RESUMO
OBJECTIVE: To explore the effects of transient correction of enhanced corticoadrenal activity in monosodium L-glutamate (MSG)-damaged female rats on peripheral insulin sensitivity and in vitro retroperitoneal (RP) adipocyte function. DESIGNS: A dose of 4 mg/g body weight (BW) of MSG or vehicle (CTR) was i.p. injected, once every 2 days, between days 2 and 10 of age, in female rats. Intact and 21 day-operated (sham or adrenal enucleation (AE)) rats from both (CTR and MSG) groups were used for experimentation on day 120 of age. Circulating levels of several hormones, in basal and after i.v. high-glucose load conditions, and RP adiposity morphology and function were then evaluated. RESULTS: MSG rats developed increased adrenocortical function, hyperadiposity, hyperleptinemia, hyperinsulinemia and decreased peripheral insulin sensitivity. These characteristics were fully reversed after transient correction of corticoadrenal hyperactivity induced by AE. In addition, in vitro experimentation with isolated RP adipocytes indicated that cells from intact MSG animals displayed decreased sensitivity to insulin and dexamethasone stimulation of leptin secretion. Interestingly, adipocyte dysfunction in MSG rats was fully abrogated after AE-induced transient correction of insulinemia, leptinemia and adrenocortical activity. Importantly, the reversion of these metabolic abnormalities, induced by AE for 21 days, in MSG animals did occur, despite no significant changes in BW values. CONCLUSION: Our results support that the changes in adipocyte characteristics and peripheral insulin resistance, developed in this pseudo-obese female rat model, are mainly due to increased glucocorticoid production. Importantly, appropriate correction of the enhanced adrenocortical activity fully reversed these abnormal functions.
Assuntos
Adipócitos/fisiologia , Adiposidade/fisiologia , Córtex Suprarrenal/fisiopatologia , Doenças Hipotalâmicas/fisiopatologia , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Tecido Adiposo/patologia , Tecido Adiposo/fisiopatologia , Animais , Glicemia/metabolismo , Células Cultivadas , Corticosterona/sangue , Dexametasona/farmacologia , Feminino , Glucocorticoides/biossíntese , Doenças Hipotalâmicas/induzido quimicamente , Doenças Hipotalâmicas/complicações , Insulina/sangue , Insulina/farmacologia , Resistência à Insulina/fisiologia , Leptina/sangue , Masculino , Obesidade/etiologia , Obesidade/patologia , Obesidade/fisiopatologia , Ratos , Ratos Sprague-Dawley , Glutamato de SódioRESUMO
The present study was designed to assess the effect of maternal undernutrition, during gestation and lactation, on the neuroendocrine [hypothalamo-pituitary-adrenal (HPA)]-immune axis response to endotoxin (LPS) administration. For this purpose, 21-day-old male rats from both well-nourished (WN) and undernourished (UN) mothers were examined 2 h after injection (i.p.) of vehicle alone (VEH) or containing LPS (130 microg/kg BW). Circulating levels of glucose (GLU), ACTH, corticosterone (B), tumor necrosis factor-alpha (TNFalpha) and leptin were explored. The results indicate that: (a) mother body weight was significantly (p < 0.05) reduced, as a consequence of UN, at the second and third weeks of pregnancy; (b) no differences in basal glycemia were found in the two groups of pups, and LPS treatment did not induce hypoglycemia, in either group; (c) basal plasma ACTH, B and TNFalpha levels were similar in the two groups, and LPS-induced ACTH, B and TNFalpha secretions, although severalfold higher than respective VEH values (p < 0.05) in pups from WN mothers, were fully (ACTH and B) and partially (TNFalpha) abolished in products from UN mothers; (d) both mean body weights and basal plasma leptin levels were significantly (p < 0.05) lower in pups from UN than from WN mothers, and LPS administration did not modify plasma leptin values in products from both groups. In addition, results of dispersed total adrenal cells incubated in vitro indicate that: (a) both basal and ACTH (22 pM)-induced B secretion were significantly (p < 0.05) lower in cells from UN than WN pups, and (b) leptin (100 nM) was able to inhibit partially ACTH-stimulated B output by adrenal gland (AG) cells from WN pups; however, it failed to inhibit ACTH-stimulated glucocorticoid release by AG cells from UN pups. The present results indicate that undernutrition in mothers, during the very critical periods of gestation and lactation, induces in their male pups at weaning: (a) reduced circulating leptin levels and body weight values; (b) metabolic adaptation to normal carbohydrate metabolism; (c) hyporesponsiveness of the HPA and immune (TNFalpha) axes during endotoxemia, and (d) leptin resistance at the adrenocortical level. This study strongly supports that undernutrition of mothers results in neuroendocrine immune dysfunction of their pups; however, adrenal resistance to the inhibitory effect of leptin on glucocorticoid output is developed, probably as an adaptive mechanism to counteract unfavorable metabolic conditions.
