ISSN:0028-3835    

DOI:10.1159/000126981

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The paraventricular nucleus (PVN) of the hypothalamus, where the CRF-containing neurosecretory cells controlling the hypothalamo-pituitary-adrenal (HPA) axis are located, receives a dense noradrenergic innervation from the A1 group of the caudal ventrolateral medulla. In the present study we studied the relationship between release of noradrenaline (NA) in the PVN and activation of the HPA axis in response to electrical stimulation of the A1 region. In the urethane-anesthetized male rat, extracellular NA in the PVN was monitored on line by electrochemical recording while the activity of the HPA axis was estimated by measurement of ACTH in blood samples. A 1 min, 10 Hz stimulation evoked a significant increase of extracellular NA in the PVN as well as an ACTH surge in blood. The NA and ACTH response evoked by stimulation in the 3- to 14-Hz range were found to be frequency dependent. However, whilst the NA response increased in an exponential manner with respect to frequency, the ACTH response appeared to plateau between 10 and 14 Hz. Specific lesions of the noradrenergic terminals in the PVN, by bilateral local administration of 6-hydroxydopamine, markedly reduced the ACTH response to stimulation. Intracerebroventricular injection of desmethylimipramine, a NA uptake inhibitor, enhanced the increase in extracellular NA evoked by submaximal stimulation about 2.5-fold but did not modify the corresponding ACTH response. Combined intracerebroventricular injection of α-and β-adrenergic antagonists, phentolamine and propanolol respectively, did not prevent the ACTH response evoked by stimulation. Following stimulation of the caudal ventrolateral medulla, the ACTH response thus appears to result from the stimulation of the Al noradrenergic group projecting to the PVN. However, the inability of pharmacological manipulations which enhance or block central noradrenergic transmission to influence the ACTH response suggests that the noradrenergic endings in the PVN originating from the A1 group use a transmitter other than NA to activate the HPA axis at the PVN leve

ISSN:0028-3835    

DOI:10.1159/000126982

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The behavioral and immunoendocrine effects of formalin-induced pain were studied in male rats following a subcutaneous injection of formalin (50 µl; 0.1%, F01 groups, 10%, F10 groups) or sham injection (control groups). After treatment, animals were tested in a transparent open field for either 30 or 60 min and thereafter sacrificed by decapitation. Plasma was collected for adrenocorticotropic hormone (ACTH), corticosterone, β-endorphin (β-EP) and interleukin-6 (IL-6) determinations. Pain-evoked responses (licking, flexing, paw jerk), standard measures of activity (locomotion, rearing, olfactory exploration) and self-grooming were recorded. The higher formalin concentration induced stronger pain-evoked behavioral responses, paralleled by higher levels of ACTH, β-EP and IL-6, but did not affect the other behavioral parameters. In contrast, the lower formalin concentration induced a marked increase in locomotion and rearing and a decrease in ACTH levels. In both formalin-injected groups, corticosterone did not differ from contr

