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estrogênios/administração & dosagem , Feminino , Ovariectomia , Ratos , Ratos Wistar , Substância Negra/metabolismoRESUMO
AIMS: Considering that serotoninergic agents attenuate symptoms of anxiety and are used to treat depression, we investigated whether subchronic treatment with imipramine, a serotonin/noradrenaline reuptake inhibitor, would prevent the anxiogenic-like behaviour induced by acute and/or chronic ethanol withdrawal. We also investigated whether those changes were related to the disfunctioning of hypothalamic-pituitary-adrenal (HPA) axis and serotonergic neurotransmission. MAIN METHODS: 264 Male Wistar rats were treated with ethanol 6% (vol./vol.) for 21 days. Acute ethanol withdrawal was induced by abrupt discontinuation of treatment and sustained for 48â¯h. Protracted abstinence was sustained for an additional period of 21 days. Behavioural tests included the Elevated Plus Maze (EPM) or Light/Dark Box (LDB) after acute abstinence, and the Forced Swim Test (FST) after protracted abstinence. Imipramine (15â¯mg/kg, i.p.) was administered 24, 19 and 1â¯h before EPM or LDB tests. KEY FINDINGS: Acute abstinence decreased exploration of the open arms of the EPM, without changing exploration of LDB. Additionally, chronic abstinent rats displayed more time immobile in the FST, when compared to control animals. These effects were attenuated by imipramine treatment, without changing basal response. Imipramine prevented protracted abstinence -induced decrease in glucocorticoid receptor (GR) and serotonin transporter (SERT) expression in the dorsal hippocampus. SIGNIFICANCE: Our findings indicate that chronic ethanol withdrawal affects the hippocampal serotonergic system by decreasing serotonin transporter expression. It also disturbs the HPA axis functioning through an imbalance on GR and mineralocorticoid (MR) expression.
Assuntos
Abstinência de Álcool , Ansiedade , Comportamento Animal , Depressão , Hipocampo , Proteínas de Ligação a RNA , Receptores de Glucocorticoides , Animais , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imipramina , Masculino , Proteínas de Ligação a RNA/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Ratos , Ratos Wistar , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismoRESUMO
Women are born with an abundant but finite pool of ovarian follicles, which naturally and progressively decreased during their reproductive years until menstrual periods stop permanently (menopause). Perimenopause represents the transition from reproductive to non-reproductive life. It is usually characterized by neuroendocrine, metabolic and behavioral changes, which result from a follicular depletion and reduced number of ovarian follicles. During this period, around 45-50 years old, women are more likely to express mood disorders, anxiety, irritability and vasomotor symptoms. The current animal models of reproductive aging do not successfully replicate human perimenopause and the gradual changes that occur in this phase. While the traditional rat model of menopause involves ovariectomy or surgical menopause consisting of the rapid and definitive removal of the ovaries resulting in a complete loss of all ovarian hormones, natural or transitional menopause is achieved by the selective loss of ovarian follicles (perimenopause period). However, the natural aging rodent (around 18-24 months) model fails to reach very low estrogen concentrations and overlaps the processes of somatic and reproductive aging. The chronic exposure of young rodents to 4-vinylcyclohexene diepoxide (VCD) is a well-established experimental model for perimenopause and menopause studies. VCD induces loss of ovarian small follicles (primary and primordial) in mice and rats by accelerating the natural process of atresia (apoptosis). The VCD, ovary-intact or accelerated ovarian failure (AOF) model is the experimental model that most closely matches natural human progression to menopause mimicking both hormonal and behavioral changes typically manifested by women in perimenopause. Graphical abstract: The female reproductive system is regulated by a series of neuroendocrine events controlled by central and peripheral components. (A). The mechanisms involved in this control are extremely complex and have not yet been fully clarified. In female mammals whose ovulation (the most important event in a reproductive cycle) occurs spontaneously, reproductive success is achieved through the precise functional and temporal integration of the hypothalamus-pituitary-ovary (HPO) axis. (B). In women, loss of fertility appears to be primarily associated with exhaustion of ovarian follicles, and this process occurs progressively until complete follicular exhaustion marked by the final menstrual period (FMP). (C). While in female rodents, reproductive aging seems to begin as a neuroendocrine process, in which changes in hypothalamic/pituitary function appear independently of follicular atresia. The traditional rat model of menopause, ovariectomy or surgical menopause consists of the rapid and definitive removal of the ovaries resulting in a complete loss of all ovarian hormones. (D). The chronic exposure (15-30 days) to the chemical compound 4-vinylcyclehexene diepoxide (VCD) in young rodents accelerates gradual failure of ovarian function by progressive depletion of primordial and primary follicles, but retains residual ovarian tissue before brain alterations that occurs in women in perimenopause. Low doses of VCD cause the selective destruction of the small preantral follicles of the ovary without affecting other peripheral tissues.
RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Citral (3,7-dimethyl-2,6-octadienal) is the main component of Cymbopogon citratus (DC) Stapf, an herb with analgesic properties. Arthritic pain is the main unpleasant component of rheumatoid arthritis. The pharmacological approaches used to treat arthritic pain are often accompanied by adjuvant drugs or non-pharmacological treatments, showing a constant need in identifying new efficient analgesic drugs. AIM OF THE STUDY: To test the hypothesis that citral, which is a monoterpenoid compound with therapeutic properties, reduces nociception, spinal pro-nociceptive and pro-inflammatory signaling, and systemic oxidative stress in arthritic rats. MATERIALS AND METHODS: Complete Freund's adjuvant (CFA) was administrated in the left knee joint of rats. Oral treatment with citral was performed during eight days and mechanical allodynia was monitored during the period of treatment to evaluate the analgesic effect of citral. We assessed the levels of serotonin (5-hydroxytryptamine, 5-HT) in the lumbar dorsal horn of the spinal cord (DHSC) and the profiles of expression of the glycogen synthase kinase-3ß (GSK3ß), which is a 5-HT-regulated intracellular protein, and of the stress-activated protein kinase (SAPK)/jun N-terminal kinase (JNK) in the DHSC. Plasma levels of superoxide dismutase (SOD) were assessed as an indicator of oxidative stress. RESULTS: Administration of CFA induced mechanical allodynia associated with reduced spinal GSK3ß phosphorylation, increased spinal SAPK/JNK phosphorylation, and increased plasma SOD levels. Oral administration of citral reversed mechanical allodynia, increased endogenous spinal 5-HT levels, reduced spinal SAPK/JNK phosphorylation, and reduced plasma SOD levels. CONCLUSION: Citral shows anti-nociceptive effects in an animal model of arthritic pain by modulating spinal nociceptive signaling.
Assuntos
Monoterpenos Acíclicos/farmacologia , Artrite Experimental/tratamento farmacológico , Cymbopogon/química , Estresse Oxidativo/efeitos dos fármacos , Monoterpenos Acíclicos/isolamento & purificação , Analgésicos/isolamento & purificação , Analgésicos/farmacologia , Animais , Artrite Experimental/patologia , Adjuvante de Freund , Hiperalgesia/tratamento farmacológico , Masculino , Dor/tratamento farmacológico , Dor/patologia , Ratos , Ratos Wistar , Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Superóxido Dismutase/metabolismoRESUMO
During the transition to menopause, women experience a variety of physical and psychological symptoms that are directly or indirectly linked to changes in hormone secretion. Establishing animal models with intact ovaries is essential for understanding these interactions and finding new therapeutic targets. In this study, we assessed the endocrine profile, as well as the estrous cycle, in the 4-vinylcyclohexene diepoxide (VCD)-induced follicular depletion rat model in 10-day intervals over 1 month to accurately establish the best period for studies of the transition period. Twenty-eight-day-old female rats were injected daily with VCD or oil s.c. for 15 days and euthanized in the diestrus phase approximately 70, 80, 90 and 100 days after the onset of treatment. The percentage of rats showing irregular cycles and the plasma level of FSH increased only in the 100-day VCD group. Plasma anti-Müllerian hormone (AMH) and progesterone were lower in all VCD groups compared to control groups, while estradiol remained unchanged or higher. As in control groups, dihydrotestosterone (DHT) progressively decreased in the 70-90-day VCD groups; however, it was followed by a sharp increase only in the 100-day VCD group. No changes were found in plasma corticosterone, prolactin, thyroid hormones or luteinizing hormone. Based on the estrous cycle and endocrine profile, we conclude that 1) the time window from 70 to 100 days is suitable to study a perimenopause-like state in this model, and 2) regular cycles with low progesterone and AMH and normal FSH can be used as markers of the early/mid-transition period, whereas irregular cycles associated with higher FSH and DHT can be used as markers of the late transition period to estropause.
