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Biomedical subjects

E Spinedi

Publications and source records attributed to E Spinedi.

47 records · Page 3Linked to original sources
PubMed1984

Increased responsiveness of the hypothalamic-pituitary axis after neurotoxin-induced hypothalamic denervation.

Neonatal treatment with monosodium glutamate (MSG) induces severe neuronal damage in selected brain areas, which in turn results in a number of neuroendocrine abnormalities during adult life. The present study was designed to determine what effects this partial and selective denervation of the hypothalamic-pituitary axis may have on the sensitivity of two key components of that axis, the median eminence (ME) and the anterior pituitary (AP). In order to test any changes in response that may occur after MSG treatment, the release of several peptide hormones from either the ME or the AP was evaluated in vitro, employing specific or general secretagogues. Male newborn pups of the Holtzman strain were injected with MSG every other day for 5 days, starting on day 2 of life; littermate controls received an injection of 10% NaCl. All animals were used when adult, at about 5-7 months of age. After decapitation, ME and AP tissues from control and MSG-treated rats were dissected out and incubated in vitro. Release of LHRH, SRIF, arginine vasopressin, and oxytocin from the ME was measured by direct RIA, under basal conditions and after stimulation with high K+ medium (28 mM). The results clearly indicate a marked hyperresponse of the release of each of the four neuropeptides by ME fragments from MSG-lesioned animals. The altered release was not attributable to changes in ME peptide content. In the case of the AP, the release of ACTH, LH, PRL, and GH in response to high K+ or, in some cases, to specific releasing factors, was evaluated in a dispersed cell preparation. The release of all four protein hormones was increased by high K+, and again the MSG-lesioned rats showed a pronounced hyperresponse. Corticotropin-releasing factor, at concentrations of 10(-9) and 10(-8) M enhanced ACTH release from control and MSG-lesioned rats, but the latter presented a marked hyperresponse. A similar observation on LH release was seen after stimulation with LHRH (10(-9) M). The results indicate that the neuronal damage induced by neonatal MSG treatment results in a generalized hyperresponsiveness in vitro to either specific or general secretagogues by ME or AP tissues, which may suggest the development of a denervation-type supersensitivity in the hypothalamic-pituitary axis. Since the release of these peptide hormones is sluggish in MSG-lesioned rats under in vivo conditions, it seems plausible to conclude that the major defect after the neurotoxin damage may reside in the loss of neurotransmitter systems normally innervating and regulating the activity of the peptidergic neurons.

Adrenocorticotropic Hormone↗
PubMed1983

Angiotensin II and ACTH release: site of action and potency relative to corticotropin releasing factor and vasopressin.

The present studies were designed to test, using a combination of in vivo and in vitro paradigms, the potency of angiotensin II (AII) to release ACTH, in relation to that of other neural peptides with corticotropin-releasing activity (CRA), such as synthetic corticotropin releasing factor (CRF), arginine vasopressin (AVP) and oxytocin (OXY); and to determine whether a central or peripheral locus is the primary site of action of the peptide. Injection of AII (1 and 5 micrograms, i.p.) in intact unanesthetized male rats, resulted in an increase in plasma ACTH and beta-endorphin-like immunoreactivity (beta-end-LI) levels after the largest dose. The responses, however, were not as pronounced as those elicited by 0.5 microgram of CRF or 1 micrograms of AVP. Injection of AII (i.v., 1 or 5 micrograms) in centrally blocked rats (pretreated with chlorpromazine-morphine-nembutal) failed to elicit any increase in either ACTH or bet a-end-LI levels, whereas 0.5 microgram of either CRF or AVP increased both hormones several fold. In vitro studies using dispersed anterior pituitary cells obtained from male donor rats showed that AII as well as AIII could increase ACTH release at doses of 10(-8) M or larger. Under the same conditions, CRF and AVP stimulated ACTH release to a greater degree at 10(-10) and 10(-9) M, respectively. On the other hand, OXY was stimulatory at 10(-8) M. Dose-response studies indicated a rank order of CRA as follows: CRF greater than AVP greater than OXY greater than AII = AIII. Both AII and AIII showed additive effects when coincubated with either CRF or AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Binding of prolactin by fetal human lung cell membrane fractions.