ISSN:0028-3835    

DOI:10.1159/000126983

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Our recent studies suggest that lipocortin 1 (LC1), a potential mediator of the anti-inflammatory, antiproliferative and anti-fever actions of glucocorticoids in peripheral tissues, may also contribute to the powerful negative feedback actions of the steroids on the hypothalamo-pituitary-adrenal (HPA) axis. In the present study we have used (1) an in vitro model to examine the influence of a specific neutralizing monoclonal anti-LC1 antibody (anti-LC1 mAb) on the capacity of dexamethasone to suppress the cytokine-induced release of the 41-amino acid corticotropin-releasing factor (CRF-41) and arginine vasopressin (AVP) from the rat hypothalamus and (2) a passive immunization protocol to assess the contribution of LCI to the inhibitory actions of dexamethasone on the HPA responses to immunological (i.p. injection of interleukin 1β, IL-1β) and surgical (laparotomy under ether anaesthesia) stress. In vitro, Il-1α (0.2 ng/ml), IL-1β (0.5 ng/ml), IL-6 (10ng/ml) and IL-8 (1 ng/ml) each caused significant increases in the release of immunoreactive (ir)-CRF-41 and ir-AVP from hypo-thalami removed from rats adrenalectomized 10-12 days before autopsy; these responses were readily inhibited by preincubation of the tissue with dexamethasone (10-7M). The inhibitory actions of the steroid were attenuated and, in many instances, abolished by inclusion in the medium of a monoclonal anti-LCI antibody (LCI mAb, diluted 1:15,000); an isotype-matched control antibody (antispectrin α+β, diluted 1:15,000) was ineffective in this regard. IL-1α (0.2 ng/ml), IL-1β (0.5 ng/ml) and IL-6 (10 ng/ml) also initiated similar increases in the release of CRF-41 and AVP from hypothalami from intact rats which were effectively blocked by dexamethasone (10–7M). However, although the inhibitory actions of the steroid on the pharmacologically evoked release of CRF-41 were specifically overcome by anti-LC1 mAb (diluted 1:15,000), the steroid blockade of AVP release was not. In vivo, rats pretreated with either a polyclonal anti-LC 1 antibody (anti-LCI pAb, 1 ml/day s.c. for 2 days) or a corresponding volume of a nonimmune sheep serum (NSS) responded to immunological (IL-1β, 3 µg/kg i.p.) or surgical (laparotomy under ether anaesthesia) trauma with significant increases in the serum ACTH and corticosterone concentrations. In the NSS-treated groups, dexamethasone (100 µg/kg), which had no effect on the prestress concentrations of ACTH and corticosterone in the blood, completely prevented the HPA responses to both IL-1β and laparotomy. The steroid treatment also abolished the HPA responses to laparotomy in rats pretreated with anti-LC1 pAb. By contrast, passive immunization against LC1 largely overcame the ability of dexamethasone to inhibit the hypersecretions of ACTH and corticosterone provoked by IL-1β (3 µg/kg i.p.). The results suggest that LC1 plays an important role in mediating the inhibitory actions of dexamethasone on the HPA responses to cytokines in vi

ISSN:0028-3835    

DOI:10.1159/000126984

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Aging, as well as some frequently associated pathological conditions (depression, dementia, Alzheimer’s disease, etc.), has been shown to have a profound impact on the normal functioning of the hippocampus-hypothalamo-pituitary-adrenocortical axis system. The hypothalamo-pituitary-adrenocortical axis in the aged rat is characterized by an increase in the basal level of circulating corticosterone, an impaired ability to recover from the adrenocortical stress response, and a reduced sensitivity to the dexamethasone suppression test. All these alterations may arise from a reduced hippocampal negative feedback control of the axis, as suggested by the age-dependent loss of hippocampal adrenocorticoid receptors. Among the hypothalamic corticotropin secretagogues, corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) are considered the main physiological mediators of hypothalamic control of ACTH release. Thus, we have investigated the dynamic and the temporal course of the adrenocortical response to CRH and AVP in the aged rat. Freely moving jugular-catheterized male Sprague-Dawley rats (3- and 24-month-old) were injected with CRH (0.5, 0.05 and 0.01 µg/kg i.v.), or AVP (1.0, 0.1 and 0.05 µg/kg i.v.), or CRH and AVP in combination. In addition, adrenocortical sensitivity to corticotropin has been studied by injecting ACTH (10 ng/kg i.v.). Our study has (1) indicated that the response to ACTH secretagogues is dampened with aging, and (2) shown in the aged rat a slower recovery. Moreover, the results had confirmed the age-dependent increase in the basal level of corticosterone in the rat, and shown no age-related differences in the glucocorticoid response to A

