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Biomedical subjects

E M Sternberg

Publications and source records attributed to E M Sternberg.

At least 73 records · Page 4Linked to original sources
PubMed1992

Hippocampal 8-[3H]hydroxy-2-(di-n-propylamino) tetralin binding site densities, serotonin receptor (5-HT1A) messenger ribonucleic acid abundance, and serotonin levels parallel the activity of the hypothalamopituitary-adrenal axis in rat.

We have previously demonstrated that susceptibility of the Lewis rat to inflammatory disease, compared with the relatively resistant Fischer F344/N rat, is related to a hyporesponsive hypothalamopituitary-adrenal axis to inflammatory and other stress mediators. Because serotonin (5-HT) and the 5-HT1A receptor are important stimulators of this axis, we have investigated the levels of 8-[3H]-hydroxy-2,3-(di-n-propylamino)tetralin binding sites, 5-HT1A mRNA, 5-HT, and 5-hydroxyindoleacetic acid in various brain regions of Lewis, outbred Harlan Sprague Dawley, and Fischer F344/N rats. Lewis rats expressed significantly fewer hippocampal and frontal cortical 8-[3H]-hydroxy-2,3-(di-n-propylamino)tetralin binding sites and less 5-HT1A mRNA than Harlan Sprague Dawley and Fischer F344/N rats. Adrenalectomy increased the number of 8-[3H]hydroxy-2,3-(di-n-propylamino)tetralin binding sites and 5-HT1A mRNA expression in the hippocampus of all three strains. Levels of hippocampal 5-HT in Fischer F344/N rats were significantly greater than levels detected in the same regions from Lewis and Harlan Sprague Dawley rats. Hypothalamic 5-HT and 5-hydroxyindoleacetic acid levels in Harlan Sprague Dawley rats were higher than the same area from the other two strains. Adrenalectomy increased the levels of 5-hydroxyindoleacetic acid in the hypothalamus of all three strains. We conclude that hippocampal 5-HT1A receptor densities and 5-HT levels in the rat parallel the activity and responsiveness of the hypothalamopituitary-adrenal axis.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Neurotransmitter-induced hypothalamic-pituitary-adrenal axis responsiveness is defective in inflammatory disease-susceptible Lewis rats: in vivo and in vitro studies suggesting globally defective hypothalamic secretion of corticotropin-releasing hormone.

The susceptibility of female Lewis (LEW/N) rats to the development of streptococcal cell wall (SCW)-induced arthritis and other autoimmune phenomena is associated with the inability of their hypothalamic-pituitary-adrenal (HPA) axis to adequately respond to inflammatory stimuli. In contrast, resistance to the development of SCW-induced arthritis and other inflammatory autoimmune manifestations in histocompatible female Fischer rats (F344/N) is related to their intact HPA axis response to inflammatory mediators. To evaluate the mechanism and the specificity of the HPA axis defect in LEW/N rats, we examined the ability of three major excitatory neurotransmitter systems to activate the HPA axis in both Lewis and Fisher rats. The responsiveness of plasma ACTH and corticosterone to the cholinergic muscarinic receptor agonist arecoline, the alpha 1-adrenergic receptor agonist methoxamine and the serotonin (5-HT) type 2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane were significantly blunted and/or abolished in LEW/N compared to F344/N rats. To localize the HPA axis defect to the hypothalamic CRH neuron, we evaluated the ability of explanted hypothalami from the two strains to secrete immunoreactive CRH in vitro, in response to acetylcholine (ACh), norepinephrine (NE), 5-HT and the 5-HT agonist quipazine. LEW/N hypothalami released less immunoreactive CRH (iCRH) in response to ACh, NE, 5-HT and quipazine than F344/N hypothalami. The dose-response curves of these compounds in the former were shifted to the right and/or abolished, suggesting decreased sensitivity of LEW/N hypothalami to these neurotransmitters.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1992

In vitro regulation of pituitary ACTH secretion in inflammatory disease susceptible Lewis (LEW/N) and inflammatory disease resistant Fischer (F344/N) rats.

