RESUMO
Temporal lobe epilepsy (TLE), the most common form of epilepsy is often resistant to pharmacological treatment. Neuronal loss observed in epileptic brain may be result of an overproduction of free radicals (oxidative stress). Oxidative stress is characterized by an imbalance between antioxidant defenses and oxidizing agents (free radicals), which can lead to tissue injury. The n-3 PUFAs are important for the development and maintenance of central nervous system functions. Research by our group has shown that chronic treatment with fish oil, immediately after status epilepticus (SE), exhibits both neuroprotective effects and effects on neuroplasticity. The main purpose of this research was to evaluate if fish oil exhibits a protective effect against oxidative stress. Animals were subjected to TLE model by pilocarpine administration. After 3 h of SE they were randomly divided into the following groups: control animals treated daily with vehicle or with 85 mg/kg of fish oil and animals with epilepsy treated daily with vehicle or with 85 mg/kg of fish oil. After 90 days, superoxide anion production, enzymatic activity of superoxide dismutase (SOD) and catalase (CAT) and protein expression of NAD(P)H oxidase subunits (p47(PHOX) and gp91(PHOX)) were analyzed. Our results showed evidences that reactive oxygen species are increased in animals with epilepsy and that fish oil supplementation could counteract it. Fish oil supplementation promoted protection against oxidative stress by multiple ways, which involved the reduction of activity and expression of NAD(P)H oxidase subunits and increased the activity and expression of antioxidants enzymes, contributing to well-known neuroprotective effect in epilepsy.
Assuntos
Modelos Animais de Doenças , Epilepsia/prevenção & controle , Óleos de Peixe/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Pilocarpina/toxicidade , Animais , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Masculino , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
Changes in the maternal environment can induce fetal adaptations that result in the progression of chronic diseases in the offspring. The objective of the present study was to evaluate the effects of maternal chronic sleep restriction on blood pressure, renal function and cardiac baroreflex response on male offspring at adult age. Female 3-month-old Wistar rats were divided in two experimental groups: control (C) and chronic sleep restricted (CSR). Pregnancy was confirmed by vaginal smear. Chronic sleep restricted females were subjected to sleep restriction by the multiple platform technique for 20 h daily, between the 1st and 20th day of pregnancy. After birth, the litters were reduced to 6 rats per mother, and were designated as offspring from control (OC) and offspring from chronic sleep restricted (OCSR). Indirect blood pressure (BPi - tail cuff) was measured by plethysmography in male offspring at 3 months old. Following, the renal function and cardiac baroreflex response were analyzed. Values of BPi in OCSR were significantly higher compared to OC [OC: 127 ± 2.6 (19); OCSR: 144 ± 2.5 (17) mmHg]. The baroreflex sensitivity to the increase of blood pressure was reduced in OCSR [Slope: OC: -2.6 ± 0.15 (9); OCRS: -1.6 ± 0.13 (9)]. Hypothalamic activity of ACE2 was significantly reduced in OCSR compared to OC [OC: 97.4 ± 15 (18); OSR: 60.2 ± 3.6 (16) UAF/min/protein mg]. Renal function alteration was noticed by the increase in glomerular filtration rate (GFR) observed in OCSR [OC: 6.4 ± 0.2 (10); OCSR: 7.4 ± 0.3 (7)]. Chronic sleep restriction during pregnancy caused in the offspring hypertension, altered cardiac baroreflex response, reduced ACE-2 activity in the hypothalamus and renal alterations. Our data suggest that the reduction of sleeping time along the pregnancy is able to modify maternal homeostasis leading to functional alterations in offspring.