ISSN:0028-3835    

DOI:10.1159/000126985

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

There is increasing evidence indicating that the production of cytokines and prostaglandins (PG) may be interrelated and is regulated by glucocorticoids (GC). In the present study we examined the effect of the bacterial endotoxin lipopolysaccharide (LPS) and interleukin-1 (IL-1) on the ex vivo production of PGE2 by the dorsal hippocampus of the mouse which contains high levels of receptors to IL-1. The roles of IL-1 receptors and GC in the regulation of LPS- or IL-1-induced PGE2 production were also studied. In control mice the basal rate of PGE2 ex vivo synthesis by slices of dorsal hippocampus was about 250 pg/mg protein/60 min. Intraperitoneal injection of either LPS (1-50 µg/mouse) or IL-1α (50-200 ng/mouse) increased the production of PGE2 in a dose- and time-dependent manner. Both LPS and IL-lα induced a maximal 2.5-fold increase in PGE2 production at 6 h after the injections. IL-1β was less effective by approximately 30% as compared to IL-1α. In mice treated with the IL-1 receptor antagonist or with the IL-1 antagonist α-melanocyte-stimulating hormone (α-MSH), the effects of LPS and IL-1 on PGE2 production were completely abolished. Intraperitoneal injections of dexamethasone (DEX) 5 or 30 µg/mouse 2 h prior to the administration of IL-1α significantly enhanced the effect of the cytokine on PGE2 production. In mice treated with 100 µg DEX/mouse, the facilitatory effect of the lower DEX doses in IL-1-induced PGE2 production was abolished. In adrenalectomized mice (6 days), the administration of IL-1 failed to affect hippocampal PGE2 production. Injection of DEX (30 µg/mouse) 18 and 2 h prior to IL-1α restored the effect of IL-lα on the production of PGE2. These results suggest: LPS and IL-1α or β can stimulate PGE2 biosynthesis by the mouse dorsal hippocampus; this effect is mediated by the specific IL-1 receptors and can be antagonized by α-MSH; in the mouse, GC may exert a permissive, a stimulatory or an inhibitory effect on IL-1-induced PGE2 hippocampal production. The relative intensity of each of these effects depend on the level of

ISSN:0028-3835    

DOI:10.1159/000126986

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The effects of interleukin-1β (IL-1), interleukin-6 (IL-6), tumor necrosis factor α (TNF) and lipopolysaccharide (LPS) on hippocampal corticosteroid receptors were studied in the rat. Type I (mineralocorticoid) and type II (glucocorticoid) receptors were measured in hippocampal cytosolic fractions with the radioligand binding technique, using 3H-corticosterone and 3H-RU 28362, respectively. LPS, administered intraperitoneally (50 µg/kg 8 h before sacrifice or 100 µg/kg injected twice, 16 and 8 h before sacrifice) to rats which had been previously adrenalectomized to allow for clearance of endogenous corticosterone, did not modify either type of corticosteroid receptors in the hippocampus. IL-1, IL-6, TNF or saline were injected intracerebroventricularly (50 ng/rat) and the animals were killed 3 h after. Type I receptors were not affected by any of the cytokines studied. Moreover, no changes in type II receptors were observed after IL-1 or IL-6 administration. In contrast, hippocampal type II receptors were dramatically decreased after the injection of TNF. The TNF-induced downregulation of type II receptors was secondary to a marked decrease in the affinity of the receptors (Kd increased 7.2-fold), accompanied by a 51% decrease in receptor number (Bmax). These results emphasize the important role played by TNF in the modulation of the hypothalamic-pituitary-adrenal axis during immune/inflammatory processes and extend the central sites of action of this cytokine to the corticosteroid receptors of the hippocam

ISSN:0028-3835    

DOI:10.1159/000126987

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Changes in concentrations of cytokines in plasma and in hypothalamic push-pull perfusates of guinea pigs were measured within the 1 st hour after intramuscular injections of bacterial Hpopolysaccharide (LPS; Escherichia coli, 20 µg/kg) or solvent (0.9% saline). In control animals injected with solvent, interleukin (IL)-1 and tumor necrosis factor alpha (TNF-α) were not detectable in plasma. Only IL-6 was present in picogram quantities. Within 45 min after injection of LPS, the concentrations of IL-1, TNF-α, and IL-6 increased in the plasma: by several orders of magnitude for TNF-α and about tenfold for IL-G. Picogram amounts of biologically active IL-1 were detected in plasma after injection of LPS. No steady state levels of systemic cytokines were reached during the experimental period. In hypothalamic perfusates of animals injected with the solvent, no IL-1 was detectable. TNF-α could be detected at higher concentrations than IL-6. IL-6 was detectable at tenfold lower concentrations than in the plasma. In animals injected with LPS, the hypothalamic concentration of IL-6 started to increase during the period 15-30 min and the concentrations of TNF-α during the period 30-45 min after LPS injection. The concentrations of IL-6 increased by 300-400% and did not exceed picogram values. No progressive increase of hypothalamic levels of these cytokines was observed during the time course of the experiment. The method used did not detect any changes in the amount of biologically active IL-1 in hypothalamic perfusates of LPS-treated animals. No obvious correlation between concentrations of cytokines in plasma and hypothalamic perfusate was observed, indicating the brain origin of the cytokines. Since the increase in IL-6 goes in parallel with resetting of the body thermostat to the higher level, the data support the hypothesis that the increase in the concentration of IL-6 in the brain, occurring during the early phase of the fever, induces the febrile res