Assuntos
Sistema Hipotálamo-Hipofisário/fisiopatologia , Síndromes de Imunodeficiência/etiologia , Distúrbios Nutricionais/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Complicações na Gravidez/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal , Adaptação Fisiológica , Glândulas Suprarrenais/citologia , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/farmacologia , Animais , Animais Lactentes , Glicemia/análise , Peso Corporal , Corticosterona/sangue , Corticosterona/metabolismo , Feminino , Idade Gestacional , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/fisiopatologia , Lactação , Leptina/sangue , Leptina/farmacologia , Lipopolissacarídeos/toxicidade , Masculino , Troca Materno-Fetal , Neuroimunomodulação/fisiologia , Gravidez , Ratos , Ratos Endogâmicos F344 , Fator de Necrose Tumoral alfa/análise , DesmameRESUMO
Neuroendocrine-immune interactions are vital for the individual's survival in certain physiopathological conditions such as sepsis and tissular injury. It is known that several snake venoms (SV) are potent neurotoxic compounds and that their main component is a specific phospholipase type 2 (PLA2). It has been recently described that the venom from crotalus durissus terrificus (SV) possesses a cytotoxic effect in different in vitro and in vivo animal models. In the present study we investigated whether SV is able to stimulate both TNFalpha and neuroendocrine functions in a sexual dimorphic fashion. For this purpose the modulatory role of endogenous sex steroids during neurotoxemia was evaluated. Our results indicate that SV (25 microg/animal) stimulates the hypothalamo-pituitary-adrenal axis and TNFalpha secretion when administered (ip) to adult male mice, such responses were characterized by a time-related enhance in plasma glucose, ACTH, corticosterone and TNFalpha levels. SV-stimulated glycemia, corticosteronemia and adrenal glucocorticoid were sexually dimorphic. Twenty-day gonadectomized mice showed a similar sexual dimorphism to that found in intact animals, however, they additionally showed a sexual dimorphic pattern in cytokine release in plasma 30 min post-SV. Estradiol (E2) treatment, in gonadectomized mice, abolished some characteristics of the sexual dimorphism, such as hyperglycemia, hypercorticosteronemia and hypercytokinemia. Finally, in vitro experiments indicate that: a) gonadectomy increased spontaneous and SV-stimulated cytokine output by incubated peripheral mononuclear cells (PMNC), regardless of the sex; and b) despite E2 treatment, in gonadectomized, did not modify the pattern of basal and SV-elicited TNFalpha secretion induced by orchidectomy, fully reversed the enhance in basal and SV-stimulated cytokine release found after ovariectomy alone. Our results further indicate that neurotoxemia, due to SV challenge, induces several symptoms common to those of inflammatory stress; they also strongly support that both gender and endogenous sex steroids are responsible for neuroendocrine-immunological sexual dimorphism.
Assuntos
Glândulas Suprarrenais/fisiologia , Venenos de Crotalídeos/farmacologia , Sistema Hipotálamo-Hipofisário/fisiologia , Fosfolipases A , Caracteres Sexuais , Fator de Necrose Tumoral alfa/metabolismo , Hormônio Adrenocorticotrópico/sangue , Animais , Glicemia/metabolismo , Corticosterona/sangue , Estradiol/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/metabolismo , Orquiectomia , Ovariectomia , Fosfolipases A2RESUMO
It is well recognized that the reciprocal interaction established between the immune and neuroendocrine systems is crucial for the homeostatic adaptation of individuals during septicemia. In the present study, using an in vivo rat model, we investigated the degree of participation of central and peripheral epinergic systems in the modulation of the hypothalamic-pituitary-adrenal and immune axes' functions during endotoxemia. For this purpose, acute endotoxemia was induced in adult male rats pretreated intraperitoneally with either different inhibitors of phenylethanolamine-N-methyltransferase (PNMT) [which are active either peripherally (SKF 29661) or both peripherally and centrally (SKF 64139), thus lowering epinephrine (EPI) synthesis] or vehicle only (CTRL). Twelve hours after pretreatment, animals were intraperitoneally injected with vehicle alone (basal) or vehicle containing bacterial lipopolysaccharide (LPS) and sacrificed 2 h later. A significant (p < 0.05 vs. the respective basal value) hypoglycemia was found in all groups studied. No pretreatment modified basal plasma adrenocorticotropic hormone (ACTH), glucocorticoid and cytokine concentrations. Endotoxin-stimulated ACTH secretion was severalfold (p < 0.05) higher than the respective basal value in CTRL and in SKFs-pretreated rats; however, the plasma ACTH levels after LPS were significantly (p < 0.05 vs. CTRL and SKF-29661 values) reduced in SKF-64139-pretreated rats. All groups studied showed an appropriate adrenal response to endotoxin challenge. Although no differences were found in basal anterior pituitary (AP) ACTH content among groups, LPS treatment significantly (p < 0.05 versus the respective basal value) decreased AP ACTH in CTRL and SKF 29661 groups. No pretreatment modified the basal medial basal hypothalamus (MBH) corticotropin-releasing hormone (CRH) content. Conversely, SKF 64139 pretreatment significantly (p < 0.05 vs. CTRL and SKF 29661 values) reduced basal median eminence (ME) CRH content, and LPS administration significantly (p < 0.05) decreased ME CRH in CTRL and SKF-29661-pretreated rats. SKF 64139 pretreatment significantly (p < 0.05) enhanced basal MBH and ME arginine vasopressin (AVP) contents. LPS administration significantly (p < 0.05) decreased MBH AVP in CTRL and SKF-29661-pretreated rats and diminished (p < 0.05 vs. basal values) ME AVP in all groups. The plasma tumor necrosis factor alpha (TNFalpha) concentrations were enhanced severalfold (p < 0.05 vs. basal values) after LPS treatment in CTRL rats, but not in SKFs-treated animals. In order to explore the reduced cytokine release after LPS in PNMT-inhibited rats, additional ex vivo experiments were performed by using peripheral mononuclear cells (PMNC) from both CTRL and SKF-29661-pretreated rats. The results of these experiments confirmed an immune dysfunction after inhibition of peripheral EPI synthesis; in fact, basal and concanavalin-A-stimulated TNFalpha secretions were significantly (p < 0.05) lower in SKF-29661-treated than in CTRL PMNC, while, interestingly, addition of EPI (10(-7) M) to the medium fully restored these effects. These data demonstrate that: (1) the mechanism whereby LPS-induced hypoglycemia was independent of epinergic activity; (2) selective central inhibition of epinergic function reduced endotoxin-stimulated ACTH secretion, an effect that could mainly be due to a decrease in CRH-ergic activity; (3) the central epinergic system positively and negatively modulates CRH- and AVPergic functions, respectively, and (4) inhibition of peripheral PNMT activity reduced immune system function in vivo and ex vivo. It is further suggested that low peripheral levels of EPI could be beneficial for the body's defense mechanisms during endotoxic shock.
Assuntos
Epinefrina/fisiologia , Sistema Hipotálamo-Hipofisário/imunologia , Neuroimunomodulação/fisiologia , Norepinefrina/fisiologia , Sistema Hipófise-Suprarrenal/imunologia , Tetra-Hidroisoquinolinas , Reação de Fase Aguda/imunologia , Hormônio Adrenocorticotrópico/metabolismo , Animais , Hormônio Liberador da Corticotropina/metabolismo , Inibidores Enzimáticos/farmacologia , Hipoglicemia/induzido quimicamente , Hipoglicemia/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Isoquinolinas/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Neuroimunomodulação/efeitos dos fármacos , Feniletanolamina N-Metiltransferase/antagonistas & inibidores , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Ratos Endogâmicos F344 , Fator de Necrose Tumoral alfa/metabolismo , Vasopressinas/metabolismoRESUMO
Chronic malnutrition is one of the most important causes of several metabolic, immune and neuroendocrine dysfunctions. The aim of the present study was to determine the influence of chronic food restriction on basal neuroendocrine, immune and adipocyte functions and during the acute-phase response to endotoxic shock in female rats. The effect of refeeding of undernourished rats on the above-mentioned functions was also investigated. For these purposes, plasma total protein, glucose, triglycerides, ACTH, corticosterone, tumor necrosis factor-alpha (TNF) and leptin (LEP) levels were determined in basal condition and 2 h after endotoxin (LPS; 180 microgram/kg body weight, i.p.) administration in 3 different groups: (1) well-nourished (WN) controls; (2) undernourished (UN) rats as a consequence of chronic food restriction, and (3) UN rats re-fed to restoration of their body weights in the WN rat range. The results indicate that UN rats, in comparison with WN controls, developed an arrest in body weight gain as well as in basal hypoglycemia, hypotriglyceridemia, hypoleptinemia, hypercorticosteronemia and enhanced adrenal glucocorticoid content; however, no changes in basal total protein, ACTH and TNF plasma levels and in anterior pituitary ACTH concentrations were found. When endotoxic shock was induced, the LPS-induced hypoglycemia developed in WN rats was abolished in UN animals, and both ACTH and TNF plasma concentrations after endotoxin, albeit significantly (p < 0.05) higher than the respective basal values, were significantly (p < 0.05) lower in UN than in WN control rats. Despite the high basal plasma corticosterone concentration in UN vs. WN rats, the LPS-induced glucocorticoid release was similar in WN and UN rats. Additionally, LPS treatment did not modify basal plasma LEP levels, regardless of the group. Interestingly, UN rats fed ad libitum for 15 days restored their body weight to WN rat range values, and the various metabolic dysfunctions seen in UN rats in both basal and post-LPS conditions were fully normalized. Our results clearly indicate that chronic undernutrition not only affects, as earlier described, reproductive function but also metabolic, neuroendocrine, immune and adipocyte functions, and that the effects induced by undernutrition can be fully reversed after recovery of normal body weight. The present study strongly supports the involvement of the metabolic status in the effectiveness of the defense mechanisms developed in patients in inflammatory stress conditions.
