Biomedical subjects

J R Seckl

Publications and source records attributed to J R Seckl.

At least 19 recordsLinked to original sources

PubMed1992

Central 6-hydroxydopamine lesions decrease mineralocorticoid, but not glucocorticoid receptor gene expression in the rat hippocampus.

The role of hippocampal noradrenergic inputs in the modulation of corticosteroid receptor expression has been investigated. Adult male rats were given central 6-hydroxydopamine (6-OHDA) and the expression of hippocampal mineralocorticoid (MR) and glucocorticoid (GR) receptor mRNA was examined after two weeks by in situ hybridization histochemistry. Expression of MR mRNA was significantly decreased in all subregions of the hippocampus except CA2, but 6-OHDA lesions had no effect on GR mRNA expression. These data reveal differential regulation of the two receptor types by noradrenergic inputs.

Animals↗

PubMed1992

Medial septal cholinergic lesions increase hippocampal mineralocorticoid and glucocorticoid receptor messenger RNA expression.

Loss of the cholinergic innervation of the hippocampus and failure of central (presumably hippocampal) suppressive control of hypothalamic-pituitary-adrenal axis activity are important features of Alzheimer's dementia. We have examined the effects of electrolytic lesions of the medial septal cholinergic innervation on mineralocorticoid (MR) and glucocorticoid (GR) receptor mRNA expression in rat hippocampus using in situ hybridization histochemistry. Expression of both MR and GR mRNA was significantly increased in a subregions of the hippocampus, but not neocortex, with the greatest increase in the CA1 area for MR mRNA and dentate gyrus for GR mRNA. Since glucocorticoids potentiate the effects of neurotoxins in the hippocampus, the increased expression of receptors following loss of cholinergic inputs in Alzheimer's disease may increase hippocampal neuronal vulnerability.

Acetylcholine↗

PubMed1992

Increase in substance P and CGRP, but not somatostatin content of innervating dorsal root ganglia in adjuvant monoarthritis in the rat.

Neuropeptides, synthesized in dorsal root ganglia (DRG), are implicated in nociception and neurogenic inflammation. Alterations in DRG neuropeptide levels have been described in polyarthritic rats, but these models are associated with widespread systemic disease. Using mild adjuvant-mediated monoarthritis of the left carpal joint we found significant increases in substance P (+69%) and calcitonin gene-related peptide (CGRP; +204+), but not somatostatin in ipsilateral C6/7 DRG. Peptide levels in contralateral DRG and other ipsilateral DRG were unaltered. Substance P and CGRP in DRG may be of importance in the pathogenesis and maintenance of adjuvant arthritis.

Animals↗

PubMed1992

The effects of cortisol infusion upon hormone secretion from the anterior pituitary and subjective mood in depressive illness and in controls.

The aims of this study were to determine whether the administration of cortisol has a significant effect on mood in patients with depression and whether the effects of cortisol on changes in plasma hormone concentrations are like those of synthetic corticosteroids. Twelve patients had major depression and one each had dysthymic disorder and a depressive adjustment disorder. Five were male and nine were female. All were in-patients. Eight normal subjects, two females and six males, were used as controls. Basal beta-endorphin concentrations were 2- to 3-fold higher in depressed patients than in control subjects, but there were no significant differences between the patient and control groups in the basal (pre-infusion) plasma concentrations of ACTH, cortisol, growth hormone or prolactin. Cortisol, but not saline infusion resulted in a significant improvement in self rated mood. Surprisingly, cortisol infusion at first increased plasma beta-endorphin concentrations. At later times after cortisol infusion, plasma beta-endorphin concentrations decreased as did the plasma concentrations of ACTH and growth hormone; prolactin levels were increased. These results show (i) that cortisol infusion raises mood significantly in major depression, (ii) that plasma beta-endorphin concentration is a potential marker of major depression (iii) that rather than blunting of corticosteroid effects, responses to cortisol may even be enhanced in depressive illness. The unexpected, initial increase in beta-endorphin stimulated by cortisol, suggests that the action of cortisol is not simply one of negative feedback inhibition, but may involve mineralocorticoid, as well as glucocorticoid receptors.

