Differential regulation of neurohypophysial peptides in the paraventricular nucleus.
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Animals↗
Biomedical subjects
S L Lightman
Publications and source records attributed to S L Lightman.
Stress-induced activation of CRF and c-fos mRNAs in the paraventricular nucleus are not affected by serotonin depletion.
The role of serotonin in regulating the stress response is controversial. We have investigated the effects of serotonin depletion by p-chlorophenyl-alanine (PCPA) on corticotrophin-releasing factor (CRF) mRNA and c-fos mRNA responses in the paraventricular nucleus (PVN) together with circulating levels of ACTH and corticosterone to both physical and psychological stressors in the rat. PCPA pretreatment, which resulted in a 95% depletion in hypothalamic serotonin, had no effect on basal levels of ACTH or the increase in response to the physical stress of hypertonic saline. Plasma ACTH concentrations were also not affected by serotonin depletion in response to the predominantly psychological stress of restraint. Both basal and restraint stress-induced circulating corticosterone levels were however further stimulated in the PCPA-pretreated rats suggesting a possible inhibitory serotoninergic tone at the adrenal level. C-fos mRNA was undetectable in control animals. Activation of c-fos mRNA in response to stress was unaffected by serotonin depletion and the activation of magnocellular PVN and supraoptic nucleus cells was demonstrated to be stressor dependent. Basal and stress-induced levels of CRF mRNA were unaffected by PCPA pretreatment. It appears therefore that under these experimental conditions there is little if any involvement of serotonin in either basal levels or the stress-induced activation of the hypothalamo-pituitary-adrenal axis in vivo.
Adrenocorticotropic Hormone↗
The effect of dietary protein on thyrotropin-releasing hormone and thyrotropin gene expression.
In the rat, 48 h of food deprivation significantly reduces hypothalamic paraventricular nucleus (PVN) thyrotropin-releasing hormone (TRH) gene expression, anterior pituitary thyrotropin (TSH) gene expression and circulating triiodothyronine (T3). Using in situ hybridization histochemistry, we have now assessed the effect of selective nutritional deprivation, by comparing protein-free and protein and fat-free diets with a normal diet matched for total energy content. As previously demonstrated, fasting markedly reduced PVN TRH transcripts, pituitary TSB beta transcripts, circulating T3 and body weight. Compared to rats fed a control diet, rats fed a protein-free or a protein and fat-free diet of similar energy content showed a highly significant decrease in PVN TRH transcripts, pituitary TSB beta transcripts and circulating T3 levels. The exclusion of fat from the protein-free diet did not produce any further decline in the parameters measured. This indicates that variations in the protein composition alone of the diet are sufficient to reduce hypothalamic TRH mRNA, pituitary TSB beta mRNA and plasma T3, and are the predominant factors in the TRH response to starvation.
Animals↗
Modulation of IGF-2 expression during growth and differentiation of human neuroblastoma cells: retinoic acid may induce IGF-2.
Insulin-like growth factor 2 (IGF-2) is the major autocrine growth factor for neuroblastoma. IGF-2 mRNA can just be detected in SK-N-BE(2) cell line; higher levels are present in two clones derived from it [BE(2)-C; BE(2)-M17]. IGF-2 mRNA is increased by retinoic acid (RA) only in the clones. IGF-2 expression/induction is more marked in BE(2)-M17, which shows more RA-resistance (evaluated as growth inhibition, neurite outgrowth and induction of programmed cell death). Under RA exposure, the parental line shows a more pronounced growth inhibition, neurite outgrowth and programmed cell death, as compared to its clones. BE(2)-C cells also express type 1 IGF receptor mRNA, though with a different time course than for expression of IGF-2. The data suggest that IGF-2 expression is correlated with growth, and may counteract the growth retardation, neurite outgrowth and programmed cell death effects of retinoic acid. Therefore the autocrine pattern of IGF-2 production by neuroblastoma cells may promote RA-resistance.
Brain Neoplasms↗
Expression of corticotropin-releasing factor mRNA in response to stress.
The corticotropin-releasing factor (CRF)-containing neurons of the parvocellular division of the hypothalamic paraventricular nucleus play a pivotal role in the regulation of the hypothalamo-pituitary-adrenal axis. We have studied the regulation of these neurons in the conscious rat using the technique of quantitative in situ hybridization histochemistry. Corticosteroid feedback reduces CRF mRNA levels in a dose-dependent manner, although even prolonged administration of very high doses cannot abolish CRF transcripts completely. Both physical and psychological stressors produce a robust and readily reproducible increase in CRF mRNA. These responses cannot be prevented by changes in circulating corticosteroids--a similar magnitude of response occurs with high basal levels in the adrenalectomized animal and with low basal levels during treatment with supraphysiological doses of glucocorticoid. Alterations in CRF mRNA levels in response to stress are, however, lost during the physiological condition of lactation, a state known to result in stress hyporesponsiveness, and also after 6-hydroxydopamine lesions to the catecholaminergic innervation of the paraventricular nucleus. We have also studied two conditions of chronic immunological activation of the hypothalamo-pituitary-adrenal axis--adjuvant-induced arthritis and experimental allergic encephalomyelitis. Both of these results in activation of the hypothalamo-pituitary-adrenal axis with increased plasma corticosterone and ACTH, and pituitary pro-opiomelanocortin (POMC) mRNA. Unexpectedly, however, the activation of pituitary corticotrophs does not seem to be a primary result of increased activation of the CRF neurons, which actually show a consistent fall in CRF mRNA.