Assuntos
Sistema Endócrino/química , Perimenopausa/sangue , Animais , Hormônio Antimülleriano/sangue , Biomarcadores/sangue , Cicloexenos , Di-Hidrotestosterona/sangue , Ciclo Estral/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Modelos Animais , Progesterona/sangue , Ratos , Fatores de Tempo , Compostos de VinilaRESUMO
We obtained a neurotoxic fraction (AcTx) from star fruit (Averrhoa carambola) and studied its effects on GABAergic and glutamatergic transmission systems. AcTx had no effect on GABA/glutamate uptake or release, or on glutamate binding. However, it specifically inhibited GABA binding in a concentration-dependent manner (IC(50)=0.89muM). Video-electroencephalogram recordings demonstrated that following cortical administration of AcTx, animals showed behavioral changes, including tonic-clonic seizures, evolving into status epilepticus, accompanied by cortical epileptiform activity. Chemical characterization of AcTx showed that this compound is a nonproteic molecule with a molecular weight less than 500, differing from oxalic acid. This neurotoxic fraction of star fruit may be considered a new tool for neurochemical and neuroethological research.
Assuntos
Química Encefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Convulsivantes/toxicidade , Magnoliopsida/química , Neurotoxinas/toxicidade , Extratos Vegetais/toxicidade , Animais , Ligação Competitiva , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Química Encefálica/fisiologia , Convulsivantes/isolamento & purificação , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Frutas/química , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Peso Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurotoxinas/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Ensaio Radioligante , Ratos , Ratos Wistar , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismoRESUMO
The role of norepinephrine (NE) in regulation of LH is still controversial. We investigated the role played by NE in the positive feedback of estradiol and progesterone. Ovarian-steroid control over NE release in the preoptic area (POA) was determined using microdialysis. Compared with ovariectomized (OVX) rats, estradiol-treated OVX (OVX+E) rats displayed lower release of NE in the morning but increased release coincident with the afternoon surge of LH. OVX rats treated with estradiol and progesterone (OVX+EP) exhibited markedly greater NE release than OVX+E rats, and amplification of the LH surge. The effect of NE on LH secretion was confirmed using reverse microdialysis. The LH surge and c-Fos expression in anteroventral periventricular nucleus neurons were significantly increased in OVX+E rats dialyzed with 100 nm NE in the POA. After Fluoro-Gold injection in the POA, c-Fos expression in Fluoro-Gold/tyrosine hydroxylase-immunoreactive neurons increased during the afternoon in the A2 of both OVX+E and OVX+EP rats, in the locus coeruleus (LC) of OVX+EP rats, but was unchanged in the A1. The selective lesion of LC terminals, by intracerebroventricular N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, reduced the surge of LH in OVX+EP but not in OVX+E rats. Thus, estradiol and progesterone activate A2 and LC neurons, respectively, and this is associated with the increased release of NE in the POA and the magnitude of the LH surge. NE stimulates LH secretion, at least in part, through activation of anteroventral periventricular neurons. These findings contribute to elucidation of the role played by NE during the positive feedback of ovarian steroids.