Adrenocorticotropic Hormone↗

PubMed1992

Increased expression of preprotachykinin, calcitonin gene-related peptide, but not vasoactive intestinal peptide messenger RNA in dorsal root ganglia during the development of adjuvant monoarthritis in the rat.

Neuropeptides in dorsal root ganglia (DRG) have been implicated in the pathogenesis of pain and neurogenic inflammation in experimental and clinical arthritis. Recently we demonstrated increased levels of substance P (SP) and calcitonin gene-related peptide (CGRP) confined to innervating DRG in adjuvant-mediated monoarthritis. We have now investigated whether changes in peptide content are reflected in altered neuropeptide gene expression and the time course involved. Using in situ hybridization we found marked increases in expression of beta-preprotachykinin (PPT; 81 +/- 24% rise) and alpha-CGRP (44 +/- 6% rise) mRNAs in innervating (ipsilateral L5) DRG neurones only. These increases occurred at the onset of acute inflammation (8 h) and persisted until chronic arthritis developed after 14 days. There were no changes in the proportion of DRG neurones expressing PPT or CGRP mRNAs. Messenger RNA encoding vasoactive intestinal polypeptide (VIP) was not induced. These data suggest that increased synthesis of PPT and CGRP peptides in DRG may play a role in the pathogenesis both of adjuvant-mediated acute inflammation and chronic arthritis.

Animals↗

PubMed1992

Plasma and cerebrospinal fluid arginine vasopressin in patients with and without fever.

Hyponatraemia has been described in association with a number of acute infectious diseases, mainly bacterial and tuberculous meningitis and pneumonia, and has been attributed to inappropriate secretion of arginine vasopressin (AVP). The mechanism of inappropriate AVP production is uncertain, but there is experimental evidence to suggest that fever may stimulate secretion of AVP into plasma and cerebrospinal fluid. In this study, AVP concentrations in plasma and cerebrospinal fluid from 37 febrile children with infections have been compared with those from 27 afebrile control subjects. Ten of the febrile children had meningitis (eight bacterial, two viral) and the remainder a variety of other infectious diseases. Seventy four per cent of febrile infected children were hyponatraemic (serum sodium less than 135 mmol/l) compared with only 8% of the afebrile controls. Plasma AVP concentrations were significantly higher in the febrile patients (median 2.92 pmol/l, range 1.0-23.25, n = 28) than in controls (median 1.67 pmol/l, range 0.57-6.0, n = 14) but there was no significant difference in cerebrospinal fluid AVP concentrations. There was no difference in plasma AVP concentrations between patients with meningitis and those with infections not involving the central nervous system. Careful attention should be paid to fluid and electrolyte balance in all children with acute infections.

Adolescent↗

PubMed1992

Antidepressants increase glucocorticoid and mineralocorticoid receptor mRNA expression in rat hippocampus in vivo.

Adrenal corticosteroids bind to hippocampal glucocorticoid (GR) and mineralocorticoid receptors (MR), thereby affecting neurochemical transmission leading to altered mood, behaviour and neuroendocrine control. Serotoninergic (5-HT) and noradrenergic projections innervate the hippocampus, interacting with corticosteroid-sensitive cells. We have previously demonstrated that lesions of 5-HT neurons reduce hippocampal GR and MR mRNA levels and now examine whether acute or chronic treatment with antidepressant drugs, which potentiate endogenous monoamines by inhibiting their reuptake, affect hippocampal GR and MR mRNA expression in vivo. Rats were treated with amitriptyline (20 mg/kg.day-1), desipramine (10 mg/kg.day-1) or citalopram (20 mg/kg.day-1). After 2 or 14 days animals were killed, RNA extracted and GR and MR mRNA expression quantified by slot blot hybridization. Amitriptyline for 2 days led to a significant increase in MR (by 23 +/- 6%, compared with saline-treated controls), but not GR, mRNA expression. After 14 days amitriptyline, expression of both MR (87 +/- 27% rise) and GR mRNA (56 +/- 18% rise) had increased significantly in hippocampus, but not in parietal cortex. Desipramine for 14 days also increased MR (60 +/- 9%) and GR (42 +/- 9%) mRNA expression, though 14 days of citalopram altered only MR mRNA expression (17 +/- 5%). Thus, antidepressant drug administration elevates MR and GR mRNA expression in hippocampus, but not parietal cortex, in a time-dependent manner.