ISSN:0028-3835    

DOI:10.1159/000126988

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Observations in experimental allergic encephalomyelitis (EAE), a model for multiple sclerosis (MS), have indicated that a low activity of the hypothalamo-pituitary-adrenal (HPA) system is accompanied by a high susceptibility for EAE in rat strains and that elevated corticosteroid levels are necessary for spontaneous recovery from EAE. The HPA axis activity is regulated by both corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). Both types of neurons are localized in the paraventricular nucleus (PVN) of the hypothalamus. We determined the number of immunocytochemically identified CRH-immunoreactive (CRH-IR) and AVP-immunoreactive (AVP-IR) neurons in the PVN of the human hypothalamus of 8 MS patients, aged 34–63 years, and 8 age-matched control subjects without any primary neurological or psychiatric disorders, aged 30–59 years. In addition, the number of oxytocin (OXT) immunoreactive (OXT-IR) neurons was determined, since these neurons innervate brain stem nuclei and might thus be related to autonomic disturbances in MS. In MS the staining intensity for AVP was clearly lower and for OXT slightly lower. For CRH, the staining intensity was similar in both groups, and, moreover, in MS patients the number of CRH-IR cells in the PVN was found to be about 2.4 times higher than that in the control group. The number of OXT-IR or AVP-IR cells in the PVN of MS patients was not significantly different from that of the control group. Our results point to an activation of the neuroendocrine HPA axis which may be compatible with the idea that the HPA axis is involved in recovery from MS. In addition, increased CRH activity might be causally related to depression which has high prevalence rates in MS patie

ISSN:0028-3835    

DOI:10.1159/000126989

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Lewis (LEW/N) and Fischer (F344/N) rats are histocompatible inbred strains characterized, respectively, by susceptibility and resistance to inflammatory disease. The susceptibility of LEW/N rats to inflammation has been associated with deficient corticotropin-releasing hormone (CRH), ACTH, and corticosterone responses to inflammatory stimuli, specifically attributed to a global impairment in hypothalamic CRH neuron function. In contrast to the LEW/N rats, F344/N rats demonstrate an intact hypothalamic-pituitary-adrenal (HPA) axis. Melatonin, a neurohormone initially isolated in the pineal gland, has been implicated with inhibition of the HPA axis. To investigate melatonin synthesis and secretion in LEW/N and F344/N rats, we examined the diurnal activity of pineal arylalkylamine N-acetyltransferase (NATl), the rate-limiting enzyme in melatonin biosynthesis, which demonstrates circadian rhythmicity, as well as the diurnal levels of serum melatonin, in both strains. Arylamine N-acetyltransferase (NAT2), a related enzyme activity, thought not to be regulated in a circadian manner, was examined as a control of NATl activity. Pineal NATl activity peak was observed later and reached significantly higher levels in LEW/N than in F344/N rats. Serum melatonin levels reflected the circadian pattern of the NATl activity, without, however, showing any quantitative differences between the two strains. Time-course of pineal NATl activity response to β-adrenergic stimulation was parallel in the two rat strains, whereas the magnitude of the response was greater in LEW/N than in F344/N rats. No circadian or major quantitative differences in NAT2 activity were found between the two strains. Size-exclusion HPLC chromatograms of NATl activity revealed similar patterns in both rat strains. These findings demonstrate a difference in the circadian and β-adrenergic-stimulated regulation of melatonin synthesis in the two rat strain

ISSN:0028-3835    

DOI:10.1159/000126990

出版商:S. Karger AG    

年代:1995

数据来源: Karger