PRL binding capacity to cell membrane fraction was studied in lung tissues obtained from 4 human fetuses or newborn infants. One of the fetuses was a stillborn delivered at 33 weeks of gestation. The newborn infants died for unknown causes within 24 h after birth. The gestational age was 20, 39 and 41 weeks. The cell membrane fraction was prepared by ultracentrifugation. binding capacity and affinity constants were calculated according to athe Scatchard method. No significant specific binding of PRL to lung tissue from the stillborn fetus was observed, while for the other 3 newborn infants the binding capacity was 5.7, 7.4 and 9.6 fmol PRL bound/mg of membrane protein, respectively. The affinity constants were in the order of 10(10) M-1. these preliminary results show that human neonatal lung has receptors for PRL and suggest that PRL itself may be involved in the lung maturation.

Cell Membrane↗
PubMedDate not supplied

Sexual dimorphism in the hypothalamo-pituitary-adrenal (HPA) axis and TNFalpha responses to phospholipase A2-related neurotoxin (from crotalus durissus terrifcus) challenge.

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.

Adrenal Glands↗
PubMedDate not supplied

Stimulation of the hypothalamo-pituitary-adrenocortical axis by the central serotonergic pathway: involvement of endogenous corticotropin-releasing hormone but not vasopressin.

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)

5-Hydroxytryptophan↗
PubMedDate not supplied

Role of several mediators of inflammation on the mouse hypothalamo-pituitary-adrenal axis response during acute endotoxemia.

Cytokines secreted by bacterial endotoxin-activated immune cells are substances known to stimulate the hypothalamo-pituitary-adrenal (HPA) axis function. The present study was designed to better understand the effect of different mediators of inflammation, such as cytokines and histamine, on the acute HPA axis response induced by administration of a single dose of bacterial lipopolysaccharide (LPS) in adult, male, BALB/c mice. Two different experimental designs were set up. In the first design, mice (n = 8-11 per group) were injected i.p. with LPS (90 microg/kg body weight) and killed by decapitation 2 or 6 h after treatment. Additional groups of mice were pretreated i.p. 12 h before LPS treatment with: (a) 3-4 mg IgG/kg body weight of either an anti-tumor necrosis factor-alpha (TNF)-alpha, anti-interleukin (IL)-1beta- or IL-6 serum; (b) IL-1 receptor antagonist (IL-1ra) (120 microg/kg body weight) immediately before LPS and also 3 h later (when animals were killed 6 h after LPS injection), or (c) 182 microg/kg body weight of clemastine, an antagonist of H(1) histaminergic receptors, 2 h before LPS treatment; animals were killed in a similar fashion to that described for treatment with LPS alone. In the second experimental design, mice were pretreated (i.p., 10 mg/kg body weight, 30 min before administration of a similar dose of LPS) with different blockers of histaminergic pathway function such as: (a) mepyramine, another anti-H(1), (b) cimetidine, an H(2) receptor blocker, and (c) Ralpha-methylhistamine dihydrochloride, an H(3) presynaptic receptor agonist which inhibits histamine synthesis and output. These animals were then killed by decapitation 40 min after endotoxin treatment. After decapitation, trunk blood was collected for further determination of plasma levels of both ACTH and corticosterone (B) by specific assays. The results indicate that plasma levels of both ACTH and B were several-fold increased over baseline, 2 and 6 h after LPS administration. Two hours, the effect of LPS on ACTH output was not modified by pretreatment with anti-IL-1beta IgG, anti-IL-6 IgG, anti-TNF-alpha IgG nor with IL-1ra, although IL-1ra treatment was able to fully block the IL-1beta (35 microg/kg body weight)-stimulated HPA axis function, 1 and 2 h after cytokine administration. Six hours after LPS administration, anti-IL-1beta and anti-TNF-alpha IgGs were both able to significantly reduce HPA axis response to the endotoxins, whereas anti-IL6 IgG had no effect. Anti-IL-1beta IgG reduced only B secretion, whereas anti-TNF-alpha IgG decreased both ACTH and B secretion. The blockade of histaminergic pathway functions did not impede the LPS-induced ACTH and B release regardless of the product employed. The present results indicate that TNF-alpha, and to a lesser extent IL-1beta, are the most relevant cytokines involved in HPA axis response to endotoxin administration. Our data also suggest that, in mice, HPA axis activation after infection appeared to be independent of stimulation of the histaminergic pathway.

Acute Disease↗
PubMedDate not supplied

Sex steroid regulation of the hypothalamo-pituitary-adrenal axis activity in middle-aged mice during endotoxic shock.

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.