Animals↗

PubMed1992

Ontogeny of 11 beta-hydroxysteroid dehydrogenase in rat brain and kidney.

Close regulation of circulating corticosteroid levels during the early postnatal period is crucial for normal development and maturation of the central nervous system. In the first weeks of life cerebral glucocorticoid receptor concentrations are low and the hypothalamic-pituitary-adrenal axis is relatively unresponsive to stress, which might, in part, protect the developing brain from elevated corticosteroid levels. However, central mineralocorticoid receptors are at near adult levels and free glucocorticoid concentrations may approximate adult values as corticosteroid binding globulin is absent. Thus other mechanisms controlling cerebral exposure to corticosteroids may be of importance. 11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) determines the access of corticosterone to peripheral mineralocorticoid and glucocorticoid receptors in adults in vivo by metabolizing corticosterone to inactive 11-dehydrocorticosterone. The enzyme has recently been demonstrated in brain subregions and may modulate local corticosteroid-receptor interactions. We therefore examined 11 beta-OHSD bioactivity and messenger RNA (mRNA) expression in the brain, compared with kidney, during the neonatal period. 11 beta-OHSD bioactivity (expressed as the percentage conversion of corticosterone to 11-dehydrocorticosterone) was moderately high in hippocampus and parietal cortex at birth (46 +/- 4% and 48 +/- 5%, respectively), fell significantly to a nadir (32 +/- 1% and 30 +/- 1%, respectively) at postnatal day 10 and then gradually rose to adult values (52 +/- 3% and 58 +/- 3%). By contrast, 11 beta-OHSD activity in cerebellum was high at birth (60 +/- 3%), rose significantly to a peak at postnatal day 10 (74 +/- 3%), and then fell to adult values by postnatal day 15 (64 +/- 3%). Renal 11 beta-OHSD activity was moderately high (69 +/- 3%) at birth and reached adult values (80 +/- 2%) by postnatal day 5. Northern blots showed high and similar expression of a single species of 11 beta-OHSD mRNA from birth to adulthood in the hippocampus. Only low expression of 11 beta-OHSD (two or three separate species) was found in the kidney during the first 2 weeks of life, whereas, in adults high expression of 11 beta-OHSD mRNA was detected in kidney (four species). Using in situ hybridization high 11 beta-OHSD mRNA expression was localized to the neuronal layers of the postnatal hippocampus, neocortex, and cerebellum, and low but detectable expression was found in the neonatal renal cortex. Thus, 11 beta-OHSD is highly expressed in rat brain subregions in the early postnatal period with specific developmental patterns of activity.(ABSTRACT TRUNCATED AT 400 WORDS)

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1992

Atriopeptin: an endogenous corticotropin-release inhibiting hormone.

Activation of the hypothalamic-pituitary-adrenocortical axis is a major component of the body's response to stress. Current theories on the pathophysiology of disorders associated with hyperfunction of the axis, such as depression and Cushing's stress, are based on the concept that anterior pituitary adrenocorticotropin (ACTH) secretion is stimulated by hypothalamic corticotropin-releasing hormones and inhibited by adrenal corticosteroids. Hypothalamic inhibitory control of pituitary ACTH secretion has been also postulated, but has not gained general acceptance because of the lack of definitive evidence for a corticotropin-release inhibiting hormone. It is shown here that in conscious rats stress-induced secretion of ACTH and corticosterone is markedly enhanced by the immunoneutralisation of atriopeptin. Therefore, we propose that atriopeptin is a physiologically relevant corticotropin-release inhibiting hormone.