We have previously shown that susceptibility to inflammatory disease in Lewis (LEW/N) rats is related to their limited hypothalamic-pituitary-adrenal (HPA) axis responses to a variety of inflammatory stimuli, while the relative resistance to inflammatory disease in Fischer (F344/N) rats is related to their potent HPA axis responses to these same stimuli. In vivo studies also showed that LEW/N pituitary ACTH responses to exogenous corticotropin-releasing hormone (CRH) were blunted compared to F344/N. To determine if there is a fundamental difference in pituitary corticotroph function between the two strains, independent of other factors influencing the HPA axis, we compared ACTH responses to a variety of stimuli in LEW/N and F344/N primary pituitary cell cultures. Here we show that in vitro basal ACTH secretion and peak ACTH response to CRH, forskolin and 8-bromo-cAMP are 50% lower in LEW/N than F344/N rats. However, these findings can be explained by other observations: diminished basal ACTH content, POMC mRNA, and a decreased number of corticotrophs, in pituitary cell cultures from LEW/N compared to F344/N rats. In addition, LEW/N corticotrophs were more sensitive to dexamethasone and to corticosterone suppression of CRH-stimulated ACTH secretion compared to F344/N. The data support the possibility of an HPA axis defect in LEW/N rats at the pituitary level which could be secondary to prolonged understimulation by hypothalamic CRH, or could also be partially related to enhanced glucocorticoid feedback inhibition.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1992

Differential startle amplitude and corticosterone response in rats.

Different rat strains exhibit large differences in hypothalamic pituitary-adrenal activity that have been used to determine the role of the neuroendocrine system in susceptibility to autoimmune disease. To further characterize potential behavioral correlates of these differences, the amplitude of the acoustic (ASR) and tactile (TSR) startle response and the corticosterone response to acoustic startle stimuli were compared between two histocompatible strains, Lewis (LEW/N) and Fischer (F344/N) rats, as well as outbred Harlan Sprague-Dawley (SD) rats. Startle stimuli elicited larger ASR and TSR in LEW/N rats than in F344/N rats, with SD rats exhibiting an intermediate response. The ASR habituated at a similar rate in LEW/N and F344 rats, while the ASR did not habituate in SD rats. After handling and placement in the startle chambers, the three strains did not differ in control levels of corticosterone. In contrast, exposure to acoustic startle stimuli increased corticosterone 5-fold in F344/N rats and 2-fold in SD rats, but had no effect on corticosterone in LEW/N rats. These findings suggested an inverse relationship between the amplitude of the ASR and hypothalamic-pituitary-adrenal activation across strains. This relationship was further supported by a high negative correlation between corticosterone level and ASR amplitude within the F344/N group.

Acoustic Stimulation↗
PubMed1992

Pituitary-adrenal axis responsiveness to ovine corticotropin releasing hormone in patients with rheumatoid arthritis treated with low dose prednisone.

Ovine corticotropin-releasing hormone (oCRH) stimulation tests were performed in 8 female patients with active rheumatoid arthritis treated chronically with daily low dose prednisone and 16 age matched female controls. Patients were tested on the day of treatment, 12 h after their last prednisone dose, and after withholding prednisone for 36 h. Basal levels of plasma ACTH and to a lesser extent plasma cortisol levels were elevated before each test, and significant increases in ACTH and cortisol were induced with oCRH. The dose response relationship between total ACTH and total cortisol was shifted to the right, suggesting that the patient group had mildly deficient adrenocortical responsiveness compensated for by elevated basal evening ACTH concentrations. It is not known whether the neuroendocrine abnormalities demonstrated are due to an intrinsic preexisting abnormality, active disease, drug therapy or all these factors.

Adrenocorticotropic Hormone↗
PubMed1991

Endothelial cells and the pathogenesis of rheumatoid arthritis in humans and streptococcal cell wall arthritis in Lewis rats.