Acute Disease↗
Somatostatin analogues: mechanisms of action.
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Amino Acid Sequence↗
Interleukin-1 beta measured by radioimmunoassay in the rat spleen and thymus is increased during chronic inflammatory stress.
We have developed an extraction method and radioimmunoassay for the measurement of interleukin-1 beta (IL-1 beta) in rat tissues, using an antibody specific for IL-1 beta, IL-1 beta was detected in the spleen and thymus of control rats. Adrenalectomy (ADX) had no effect upon control levels of IL-1 beta. In animals with adjuvant-induced arthritis, IL-1 beta content in the spleen and thymus increased after 14 days. These increases in tissue IL-1 beta contents were not evident in ADX arthritic animals. We conclude that IL-1 beta synthesis is stimulated in tissues of the immune system following the development of adjuvant-induced arthritis. Failure to observe elevated levels of tissue IL-1 beta in ADX arthritic rats may be evidence for tissue depletion due to increased IL-1 beta release in the absence of circulating corticosteroids.
Adrenalectomy↗
Effect of adrenalectomy and stress on interleukin-1 beta-mediated activation of hypothalamic corticotropin-releasing factor mRNA.
We have investigated the effect of (a) stress and (b) steroid feed-back on the interleukin-1 beta (IL-1 beta)-mediated increase of corticotropin-releasing factor (CRF) mRNA in the hypothalamic paraventricular nucleus. Both IL-1 beta and stress resulted in increased levels of CRF mRNA and when both were given together, the combination resulted in an additive effect on the increase in CRF transcripts. The effect of IL-1 beta was blunted by adrenalectomy, but returned when a replacement dose of dexamethasone was administered. The IL-1 beta-induced increase in CRF mRNA is dependent on the presence of circulating glucocorticoids, and its mechanism of action on CRF mRNA appears to be distinct from that activated in response to stress.
Adrenalectomy↗
Changes in hypothalamic corticotrophin-releasing factor and anterior pituitary pro-opiomelanocortin mRNA during the course of experimental allergic encephalomyelitis.
The pituitary-adrenal axis is activated during the course of experimental allergic encephalomyelitis (EAE), a paralytic disease resulting from an immunological reaction against central nervous system myelin. The magnitude of the adrenal response not only correlates with the severity of disease, but also serves an important functional role in recovery. We have shown that in EAE there are short-term changes in anterior pituitary pro-opiomelanocortin (POMC) mRNA as well as plasma corticosterone which can be detected before the development of clinical disease. At peak clinical signs when corticosterone and POMC mRNA are maximal, hypothalamic corticotrophin-releasing factor (CRF) mRNA is suppressed, suggesting that pituitary-adrenal activation is not mediated by CRF. Following recovery all parameters return to normal.
Animals↗
Preprotachykinin A gene expression in distinct hypothalamic and brain stem regions of the rat is affected by a chronic osmotic stimulus: a combined immunohistochemical and in situ hybridization histochemistry study.
Chronic osmotic stimulation influences the hypothalamoadenohypophysial axis by inhibiting the synthesis of corticotrophin releasing factor (CRF-41) in the parvocellular subdivision of the paraventricular nucleus (PVN) and, subsequently, the secretion of adrenocorticotrophin (ACTH) from the adenohypophysis. Using quantitative in situ hybridization histochemistry, we have investigated the effect of chronic osmotic stimulation on preprotachykinin A (PPT-A) mRNA levels in a number of brain areas known to send substance P-containing projections to the medial parvocellular part of the PVN. Chronic osmotic stimulation increased PPT-A gene expression in the lateral hypothalamic area, the arcuate nucleus, the catecholaminergic brain stem areas A2, C1, and C2, although PPT-A mRNA levels in the bed nucleus of the stria terminalis, the medial preoptic nucleus, the caudate-putamen, and the A1 were unaffected by chronic osmotic stimulation. In addition, immunohistochemical staining of substance P-immunoreactive elements contained within the same areas was carried out on colchicine-treated animals. Generally, those areas responding to the osmotic stimulus with increased PPT-A mRNA synthesis showed increased numbers of substance P-immunoreactive perikarya, suggesting that increased levels of mRNA are associated with increased peptide synthesis. These results provide evidence that central endogenous substance P contained in brain regions projecting to the paraventricular nucleus could have an inhibitory influence over the synthesis of CRF-41 during a chronic osmotic stimulus.