Assuntos
Fenômenos Fisiológicos Cardiovasculares , Rim/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Privação do Sono/fisiopatologia , Adulto , Enzima de Conversão de Angiotensina 2 , Animais , Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Hipotálamo/metabolismo , Masculino , Peptidil Dipeptidase A/metabolismo , Pletismografia , Gravidez , Ratos , Ratos WistarRESUMO
The present study investigated the early presence of inflammatory response in renal tissue of young offspring from diabetic mothers. The effect of L-arginine (L-arg) supplementation was also investigated. The offspring was divided into four groups: group CO (controls); group DO (diabetic offspring); group CA (CO receiving 2% L-arg solution) and group DA (DO receiving the 2% L-arg solution). Glycemia, arterial pressure and renal function were evaluated; gene and protein expression of pro-inflammatory cytokines were also measured. Blood pressure levels were significantly increased in 2 and 6 month-old DO rats, whereas L-arg administration caused a significant decrease in the DA group, at both ages. DO rats showed a significantly blunted glycemic response to exogenous insulin. In 2 month-old DO animals, renal protein expression of pro-inflammatory molecules was significantly increased. At six months of age, we also observed an increase in gene expression of pro-inflammatory molecules, whereas L-arg supplementation prevented this increase at both ages. Our data suggest that activation of inflammatory pathways is present early in the kidney of DO rats, and that L-arg can attenuate the expression of these markers of tissue inflammation. Our results also reinforce the concept that intrauterine environmental factors are a fundamental determinant in the development of metabolic and vascular diseases later in life.
Assuntos
Injúria Renal Aguda/patologia , Diabetes Mellitus Experimental/patologia , Mediadores da Inflamação/administração & dosagem , Complicações na Gravidez/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Animais , Arginina/administração & dosagem , Arginina/toxicidade , Biomarcadores/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/diagnóstico , Diagnóstico Precoce , Feminino , Mediadores da Inflamação/toxicidade , Masculino , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/etiologia , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/etiologia , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
Hypothalamic insulin inhibits food intake, preventing obesity. High-fat feeding with polyunsaturated fats may be obesogenic, but their effect on insulin action has not been elucidated. The present study evaluated insulin hypophagia and hypothalamic signaling after central injection in rats fed either control diet (15% energy from fat) or high-fat diets (50% energy from fat) enriched with either soy or fish oil. Soy rats had increased fat pad weight and serum leptin with normal body weight, serum lipid profile and peripheral insulin sensitivity. Fish rats had decreased body and fat pad weight, low leptin and corticosterone levels, and improved serum lipid profile. A 20-mU dose of intracerebroventricular (ICV) insulin inhibited food intake in control and fish groups, but failed to do so in the soy group. Hypothalamic protein levels of IR, IRS-1, IRS-2, Akt, mTOR, p70S6K and AMPK were similar among groups. ICV insulin stimulated IR tyrosine phosphorylation in control (68%), soy (36%) and fish (34%) groups. Tyrosine phosphorylation of the pp185 band was significantly stimulated in control (78%) and soy (53%) rats, but not in fish rats. IRS-1 phosphorylation was stimulated only in control rats (94%). Akt serine phosphorylation was significantly stimulated only in control (90%) and fish (78%) rats. The results showed that, rather than the energy density, the fat type was a relevant aspect of high-fat feeding, since blockade of hypothalamic insulin signal transmission and insulin hypophagia was promoted only by the high-fat soy diet, while they were preserved in the rats fed with the high-fat fish diet.
Assuntos
Dieta Hiperlipídica , Óleos de Peixe/administração & dosagem , Hipotálamo/efeitos dos fármacos , Insulina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Óleo de Soja/administração & dosagem , Tecido Adiposo/metabolismo , Animais , Gorduras na Dieta/administração & dosagem , Ingestão de Energia , Hipotálamo/metabolismo , Resistência à Insulina , Leptina/sangue , Masculino , Fosforilação , Ratos , Ratos Wistar , Glycine max , Aumento de PesoRESUMO
Dietary fibers, probably by generating short chain fatty acids (SCFA) through enterobacterial fermentation, have a beneficial effect on the control of glycemia in patients with peripheral insulin resistance. We studied the effect of propionate on glucose-induced insulin secretion in isolated rat pancreatic islets. Evidence is presented that propionate, one of the major SCFA produced in the gut, inhibits insulin secretion induced by high glucose concentrations (11.1 and 16.7 mM) in incubated and perfused pancreatic islets. This short chain fatty acid reduces [U-(14)C]-glucose decarboxylation and raises the conversion of glucose to lactate. Propionate causes a significant decrease of both [1-(14)C]- (84%) and [2-(14)C]-pyruvate (49%) decarboxylation. These findings indicate pyruvate dehydrogenase as the major site for the propionate effect. These observations led us to postulate that the reduction in glucose oxidation and the consequent decrease in the ATP/ADP ratio may be the major mechanism for the lower insulin secretion to glucose stimulus induced by propionate.