Adrenal Cortex↗

PubMed1992

Differential promoter usage by the rat 11 beta-hydroxysteroid dehydrogenase gene.

11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) catalyzes the conversion of physiological glucocorticoids to inactive products, thus protecting nonselective renal mineralocorticoid receptors from circulating glucocorticoids (ensuring aldosterone selectivity in vivo) and modulating glucocorticoid access to mineralocorticoid receptors and glucocorticoid receptors in other tissues. Detection of multiple mRNA and immunoreactive 11 beta-OHSD species in kidney, but not liver, extracts suggests the presence of tissue-specific isoforms. To determine whether differential promoter usage might explain the mRNA heterogeneity we cloned and sequenced rat 11 beta-OHSD genomic DNA. Total identity was found between the nucleotide sequence of exons 1 and 2 and the previously published rat liver cDNA. Using both primer extension and RNase protection analyses we found the predominant transcription start site in liver (+1) is 105 base pairs (bp)5' of the start of translation. In kidney two additional Cap sites were detected: 1) 264 bp 5' of exon 1; there is no in-phase open reading frame, suggesting the additional 5' sequence is not translated; and 2) 65 bp upstream of exon 2, within intron A; the predicted truncated protein lacks the first 26 hydrophobic residues. Oligonucleotide probes specific to transcripts arising from each promoter confirmed that all three are employed in kidney, whereas a single predominant species was found in liver, thus demonstrating tissue-specific differential promoter usage of the 11 beta-OHSD gene.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1992

11 beta-Hydroxysteroid dehydrogenase in the rat ovary: high expression in the oocyte.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the conversion of physiological glucocorticoids to inactive products, thus modifying the access of glucocorticoids to glucocorticoid and mineralocorticoid receptors. Glucocorticoids may affect ovarian function both indirectly and via binding to ovarian receptors. We have demonstrated 11 beta-HSD bioactivity and mRNA expression in rat ovary in vitro. The enzyme was localized to oocytes and luteal bodies immunohistochemically using two antibodies raised against purified rat liver 11 beta-HSD. These data are supported by in-situ hybridization studies, which also localized 11 beta-HSD mRNA expression to oocytes and luteal bodies. The results suggest that 11 beta-HSD may modulate the effects of glucocorticoid on ovarian function.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1992

Diabetes insipidus. Current treatment recommendations.

Cranial diabetes insipidus (DI) arises when release of arginine vasopressin (AVP, antidiuretic hormone) in response to osmotic stimuli is inadequate. The correct diagnosis and management of cranial DI is particularly important when it arises as an acute complication of surgery, trauma or in subjects who lack thirst sensation. Desmopressin (1-desamino-8-D-arginine-vasopressin, DDAVP) provides an effective and convenient replacement therapy when given by the intranasal route. However, nasal administration is difficult for some patients, and in the future oral or transcutaneous desmopressin formulations may prove to be satisfactory alternatives. By contrast, treatments for nephrogenic DI, where there is failure of the antidiuretic response to endogenous or exogenous vasopressin, have been disappointing and water replacement remains the mainstay of therapy. An understanding of the physiology and pathophysiology of water homeostasis and correct interpretation of water balance and electrolyte data are essential for correct diagnosis and management of all cases of DI.

Arginine Vasopressin↗

PubMed1991

Effect of adrenalectomy and dexamethasone on neuropeptide content of dorsal root ganglia in the rat.