Animals↗
Inflammatory cells in proliferative vitreoretinopathy subretinal membranes.
BACKGROUND: The inflammatory cell content of subretinal membranes occurring in proliferative vitreoretinopathy (PVR) has not yet been well characterized. This study was undertaken to investigate the inflammatory cells present in PVR subretinal membranes. METHODS: Eight subretinal membranes obtained surgically from eyes with PVR complicating rhegmatogenous retinal detachment were studied immunohistochemically using the avidin-biotin complex technique and a panel of monoclonal and polyclonal antibodies. RESULTS: T lymphocytes were found in five of the eight subretinal membranes. CD4+ T cells were demonstrated in four and CD8+ T cells in one of the membranes. T cells bearing the interleukin 2 receptor were found in two of four membranes studied. Macrophages were found in four membranes. No B lymphocytes or neutrophils were demonstrated, and there were no significant deposits of complement or immunoglobulins. Expression of the MHC class II antigen HLA DR was consistently found in frozen specimens. Glial cells and retinal pigment epithelial cells also were present in the membranes, often adjacent to T cells, although overall no obvious relationship was found between glial or retinal epithelial cells and T cells. CONCLUSION: The findings indicate that T lymphocytes are present in PVR subretinal membranes and have the potential to interact with other cell types in the pathogenesis of this condition.
B-Lymphocytes↗
The importance of cellular changes in the conjunctiva of patients with uveitic glaucoma undergoing trabeculectomy.
The results of trabeculectomy in patients with glaucoma secondary to uveitis are poor, but the exact cause of this remains unknown. Therefore, a study was undertaken to determine differences between conjunctiva from patients with glaucoma secondary to uveitis and that from patients with primary open angle glaucoma. Conjunctival biopsies from three patient groups were quantitatively analysed by light microscopy. Group A consisted of 10 patients with glaucoma secondary to uveitis who, prior to surgery, had been treated with topical steroids and topical beta-blocker drugs. Control groups (groups B and C) each consisted of 10 patients with primary open angle glaucoma for whom primary trabeculectomy (group B) or trabeculectomy following failure of topical beta-blockers alone (group C) was planned. Treatment with topical beta-blocker drugs was found to redistribute mast cells within the conjunctiva but to have no significant effect on cell numbers. In comparison with either control group, uveitic conjunctiva was found to contain significantly more fibroblasts, lymphocytes and macrophages. It is possible that these differences are responsible for an enhanced risk of excessive external bleb fibrosis, failure of filtration surgery and poor results with adjunctive 5-fluorouracil.
Adrenergic beta-Antagonists↗
Effect of chronic low-dose arginine vasopressin infusion on body fluid homoeostasis during adaptation from a high- to a low-sodium diet in normal man.
1. A diuresis occurs within the first 36h of salt restriction. A decline in plasma arginine vasopressin concentration may contribute to both the diuresis and antinatriuresis. 2. We have studied six normal human subjects during 36h of dietary sodium restriction. In one study subjects received an intravenous infusion of D-glucose, and in the other an infusion of arginine vasopressin (6 fmol min-1 kg-1). 3. In the D-glucose phase plasma arginine vasopressin concentration fell (1.77 +/- 0.34 to 1.02 +/- 0.13 pg/ml), urine flow increased (67.9 +/- 11.5 to 89.8 +/- 17.1 ml/h), haemoconcentration occurred (packed cell volume 40.8 +/- 0.3 to 42.8 +/- 0.5%, protein concentration 71.6 +/- 0.5 to 74.5 +/- 0.6 g/l), plasma sodium concentration fell (140 +/- 0.2 to 138 +/- 0.2 mmol/l) and plasma renin activity increased (1600 +/- 153 to 3700 +/- 356 pg of angiotensin I h-1 ml-1). 4. In the arginine vasopressin phase plasma arginine vasopressin concentration remained constant (1.5 +/- 0.13 to 1.34 +/- 0.11 pg/ml), the diuresis was reversed (65.7 +/- 9.9 to 52.1 +/- 8.9 ml/h), plasma sodium concentration fell further (139.8 +/- 0.4 to 136.1 +/- 0.4 mmol/l), the rise in plasma renin activity was reduced (arginine vasopressin 2552 +/- 292; D-glucose, 3700 +/- 356 pg of angiotensin I h-1 ml-1) and creatinine clearance was lower in the last 12h of salt restriction (arginine vasopressin, 96.1 +/- 6.9; D-glucose 116.5 +/- 6.8 ml/min). Renal sodium excretion was unaffected by arginine vasopressin infusion. 5. We conclude that the fall in plasma arginine vasopressin concentration during dietary salt restriction, whilst not affecting renal sodium excretion, may be important in the regulation of plasma sodium concentration, plasma renin activity and glomerular filtration.