Assuntos
Reação de Fase Aguda , Adipócitos/metabolismo , Sistema Imunitário/fisiopatologia , Sistemas Neurossecretores/fisiopatologia , Distúrbios Nutricionais , Choque Séptico , Reação de Fase Aguda/sangue , Reação de Fase Aguda/induzido quimicamente , Reação de Fase Aguda/imunologia , Reação de Fase Aguda/metabolismo , Adipócitos/efeitos dos fármacos , Hormônio Adrenocorticotrópico/sangue , Envelhecimento/fisiologia , Animais , Glicemia/análise , Corticosterona/sangue , Feminino , Privação de Alimentos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Leptina/sangue , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/farmacologia , Análise por Pareamento , Sistemas Neurossecretores/efeitos dos fármacos , Sistemas Neurossecretores/metabolismo , Distúrbios Nutricionais/sangue , Distúrbios Nutricionais/imunologia , Distúrbios Nutricionais/metabolismo , Ratos , Ratos Sprague-Dawley , Choque Séptico/sangue , Choque Séptico/induzido quimicamente , Choque Séptico/imunologia , Choque Séptico/metabolismo , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/análise , Aumento de PesoRESUMO
The mutation of the ob gene is known to induce a phenotype of obesity accompanied by symptoms including enhanced production of glucocorticoid. Chronic administration to ob/ob mice of leptin, the ob gene product, reverses hypercorticosteronemia. This establishes a clear relation between adipocyte and hypothalamo-pituitary-adrenal (HPA) axis functions. In the present study we investigated the acute modulatory effects of food intake-stimulated leptin secretion on HPA axis activity and hypothalamic leptin receptor (Ob-Rb) expression in 24-hour fasting, adult female, BALB/c mice after insulin-induced hypoglycemia. Our results indicate that: (1) food supply for 45 min to 24-hour fasting mice increased plasma glucose levels and reversed both hypercorticosteronemia and hypoleptinemia; (2) the insulin-induced hypoglycemia produced a marked HPA axis activation in animals with no access to food but this response was fully prevented by food intake and the consecutive increase in plasma leptin levels; (3) the inhibitory effect of leptin on the HPA axis response to insulin-induced hypoglycemia was corroborated by i.p. administration of murine leptin, and (4) fasting-induced hypothalamic Ob-Rb overexpression is not modulated by insulin itself but by leptin, since increase in leptin levels by food intake or by administration of exogenous leptin completely reversed this Ob-Rb overexpression. These results confirm the inhibitory effect of leptin on the HPA axis response to various stress stimuli. They clearly demonstrate that acute food intake in 24-hour fasting mice: (a) rapidly reduced fasting-induced hypercorticosteronemia by enhancing both spontaneous and insulin-elicited endogenous leptin secretion; (b) fully prevented HPA axis response to insulin administration, by rapidly increasing endogenous leptin secretion and probably also by diminishing the extent and the duration of insulin-induced hypoglycemia, and (c) abolished hypothalamic Ob-Rb overexpression induced by fasting itself combined with insulin treatment. The present data strongly suggests an inhibitory effect of endogenous leptin on insulin-induced HPA axis response, an interaction relevant to the physiological adaptation to starvation and caloric excess, and further supports the pivotal role played by the hypothalamus in restoring homeostasis in different allostatic states.
Assuntos
Proteínas de Transporte/genética , Ingestão de Alimentos/fisiologia , Hipoglicemiantes/farmacologia , Sistema Hipotálamo-Hipofisário/metabolismo , Insulina/farmacologia , Leptina/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Superfície Celular , Hormônio Adrenocorticotrópico/sangue , Animais , Glicemia , Metabolismo Energético/fisiologia , Jejum/fisiologia , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Leptina/sangue , Camundongos , Camundongos Endogâmicos BALB C , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , RNA Mensageiro/análise , Receptores para Leptina , Estresse Fisiológico/metabolismoRESUMO
The product of the ob/ob gene, leptin, is known to be able to exert a modulator, role on HPA axis function. The aim of the present study was to determine whether endogenous ACTH and glucocorticoids exert any regulatory effect on leptin secretion. For this purpose bilaterally adrenalectomized (ADX) or sham operated (Sham) adult male rats were implanted with an indwelling i.v. catheter. A subgroup of ADX animals received, at the same time of surgery, a s.c. corticosterone (B) pellet (75 mg) (ADX+B). All animals were subjected to experimental designs 7 days after surgery. Our results indicate, as expected, that 7-day ADX animals have several fold increased basal ACTH plasma levels and non detectable circulating B, whereas ADX+B rats showed basal plasma ACTH levels in the range of Sham values and plasma B concentrations of about 5 microg/dl. Interestingly, basal plasma leptin levels were significantly (P < 0.05) decreased by 7 days post ADX, and B replacement therapy (ADX+B) restored circulating leptin to Sham levels. Acute dexamethasone (Dxmn, 30 microg/kg body weight, i.v.) treatment induced a very rapid decrease in plasma ACTH concentrations in both Sham and ADX rats, as well as a decrease in plasma B levels in Sham rats. Interestingly, Dxm test had no effect on plasma leptin levels in Sham animals; however, in ADX rats, the synthetic glucocorticoid increased plasma leptin concentrations, restoring the levels observed in Sham rats. This effect occurred at the same time when plasma ACTH levels were decreasing toward basal Sham values. These results clearly indicate that, beside the known effects of leptin on HPA axis function, circulating ACTH and glucocorticoid are able to modulate leptin secretion in plasma. The lack of circulating glucocorticoid and/or increased plasma ACTH concentrations, are responsible for decreasing leptin output, whereas decreased plasma ACTH concentrations allow an increase of leptin secretion in blood. Our data strongly support the existence of a closed, bi-directional, circuit between HPA axis function and adipose tissue metabolism. They further indicate the physiological relevance of different types of stress associated with many phenotypes of obesity.