Endothelial cells play a fundamental role in the pathogenesis of chronic inflammatory arthritis in humans such as rheumatoid arthritis (RA), as well as experimental animal models such as streptococcal cell wall (SCW) arthritis in Lewis (LEW/N) rats. This review summarizes data in support of this concept. The earliest apparent abnormalities in synovial tissues of patients with RA and Lewis rats with SCW arthritis appear to reflect microvascular endothelial cell activation or injury. At the molecular level, the abnormalities include enhanced expression by endothelial cells of activation markers such as class II major histocompatibility complex antigens, phosphotyrosine, leukocyte adhesion molecules, oncoproteins such as c-Fos and c-Myc, and metalloproteinases such as collagenase and transin/stromelysin. The development of severe, chronic, destructive arthritis is dependent upon thymic-derived lymphocytes and is accompanied by tumorlike proliferation of cells in the synovial connective tissue stroma (blood vessels and fibroblastlike cells), which results in resorptive destruction of bone and cartilage. Multiple criteria support the analogy to a neoplastic process. Paracrine and autocrine factors such as interleukin-1 (IL-1), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), and heparin-binding fibroblast growth factors (HBGF, FGF) appear to play important roles in the generation of these lesions. Finally, in addition to the autocrine and paracrine regulatory factors, neuroendocrine factors, particularly the hypothalamic-pituitary-adrenal axis, appear to be involved in the counterregulation of the inflammatory process. The counterregulatory effects are mediated, in part, by inhibition of endothelial cell activation by corticosteroids.

Animals↗
PubMed1991

Environmental pathology. Mast cell and eosinophil infiltration in intestinal mucosa of Lewis rats treated with L-tryptophan implicated in human eosinophilia myalgia syndrome.

A recently developed animal model for the L-tryptophan-associated eosinophilia myalgia syndrome was used to examine the small intestine and colon, because there is clinical involvement at these sites in patients. Increased perivascular inflammatory infiltrates rich in degranulating mast cells, eosinophils, and monocytes were seen in the lamina propria of experimental animals when compared with controls. L-Tryptophan-associated disease also shares many clinical features with idiopathic scleroderma/eosinophilic fasciitis, in which there is gastrointestinal involvement as well. These features are similar to those found in the recently described animal model. The apparent morphologic and clinical similarities between these entities suggest that the animal model is suitable for further studying the pathogenesis of the gastrointestinal involvement in all these diseases.

Animals↗
PubMed1990

Scleroderma, fasciitis, and eosinophilia associated with the ingestion of tryptophan.

An association between the ingestion tryptophan and a syndrome characterized by scleroderma-like skin abnormalities, fasciitis, and eosinophilia has recently been recognized in the United States. We report the clinical and histopathological findings in nine patients and the results of biochemical analyses of tryptophan metabolism in seven patients with this syndrome. Edema of the extremities, frequently accompanied by pruritus, paresthesia, and myalgia, developed in the nine patients (six women and three men; age range, 30 to 66 years) 1 to 18 months after the start of therapy with tryptophan (1.5 to 3.0 g daily) for insomnia, depression, or obesity. Five patients were taking drugs (benzodiazepines) known to inhibit hypothalamic-pituitary-adrenal function, and one had adrenal insufficiency. All had blood eosinophilia in the acute phase of their illness (mean eosinophil count [+/- SD], 3.62 +/- 2.87 X 10(9) cells per liter). All had histopathological changes in the dermis and subcutaneous tissue typical of scleroderma, and seven patients had eosinophils. The fascia was inflamed and fibrotic, and adjacent skeletal muscle often showed perifascicular inflammation. Tryptophan was discontinued in all patients, and eight received prednisone. The cutaneous symptoms improved, but only two patients had complete resolution of their illness. The patients had plasma levels of tryptophan before and after an oral dose of tryptophan that were similar to those in normal subjects. Plasma levels of L-kynurenine and quinolinic acid, which are metabolites of tryptophan, were significantly higher in four patients with active disease than in three patients studied after eosinophilia had resolved or in five normal subjects (P less than 0.001)--findings consistent with the activation of the enzyme indoleamine-2,3-dioxygenase. This illness resembles eosinophilic fasciitis and probably represents one aspect of the recently reported eosinophilia-myalgia syndrome. The development of the syndrome may result from a confluence of several factors, including the ingestion of tryptophan, exposure to agents that activate indoleamine-2,3-dioxygenase, and possibly, impaired function of the hypothalamic-pituitary-adrenal axis.