Adrenal Cortex↗
PubMedDate not supplied

Decreased hypothalamo-pituitary-adrenal axis response to neuroendocrine challenge under repeated endotoxemia.

It has been established that in vivo administration of bacterial lipopolysaccharide (LPS) enhances hypothalamo-pituitary-adrenal (HPA) axis function by a mechanism involving endotoxin-stimulated cytokine release. Since under chronic LPS treatment a tolerance of the HPA axis response takes place, the aim of the present study was to determine whether mice submitted to repeated LPS administration could present an impairment in the HPA response to insulin (INS) administration, a pure neuroendocrine challenge. For this purpose, adult female BALB/c mice were injected with 200 microliters i.p. of sterile saline solution (VEH) containing 25 micrograms of LPS in a single or repeated (at 24-hour intervals, during 5 consecutive days) fashion. Animals were then killed at either 45 min after INS (0.3 IU/mouse, i.p.) or 2 h after LPS (25 micrograms/mouse) administration on experimental day 1 (D1; without any previous LPS injection), 3 (D3; mice having received 2 previous LPS injections) or 5 (D5; mice having received 4 previous LPS administrations). Control groups were injected a similar volume of VEH alone on experimental day 1 (D1; without any previous LPS injection), 3 (D3; mice having received 2 previous LPS injections) or 5 (D5; mice having received 4 previous LPS administrations); in each group, mice were killed at either 45 min or 2 h after VEH injection. Immediately after decapitation, trunk blood was collected. Plasma tumor necrosis factor alpha (TNF), ACTH and corticosterone (B) levels were determined by specific assays. Plasma TNF, ACTH and B levels were significantly increased 2 h after the first LPS treatment (D1). Although no significant increase in plasma TNF concentration was found 2 h after the third LPS injection (D3), the corticotrope response was still significant and induced a full effect on adrenal B output. Two hours after the fifth LPS administration (D5) TNF output was minimal and the HPA axis response was significantly diminished. Finally, the pattern of the HPA axis response to INS-induced hypoglycemia was similar to that elicited after LPS challenge although somewhat delayed. Our results indicate that: (1) TNF seems to play an important role in stimulating HPA axis function after single but not after repeated endotoxin administration; and (2) an impairment in the HPA axis response to both immuneneuroendocrine (LPS) and neuroendocrine (INS) stimuli takes place after repeated LPS administration. This study further suggests that the tolerance of the HPA axis response under recurrent endotoxemia could be, at least partially, due to an impairment in both immune (TNF output) and neuroendocrine functions.

Adrenal Glands↗
PubMedDate not supplied

Sexual dimorphism in the mouse hypothalamic-pituitary-adrenal axis function after endotoxin and insulin stresses during development.

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.

Animals↗
PubMedDate not supplied

Heterogeneous results of serum testosterone obtained in multiple blood samples from women with idiopathic hirsutism in both basal and post-dexamethasone conditions.

Serum radioimmunoassayable testosterone (T), cortisol and luteinizing hormone (LH) were determined before and after dexamethasone (DXM) administration in 35 patients with idiopathic hirsutism (IH). Blood samples were taken at 15-min intervals during 1 hour in both basal and post-DXM conditions. Testosterone values obtained in 5 normal women in the same conditions during the early follicular phase were (mean +/- SD): baseline, 2.26 +/- 0.49 nmol/l; post-DXM, 0.80 +/- 0.35 nmol/l. Serum T levels in the whole group of patients with IH were significantly higher than those in the control group (mean +/- SD): baseline, 3.30 +/- 1.80nmol/l; post-DXM, 1.67 +/- 1.49nmol/l. Patients with IH were divided into 4 groups according to T results in the DXM test (mean +/- SD in both basal and post-DXM conditions, respectively): group 1 (n = 13) 1.67 +/- 0.66 and 0.62 +/- 0.35nmol/l; group 2 (n = 11) 3.89 +/- 1.63 and 3.09 +/- 1.49nmol/l; group 3 (n = 6) 3.96 +/- 1.46 and 0.87 +/- 0.73nmol/l; and group 4 (n = 5) 5.45 +/- 1.25 and 2.05 +/- 0.38nmol/l. In all cases, maximal adrenal inhibition, as judged by serum cortisol, was obtained. No LH modifications after DXM were obtained in any of the cases. Our results demonstrate that there is no common androgenic abnormality in IH. It is possible to obtain normal or high circulating T levels. The findings of this study also suggest that the adrenals, to ovary or both may be the sources of high T levels.

Adolescent↗