Assuntos
Hormônio Adrenocorticotrópico/fisiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Proteínas/metabolismo , Adrenalectomia , Hormônio Adrenocorticotrópico/sangue , Animais , Corticosterona/farmacologia , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Leptina , Masculino , Ratos , Ratos WistarRESUMO
Immune neuroendocrine interactions are vital for the individual's survival in certain physiopathological conditions, such as sepsis and tissular injury. It is known that several animal venoms, such as those from different snakes, are potent neurotoxic compounds and that their main component is a specific phospholipase A type 2 (PLA2). It has been described recently that the venom from Crotalus durissus terrificus [snake venom (SV), in the present study] possesses some cytotoxic effect in different in vitro and in vivo animal models. In the present study, we investigated whether SV and its main component, PLA2 (obtained from the same source), are able to stimulate both immune and neuroendocrine functions in mice, thus characterizing this type of neurotoxic shock. For this purpose, several in vivo and in vitro designs were used to further determine the sites of action of SV-PLA2 on the hypothalamo-pituitary-adrenal (HPA) axis function and on the release of the pathognomonic cytokine, tumor necrosis factor alpha (TNF alpha), of different types of inflammatory stress. Our results indicate that SV (25 microg/animal) and PLA2 (5 microg/animal), from the same origin, stimulate the HPA and immune axes when administered (i.p.) to adult mice; both preparations were able to enhance plasma glucose, ACTH, corticosterone (B), and TNF alpha plasma levels in a time-related fashion. SV was found to activate CRH- and arginine vasopressin-ergic functions in vivo and, in vitro, SV and PLA2 induced a concentration-related (0.05-10 microg/ml) effect on the release of both neuropeptides. SV also was effective in changing anterior pituitary ACTH and adrenal B contents, also in a time-dependent fashion. Direct effects of SV and PLA2 on anterior pituitary ACTH secretion also were found to function in a concentration-related fashion (0.001-1 microg/ml), and the direct corticotropin-releasing activity of PLA2 was additive to those of CRH and arginine vasopressin; the corticotropin-releasing activity of both SV and PLA2 were partially reversed by the specific PLA2 inhibitor, manoalide. On the other hand, neither preparation was able to directly modify spontaneous and ACTH-stimulated adrenal B output. The stimulatory effect of SV and PLA2 on in vivo TNF alpha release was confirmed by in vitro experiments on peripheral mononuclear cells; in fact, both PLA2 (0.001-1 microg/ml) and SV (0.1-10 microg/ml), as well as concavalin A (1-100 microg/ml), were able to stimulate TNF alpha output in the incubation medium. Our results clearly indicate that PLA2-dependent mechanisms are responsible for several symptoms of inflammatory stress induced during neurotoxemia. In fact, we found that this particular PLA2-related SV is able to stimulate both HPA axis and immune functions during the acute phase response of the inflammatory processes.
Assuntos
Venenos de Crotalídeos/farmacologia , Sistema Imunitário/efeitos dos fármacos , Sistemas Neurossecretores/efeitos dos fármacos , Fosfolipases A/farmacologia , Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Animais , Arginina Vasopressina/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Feminino , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Hipotálamo/metabolismo , Eminência Mediana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/metabolismo , Fosfolipases A2 , Adeno-Hipófise/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Bidirectional communication between the immune and the endocrine systems is now widely accepted as essential for the survival of the organism. Since a classical nonresponsive period of the hypothalamic-pituitary-adrenal (HPA) axis takes place shortly after birth and because endogenous sex hormones modulate immune function, the aim of the present work was to determine whether sex steroids regulate the PHA axis response to immune (bacterial, lipopolysaccharide, LPS) and nonimmune (insulin, INS) stressors in mice during development. For this purpose 7-, 15-, 30-, 45- and 60-day-old mice of both sexes were intraperitoneally injected with either vehicle alone (basal) or containing LPS (2 mg/kg body weight) or INS (12 IU/kg body weight). The animals were then killed by decapitation, 2 h or 45 min after LPS or INS, respectively. Plasma samples were assayed to measure corticosterone concentrations. The results indicated that: (a) there was a transient increase in basal plasma corticosterone levels during development, with a peak value at the juvenile age, regardless of sex; (b) a higher basal plasma corticosterone concentration in females than in males characterized the adult age; (c) the infantile age is a period of the HPA axis function nonresponsive to purely neuroendocrine but not to inflammatory stimuli; (d) during the juvenile age, females showed a hyporesponsive HPA axis to neurendocrine and immune stress, whereas male mice were fully unresponsive to both challenges; (e) animals of both sexes showed a maximal HPA axis response to purely neuroendocrine stress at the prepubertal age; this response to the immune stimulus was also maximal in 30-day-old males, while it was found in females after puberty (45-day-old mice); (f) sexual dimorphism in the HPA axis response to a purely neuroendocrine stimulus was found at 30 days of age or later, while this characteristic of the response to endotoxin was not present until puberty. These data clearly suggest that these are gender-dependent characteristics of the ontogeny of the HPA and HP-gonadal axes that are responsible for the sexual dimorphism of HPA axis function in mice.