Adult↗
PubMed1989

A central nervous system defect in biosynthesis of corticotropin-releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats.

We have recently found that susceptibility to streptococcal cell wall (SCW)-induced arthritis in Lewis (LEW/N) rats is due, in part, to defective inflammatory and stress mediator-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Conversely, the relative arthritis resistance of histocompatible Fischer (F344/N) rats is related to their intact responses to the same stimuli. Specifically, LEW/N rats, in contrast to F344/N rats, have markedly impaired plasma corticotropin and corticosterone responses to SCW, recombinant human interleukin 1 alpha, the serotonin agonist quipazine, or synthetic rat/human corticotropin-releasing hormone (CRH). To explore the mechanism of this defect, we examined the functional integrity of the hypothalamic CRH neuron in LEW/N rats compared to F344/N rats. LEW/N rats, in contrast to F344/N rats, showed profoundly deficient paraventricular nucleus CRH mRNA levels and hypothalamic CRH content in response to SCW. Compared to F344/N rats, there was no increase in LEW/N hypothalamic CRH content or CRH release from explanted LEW/N hypothalami in organ culture in response to recombinant interleukin 1 alpha. These data provide strong evidence that the defective LEW/N corticotropin and corticosterone responses to inflammatory and other stress mediators, and the LEW/N susceptibility to experimental arthritis, are due in part to a hypothalamic defect in the synthesis and secretion of CRH. The additional finding of deficient expression in LEW/N rats of the hypothalamic enkephalin gene, which is coordinately regulated with the CRH gene in response to stress, suggests that the primary defect is not in the CRH gene but is instead related to its inappropriate regulation.

Animals↗
PubMed1989

Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats.

Inbred Lewis (LEW/N) female rats develop an arthritis in response to group A streptococcal cell wall peptidoglycan polysaccharide (SCW), which mimics human rheumatoid arthritis. Histocompatible Fischer (F344/N) rats do not develop arthritis in response to the same SCW stimulus. To evaluate this difference in inflammatory reactivity, we examined the function of the hypothalamic-pituitary-adrenal (HPA) axis and its ability to modulate the development of the inflammatory response in LEW/N and F344/N rats. We have found that, in contrast to F344/N rats, LEW/N rats had markedly impaired plasma corticotropin and corticosterone responses to SCW, recombinant human interleukin 1 alpha, the serotonin agonist quipazine, and synthetic rat/human corticotropin-releasing hormone. LEW/N rats also had smaller adrenal glands and larger thymuses. Replacement doses of dexamethasone decreased the severity of LEW/N rats' SCW-induced arthritis. Conversely, treatment of F344/N rats with the glucocorticoid receptor antagonist RU 486 or the serotonin antagonist LY53857 was associated with development of severe inflammatory disease, including arthritis, in response to SCW. These findings support the concept that susceptibility of LEW/N rats to SCW arthritis is related to defective HPA axis responsiveness to inflammatory and other stress mediators and that resistance of F344/N rats to SCW arthritis is regulated by an intact HPA axis-immune system feedback loop.

Adrenocorticotropic Hormone↗
PubMed1987

Effect of serotonin (5-HT) and other monoamines on murine macrophages: modulation of interferon-gamma induced phagocytosis.