Adult↗
Control of sodium excretion in patients with cranial diabetes insipidus maintained on desamino-[8-D-arginine]vasopressin.
1. We have studied the response of six patients with cranial diabetes insipidus and six age-matched control subjects to dietary sodium restriction during constant administration of the synthetic vasopressin analogue desamino-[8-D-arginine]vasopressin. 2. Urine flow increased on the first low salt day in the normal control subjects but not in the patients with cranial diabetes insipidus. Body weight fell 1.35 kg in the control subjects but was constant in the patients with cranial diabetes insipidus. 3. Urinary sodium excretion fell at the same rate in both groups. Diurnal variation of urinary sodium excretion and creatinine clearance was present in the control subjects but not in the patients with cranial diabetes insipidus. 4. Changes in plasma sodium concentration and osmolality were similar. Plasma protein concentration increased more in the control subjects (from 69.1 +/- 1.5 to 73 +/- 1.2 versus from 71.7 +/- 1 to 73.2 +/- 1.1 milligrams). The responses of plasma atrial natriuretic peptide, plasma renin activity and salivary aldosterone concentration were similar between the two groups. Salivary aldosterone concentration levels were consistently higher in the patients with cranial diabetes insipidus. 5. We confirm that the low salt diuresis is triggered by release from the antidiuretic activity of arginine vasopressin. In the patients with cranial diabetes insipidus extracellular fluid osmoregulation appeared to be achieved by the movement of water out of and sodium into the extracellular fluid. 6. Absent posterior pituitary function and hypothalamic disturbances did not alter renal sodium conservation.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
The association of age with plasma arginine vasopressin and plasma osmolality.
We investigated the association of age with supine and ambulant plasma osmolality (pOSM) and arginine vasopressin (AVP). Twenty-eight healthy-status-defined subjects were studied. Following an overnight fast, blood samples were withdrawn after one hour supine rest and two hours' ambulation. Neither supine nor ambulant pOSM nor AVP varied significantly with age. The results suggest that in healthy subjects age does not influence plasma osmolality or AVP.
Adult↗
Endocrinology of in-vitro fertilization pregnancies during the first trimester.
The endocrine function of the corpus luteum and placenta and the inter-relationships between ovarian steroids and the placental proteins in pregnancies achieved following ovarian stimulation, in-vitro fertilization and embryo transfer (IVF-ET) have been investigated. The serum concentrations of human chorionic gonadotrophin (HCG), Schwangerschaft protein-1 (SP-1), pregnancy-associated plasma protein A (PAPP-A), progesterone and oestradiol were measured at weekly intervals between the 4th (ET plus 2 weeks) and 14th week of gestation in 86 pregnancies. The mean concentrations of the placental proteins and oestradiol were significantly higher in twin than in singleton pregnancies from as early as 5 weeks gestation, but the mean concentrations of progesterone were significantly higher only at the end of the first trimester. Ranking, as demonstrated by the presence of statistically significant correlations between serum levels of each substance analysed in week 13 with those of preceding weeks, was established for progesterone and SP-1 from the 5th week, for oestradiol and PAPP-A from the 7th week and for HCG from the 8th week of gestation. The presence of statistically significant correlations between each substance analysed suggests that the placenta becomes the dominant source of oestradiol from 8 weeks gestation and of progesterone not until 12 weeks gestation, and that the placental synthesis of HCG, SP-1, PAPP-A, oestradiol and progesterone appear to be linked. There were no statistically significant correlations between the serum concentrations of HCG and either progesterone or oestradiol until the production of each had become predominantly placental.
Adult↗
Interaction between the neuroendocrine system and arthritis.
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Adrenocorticotropic Hormone↗
Effects of glucocorticoids and chronic inflammatory stress upon anterior pituitary interleukin-6 mRNA expression in the rat.
During development of adjuvant arthritis (AA) in the rat, anterior pituitary interleukin-6 (IL-6) mRNA expression was increased. Following adrenalectomy and AA there was a further increase in the accumulation of pituitary IL-6 transcript. Corticosterone (B) replacement in adrenalectomized (ADX) animals resulted in a dose-dependent reduction in pituitary IL-6 mRNA accumulation, while in ADX plus AA animals these effects of B were less marked. Cyclosporine A (CsA) markedly reduced the AA-induced increase in IL-6 mRNA. These data are consistent with an immunologically-mediated activation of pituitary IL-6 mRNA in AA, which may contribute to the increased activity of the pituitary-adrenal axis seen in this condition.
Adrenalectomy↗