Assuntos
Endotoxinas/farmacologia , Crescimento/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiologia , Insulina/farmacologia , Sistema Hipófise-Suprarrenal/fisiologia , Caracteres Sexuais , Animais , Feminino , Glucocorticoides/sangue , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Gravidez , Estresse Fisiológico/induzido quimicamenteRESUMO
A bidirectional relationship between the immune and neuroendocrine systems is now widely accepted. Since it is well known that the thymus plays an important role in the regulation of the immune function, we decided to explore whether a lack of the thymic function may influence hypothalamic-pituitary-adrenal (HPA) axis activity. Eight-week-old female mice of both strains, nude and control BALB/c, were used to study: (a) the in vivo response of the HPA axis to several stress stimuli acting at either the hypothalamic (insulin administration and ether vapor inhalation), pituitary (CRH and vasopressin injections) or adrenal (ACTH treatment) level and (b) the in vitro response of hypothalamic fragments to high KCl (48 mM) stimulation. The results indicate that: (1) basal plasma ACTH and vasopressin levels were significantly (p < 0.05) higher in nude than in control BALB/c mice, whereas basal plasma corticosterone concentrations were similar in both strains of mice; (2) although no significant strain-related difference in the stress-induced ACTH secretion in plasma was found, hypothalamic stimuli were able to induce a significantly (p < 0.05) higher secretion of glucocorticoid in plasma in nude than in control BALB/c mice; (3) the pattern of in vitro hypothalamic CRH release was similar in both strains of animals; however, basal AVP output and that stimulated by 48 mM KCl were significantly (p < 0.05) higher in nude than in control hypothalamic fragments, and (4) whereas hypothalamic CRH, pituitary ACTH and adrenal glucocorticoid contents were similar in both strains, hypothalamic AVP content was significantly (p < 0.05) higher in athymic than in control mice. In summary, our results indicate that nude mice have an increased vasopressinergic function which could contribute to a normal HPA axis activity; thus, adult athymic mice of BALB/c origin could compensate, due to their increased vasopressinergic function, for a robust glucocorticoid release to protect themselves immediately after aggression. It remains to be determined whether this enhanced vasopressinergic function is a result of an early adrenal insufficiency due to congenital deficiency of thymic factors known to stimulate HPA axis function.
Assuntos
Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Estresse Fisiológico/fisiopatologia , Vasopressinas/fisiologia , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/farmacologia , Animais , Arginina Vasopressina/sangue , Arginina Vasopressina/metabolismo , Arginina Vasopressina/farmacologia , Corticosterona/sangue , Hormônio Liberador da Corticotropina/farmacologia , Éter , Feminino , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Potássio/farmacologia , Estresse Fisiológico/induzido quimicamenteRESUMO
In the present investigation, we examined the influence of both genetic background and sex factors in the rat hypothalamo-pituitary-adrenal (HPA) axis function under both basal and post adrenalectomy (ADX) conditions. For these purposes adult female and male rats, from Sprague-Dawley (S-D), Fischer (F344/N), Lewis (LEW/N) and Buffalo (BUF) strains, were decapitated in basal condition or several (2, 7 and 14) days after ADX. Plasma stress hormones levels and adrenal corticosterone (B) concentration as well as peptide (ACTH, CRH and vasopressin, AVP) content in different tissues (anterior pituitary, AP; medial basal hypothalamus, MBH), were then evaluated by specific assays. Our results indicate that: a) despite no sex- and strain-related differences in AP ACTH and MBH ACTH secretagogues in basal condition, there exits a clear sexual dimorphism in plasma ACTH levels as well as in both plasma and adrenal B concentrations, with values significantly higher in females than in males, regardless the strain; b) ADX abolished plasma B levels and increased AP ACTH output in a time-dependent fashion up to the 14th day post surgery; c) AP ACTH content decreased 2 days after ADX, except in BUF female rats, thereafter tending to either recover or increase sham values by two weeks post ADX; d) ADX decreased MBH CRH at all periods studied, except in BUF female animals on day 14; e) ADX clearly diminished MBH AVP only in S-D rats, and f) a sexual dimorphism was also found in AP ACTH in 7-day-ADX S-D rats and in 14-day-ADX S-D and F344/N animals; also, a dimorphic pattern in MBH CRH was found in 7-day-ADX S-D as well as in 14-day-ADX F344/N and LEW/N rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Glândulas Suprarrenais/fisiologia , Hipotálamo/fisiologia , Hipófise/fisiologia , Caracteres Sexuais , Adrenalectomia , Hormônio Adrenocorticotrópico/metabolismo , Animais , Arginina Vasopressina/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Retroalimentação , Feminino , Masculino , Adeno-Hipófise/metabolismo , Ratos , Ratos Endogâmicos BUF , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Especificidade da EspécieRESUMO