We have previously shown that serotonin (5-HT) suppresses interferon-gamma (IFN-gamma)-induced Ia expression. In the present report, we show that 5-HT as well as other monoamines, histamine and dopamine, modulate IFN-gamma-induced phagocytosis in murine bone marrow macrophages. The effect of 5-HT on IFN-gamma-induced phagocytosis varied according to the concentration of IFN-gamma to which the macrophages were exposed. At low concentrations of IFN-gamma, 5-HT augmented phagocytosis, whereas at high concentrations of IFN-gamma, 5-HT suppressed phagocytosis. At both low and high IFN-gamma concentrations the response to 5-HT was dose-related and occurred at physiologic concentrations; the half-maximal effect was 6 X 10(-7) M and 3 X 10(-7) M for low and high IFN-gamma concentrations, respectively. Both histamine and dopamine also augmented IFN-gamma (1 U/ml) induced phagocytosis, at half-maximal augmenting concentrations of 7 X 10(-8) M and 4 X 10(-7) M, respectively. The 5-HT effects were blocked by the 5-HT antagonists spiperone, ketanserin, LY53857, mCPP, and PAPP, but not by the histamine antagonists pyrilamine, chlorpheniramine, or cimetidine. Histamine augmentation of IFN-gamma-induced phagocytosis was blocked by the H1 antagonists pyrilamine and chlorpheniramine, but not by the H2 antagonist cimetidine. The dopamine effect was blocked by spiperone and pyrilamine, both of which have been shown to block dopaminergic effects in other systems. This data provides functional evidence that at least part of the modulation of IFN-gamma-induced phagocytosis by 5-HT occurs through a 5-HT receptor-mediated mechanism, and 5-HT, dopamine, and histamine modulate IFN-gamma-induced phagocytosis independently through their respective receptors.

Animals↗
PubMed1986

Effect of serotonin on murine macrophages: suppression of Ia expression by serotonin and its reversal by 5-HT2 serotonergic receptor antagonists.

Serotonin (5-HT), a mediator released from platelets at sites of inflammation, suppressed IFN-gamma-induced Ia expression in mouse bone marrow macrophages maintained in vitro. (Mean percent suppression = 63.9% +/- 9.2, n = 40.) This suppression was not toxic or endotoxin-related, was concentration-dependent, and occurred at the physiologic concentrations of 5-HT present at inflammatory sites. The concentration of 5-HT producing the half-maximal effect was 2.5 to 5.5 X 10(-8) M. Related compounds, dopamine, histamine, and tryptamine, were much less potent in suppressing IFN-gamma-induced Ia, with maximally suppressing concentrations more than 100-fold higher than the maximally suppressing 5-HT concentration. L-5-hydroxytryptophan (5-HTP), the most potent analog tested, was 10-fold less potent than 5-HT in suppressing Ia expression. The concentration of 5-HTP producing the half-maximal effect = 4 X 10(-7) M. 5-HT suppression of IFN-gamma-induced Ia expression was antagonized by the 5-HT2 type receptor antagonists spiperone, ketanserin, and LY53857. Concentrations of these agents resulting in 50% inhibition of the serotonin effect were 1.5 X 10(-8) M, 7.5 X 10(-8) M, and 4.5 X 10(-12) M, respectively. 5-HT was most effective in suppressing IFN-gamma-induced Ia when added early in culture simultaneously with IFN-gamma. These data provide functional evidence that 5-HT suppression of IFN-gamma-induced Ia expression is mediated through a 5-HT receptor with some characteristics of the 5-HT2 type. 5-HT may play a physiologic role at sites of inflammation as a modulator of the effects of IFN-gamma on macrophage function.

Animals↗
PubMed1980

Development of a scleroderma-like illness during therapy with L-5-hydroxytryptophan and carbidopa.

A scleroderma-like illness developed in a patient treated with L-5 hydroxytryptophan (L-5HTP) and carbidopa for intention myoclonus. The patient had high plasma kynurenine levels that remained high when the L-5HTP-carbidopa combination was discontinued, However, levels rose futher on drug rechallenge, suggesting that the drug unmasked an abnormality in one of the enzymes that catabolize kynurenine. Plasma kynurenine was also determined to be high in seven of 15 patients wth idiopathic scleroderma, but not in eight patients with intention myoclonus treated with L-5HTP and a decarboxylase inhibitor and in whom scleroderma did not develop or in 10 patients with Parkinson's disease treated wth L-dopa and carbidopa. Our data and studies in the literature suggest that two factors may be important in the pathogenesis of some scleroderma-like illness: high plasma serotonin and the abnormality associated with elevated kynurenine.

5-Hydroxytryptophan↗