Assuntos
Trifosfato de Adenosina/biossíntese , Glicemia/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Propionatos/farmacologia , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Insulina/sangue , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ácido Láctico/metabolismo , Masculino , Piruvatos/metabolismo , Ratos , Ratos Endogâmicos , Taxa Secretória/efeitos dos fármacosRESUMO
During cold exposure, homeothermic animals mobilize glucose with higher efficiency than at thermoneutrality. An interaction between the insulin signal transduction machinery and high sympathetic tonus is thought to play an important role in this phenomenon. In the present study, rats were exposed to cold during 8 days and treated, or not, with a beta3-adrenergic agonist, BRL37344 sodium 4-2-2-(3-chlorophenyl)-2-hydroxyethyl amino propyl phenoxy-acetic acid sodium (BRL37344), or antagonist, SR59230A 3-(2-ethylphenoxy)-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate (SR59230A), to evaluate the cross-talk between insulin and beta3-adrenergic intracellular signaling in brown adipose tissue. The drugs did not modify food ingestion, body temperature, and body weight in control and cold-exposed rats. Treatment of control rats with BRL37344 led to higher insulin-induced tyrosine phosphorylation of the insulin receptors, insulin receptor substrate (IRS)-1 and ERK, higher insulin-induced IRS-1/PI3-kinase association, and higher [Ser(473)] phosphorylation of Akt. Cold exposure alone promoted higher insulin-induced tyrosine phosphorylation of the insulin receptors, IRS-1, IRS-2, and ERK, and higher insulin-induced IRS-1 and IRS-2/PI3-kinase association. Except for the regulation of ERK, SR59230A abolished all the cold-induced effects upon the insulin signal transduction pathway. However, this antagonist only partially inhibited the cold-induced increase of glucose uptake. Thus, the sympathetic tonus generated during cold-exposure acts, in brown adipose tissue, through the beta3-adrenergic receptor and modulates insulin signal transduction, with the exception of ERK. However, insulin-independent mechanisms other than beta3-adrenergic activation participate in cold-induced glucose uptake in brown adipose tissue of rats.
Assuntos
Tecido Adiposo Marrom/fisiologia , Temperatura Baixa , Insulina/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Transdução de Sinais/fisiologia , Adaptação Fisiológica/fisiologia , Tecido Adiposo Marrom/inervação , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Etanolaminas/farmacologia , Glucose/metabolismo , Masculino , Propanolaminas/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologiaRESUMO
The phosphatidylinositol 3-kinase-independent pathway to induce glucose transport may involve the tyrosine phosphorylation of the protooncogene c-Cbl. In the present study, we examined whether acute exposure to insulin stimulates the tyrosine phosphorylation of Cbl and its association with Cbl-associated protein (CAP) in muscle and adipose tissue of rats in vivo. We report herein that insulin induces Cbl tyrosine phosphorylation and association with CAP in adipose tissue but not in muscle. We also examined the expression and tyrosyl-phosphorylation state of Cbl and CAP/Cbl association in adipose tissue of rats submitted to prolonged fasting and in monosodium glutamate (MSG)-insulin-resistant rats. An increase in Cbl phosphorylation is observed in the fat of MSG rats, parallel with an increase in association of CAP-Cbl as well as an augment in CAP and Cbl protein expression in the adipose tissue of these animals. These events are accompanied by a decrease in insulin-stimulated insulin receptor/ insulin receptor substrate (IRS)-1 tyrosine phosphorylation and an increase in the IRS-2/phosphatidylinositol 3-kinase/Akt/Foxo1 pathway. In adipocytes of fasted rats, there is a decrease in CAP and Cbl protein expression, insulin-induced Cbl phosphorylation, and the association with CAP. In parallel, there is also a decrease in the insulin receptor/IRSs/Akt/Foxo1 pathway. Thus, insulin is able to induce Cbl tyrosine phosphorylation and its association with CAP in the adipose tissue of normal rats. In addition, our data provide evidence that the CAP-Cbl pathway may have a role in the modulation of adiposity in fasting and in MSG-treated rats.