Susceptibility to inflammatory disease in infantile Lewis (LEW/N) female rats seems to be related to their impaired hypothalamo-pituitary-adrenal (HPA) axis response to different inflammatory stimuli, while the relative resistance to this type of disease in Fischer (F344/N) female rats is apparently due to their potent HPA axis response to the same stimuli. In the present study, we attempted to elucidate whether there is an impairment in the HPA axis response in the juvenile female LEW/N rat to inflammatory and noninflammatory stimuli, and also to determine whether the endogenous sex-steroid environment influences the HPA axis function in both strains of rats. For these purposes, juvenile F344/N and LEW/N rats of both sexes were submitted to different treatments: (a) inhalation of normal atmosphere or ether vapors for 1 min (Ether); (b) i.p. injection of vehicle alone or containing CRH (0.5 microgram/rat), arginine vasopressin (AVP; 5 micrograms/rat, angiotensin II (AII; 5 micrograms/rat), insulin (INS; 0.3 IU/rat), bacterial lipopolysaccharide (LPS; 100 micrograms/rat) or snake venom (SV; 100 micrograms/rat). Rats were then killed at different time intervals (in min) after treatments: 20 for Ether, AVP and CRH, 30 for AII, 45 for INS, 60 for SV and 120 for LPS.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Sistema Hipotálamo-Hipofisário/fisiologia , Mediadores da Inflamação/farmacologia , Sistema Hipófise-Suprarrenal/fisiologia , Caracteres Sexuais , Hormônio Adrenocorticotrópico/sangue , Angiotensina II/farmacologia , Animais , Arginina Vasopressina/metabolismo , Arginina Vasopressina/farmacologia , Glicemia/análise , Hormônio Liberador da Corticotropina/metabolismo , Éter/farmacologia , Feminino , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Mediadores da Inflamação/administração & dosagem , Insulina/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Venenos de Serpentes/farmacologiaRESUMO
Many studies have documented the presence of a sexually dimorphic response of neuroendocrine functions in response to immune signals. The aims of the present study were to evaluate the hypothalamopituitary-adrenal (HPA) axis response to inflammatory stress stimulus in 15-month-old mice, and to determine whether such a response depends on circulating sex steroids. Our results indicate that in the 15-month-old mice: (1) there is a sexual dimorphism in the HPA axis activity in basal condition and after endotoxin treatment with generally higher levels of several parameters of this axis in female than in male mice, (2) gonadectomy alone, followed by sex steroid therapy, modulates HPA axis function in both basal and stress conditions, and (3) whereas estradiol plays a stimulatory role on adrenal function, testosterone inhibits adrenal glucocorticoid production. This study further suggests a clear sexual dimorphism in middle-aged mice injected with endotoxin. These results may be relevant for the treatment of sepsis in aged patients.
Assuntos
Córtex Suprarrenal/imunologia , Endotoxinas/farmacologia , Hormônios Esteroides Gonadais/farmacologia , Sistema Hipotálamo-Hipofisário/imunologia , Hormônio Adrenocorticotrópico/sangue , Animais , Corticosterona/sangue , Feminino , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Fisiológico , Fatores de TempoRESUMO
Bacterial lipopolysaccharide (LPS) stimulates the hypothalamo-pituitary-adrenal axis by a mechanism involving the release of cytokines, which activate the CRH-ACTH system and, as a result, increase glucocorticoid secretion. In the present study we investigated the possibility that endogenous sex hormones modulate the in vivo endotoxin-stimulated adrenal and immune responses in adult BALB/c mice. In preliminary experiments we determined that the maximal glucocorticoid release in response to LPS (50 micrograms, ip) administration was reached 2 h after treatment. The endotoxin effect on the adrenal and immune responses was then tested in male, randomly cycling female, 20-day-gonadectomized and 20-day-gonadectomized mice treated with either testosterone or estradiol. In addition, in vitro experiments were performed to determine whether 1) LPS exerts any direct effect on basal and ACTH-stimulated corticosterone release, and 2) adrenal function is influenced by bilateral gonadectomy and sex steroid therapy. Our results indicate that 1) randomly cycling female mice have significantly more pronounced corticosterone secretion than males 2 h after endotoxin injection, although the tumor necrosis factor responses were similar; 2) the response of the hypothalamo-pituitary-adrenal axis to endotoxin stimulation in female mice was invariable throughout the different stages of the normal estrous cycle; 3) gonadectomy leads to enhanced (P < 0.05) adrenal and immune responses to LPS stimulation compared to the responses in shams; 4) the endotoxin-elicited adrenal and immune overresponses observed in gonadectomized mice are reversed by testosterone treatment, regardless of sex; 5) LPS does not directly modify spontaneous and ACTH-stimulated adrenal corticosterone secretion; and 6) gonadectomy alone or combined with sex steroid therapy does not increase the in vitro adrenal response to ACTH stimulation. Our findings further suggest an evident neuroendocrine-immunological sexual dimorphism during the acute phase of inflammatory processes.
Assuntos
Endotoxinas/farmacologia , Estradiol/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Orquiectomia , Ovariectomia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Caracteres Sexuais , Testosterona/farmacologia , Hormônio Adrenocorticotrópico/farmacologia , Animais , Corticosterona/sangue , Estro/fisiologia , Feminino , Glucocorticoides/classificação , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/fisiologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Sistemas Neurossecretores/efeitos dos fármacos , Sistemas Neurossecretores/fisiologia , Fatores de Tempo , Fator de Necrose Tumoral alfa/análiseRESUMO
Antigen-activated immune cells acutely release cytokines which, besides their effects on the immune system, increase hypothalamopituitary-adrenocortical (HPA) function to counteract the inflammatory process. The present study was designed to test, using in vitro paradigms, whether there exists a hypothalamic and/or a median eminence site of action, whereby different substances derived from the immune system could stimulate the CRH and/or the arginine-vasopressin (AVP) neuronal pathway. For this purpose, whole medial basal hypothalamus (containing the median eminence) were dissected from female rats and incubated in vitro with several concentrations of interleukin-1 (IL-1)beta, interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, thymosin fraction 5 (TF5) or bacterial lipopolysaccharide (LPS). After a 40-min incubation period, the amounts of CRH and AVP released into the incubation medium were measured by specific radioimmunoassays (RIAs). Additional experiments were carried out by superfusing isolated rat median eminence fragments with the different test substances; CRH and AVP released into the medium were also measured by RIAs. The results indicated that IL-1 beta (10(-11) to 10(-7) M), IL-6 (0.06 x 10(-10) to 0.4 x 10(-10) M), TNF-alpha (6 x 10(-9) to 6 x 10(-7) M) and TF5 (5-500 micrograms/ml) but not LPS (1-100 ng/ml) significantly enhanced hypothalamic CRH secretion above baseline in a concentration-related fashion. Additionally, superfusion experiments demonstrated that, among all test substances, only IL-6 possesses a direct and dose-dependent CRH-releasing activity at the median eminence level. Conversely, no preparation enhanced basal AVP release in either in vitro design.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Hormônio Liberador da Corticotropina/fisiologia , Citocinas/farmacologia , Interleucina-6/farmacologia , Eminência Mediana/efeitos dos fármacos , Neurônios/fisiologia , Vasopressinas/fisiologia , Angiotensina II/farmacologia , Animais , Arginina Vasopressina/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Feminino , Hipotálamo/metabolismo , Hipotálamo Médio/metabolismo , Lipopolissacarídeos , Potássio/farmacologia , Ratos , Ratos Endogâmicos , Timosina/análogos & derivados , Timosina/farmacologiaRESUMO
Many reports indicate that serotonin plays a role in the regulation of the hypothalamo-pituitary-adrenocortical axis. The present study was designed to elucidate whether the activation of the central serotonergic pathway enhances adrenocorticotropin and corticosterone secretion, and if so, whether the CRH and vasopressin neuronal systems could be mediating this effect. Intraperitoneal administration of a low dose of L-5-hydroxytryptophan (an aromatic L-amino acid precursor of serotonin synthesis; 20 mg/kg bw, 30 minutes before the sacrifice) in rats pretreated with pargyline (a brain monoamine oxidase inhibitor, which enhances monoamine activity; 75 mg/Kg bw, 16 hours before the sacrifice) and carbidopa (a peripheral active inhibitor of the decarboxylation of aromatic L-amino acids, which would permit more monoamine precursor to be available to the brain; 50 mg/Kg bw, 90 minutes before the sacrifice) increased ACTH and corticosterone secretion in plasma. Such an effect was partially blocked by metergoline (a serotonin type-1 and-2 receptor blocker; 1 mg/Kg bw, 90 minutes before the sacrifice), but not by spiperone (a serotonin type-2 and dopamine receptor antagonist; 0.5 mg/Kg bw. 90 minutes before the sacrifice). The activation of the central serotonergic system enhanced the CRH content in the median eminence, whereas it decreased the content of this neuropeptide in the medial basal hypothalamus. These effects were fully abolished by metergoline, but not by spiperone pretreatment. The activation of the serotonergic pathway did not influence the vasopressinergic neuronal system. In vitro experiments using hypothalamic-median eminence fragments incubated with serotonin solutions indicate that this monoamine possesses a CRH releasing effect at concentrations of 1 microM or more.(ABSTRACT TRUNCATED AT 250 WORDS)