Neuropeptides, including substance P (SP), calcitonin gene-related peptide (CGRP) and somatostatin (SS) in dorsal root ganglia (DRG) may play a role in neurogenic inflammation and pain transmission. Adrenal corticosteroids regulate neuropeptide synthesis in some areas of the CNS and may modulate neurogenic inflammation and sensory perception. We have investigated the effects of adrenalectomy and dexamethasone (0.2 mg/kg/day) treatment on neuropeptide content of rat cervical DRG using specific and sensitive radioimmunoassays. In control animals, a differential distribution of neuropeptide was found; SP and CGRP content increased from C4 to C7 in contrast to SS content, which decreased from C4 to C7. Ten days following adrenalectomy, the mean SS content of cervical DRG decreased significantly to 79.6 +/- 4.5% of sham-operated controls. In contrast, SP and CGRP content increased significantly 10 days after adrenalectomy to 134.6 +/- 6.9% and 132.0 +/- 11.6% of sham-operated controls, respectively. The effects of adrenalectomy on CGRP and SS were reversed by administration of dexamethasone. These results suggest that glucocorticoids affect the neuropeptide content of DRG in the adult rat.

Adrenalectomy↗

PubMed1991

Distribution of glucocorticoid and mineralocorticoid receptor messenger RNA expression in human postmortem hippocampus.

Corticosteroids bind to hippocampal glucocorticoid (GR) and mineralocorticoid (MR) receptors, thereby affecting behaviour and neurochemical transmission. Rat hippocampus has high levels of both receptors and their messenger RNAs (mRNA), but there is little information on receptors in human brain. We used in situ hybridization to determine the distribution of GR and MR mRNA expression in human hippocampus. Frozen sections of human postmortem hippocampus (5 patients, 58-88 years old, without cerebral pathology) were postfixed in paraformaldehyde and hybridized with 35S-UTP-labelled cRNA probes (transcribed in vitro from human cDNA subclones) under stringent conditions. Control included hybridization with sense probes and heterologous cRNA competition studies. GR mRNA was highly expressed in dentate gyrus, CA3 and CA4, but levels were significantly lower in CA1 and CA2. MR mRNA was also very highly expressed in hippocampus, with significantly higher levels in dentate gyrus and CA2, CA3 and CA4 than CA1. Controls confirmed the specificity of hybridization and there was little hybridization of sense probes. High GR and MR mRNA expression is found in both rat and human hippocampus but the subregional distributions clearly differ between the species.

Aged↗

PubMed1991

Liquorice.

Explore the source record for details and available documents.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1991

Intracerebroventricular vasopressin reduces CSF absorption rate in the conscious goat.

Cerebrospinal fluid (CSF) levels of vasopressin (AVP) are elevated in some disorders associated with raised intracranial pressure. We have previously demonstrated that intracerebroventricular infusion of AVP in the conscious goat leads to elevation of intracranial pressure by a mechanism independent of changes in arterial blood pressure or circulating neurohypophysial peptide concentrations. We have now examined the effect of increasing CSF AVP levels on CSF dynamics using the technique of ventriculo-cisternal perfusion in the conscious goat. Intracerebroventricular perfusion with 5 pmol/min AVP in artificial CSF did not alter CSF formation rate but significantly reduced CSF absorption rate (24% decrease; p less than 0.01), when compared with perfusion using artificial CSF alone. This AVP-mediated reduction in CSF absorption rate may represent increased resistance to resorption of CSF or may reflect the effect of raised intracranial pressure.

Analysis of Variance↗

PubMed1991

Use of in situ hybridization to investigate the regulation of hippocampal corticosteroid receptors by monoamines.

The hippocampus receives major noradrenergic and serotoninergic (5-HT) innervations which interact with corticosteroid-sensitive cells. However, the subregional localization of these actions and the corticosteroid receptor types involved have not been defined and current ligand binding techniques for estimating corticosteroid receptors are hampered by several methodological limitations. We have developed in situ hybridization histochemical techniques to allow specific and sensitive estimation of glucocorticoid (GR) and mineralocorticoid receptor (MR) mRNA expression in rat hippocampus. Investigation of the effects of 5,7-dihydroxytryptamine lesions of 5-HT neurons showed significantly reduced GR and MR mRNA expression in some hippocampal subregions. Both abnormal 5-HT neurotransmission and excessive corticosteroid secretion are associated with major affective disorder, particularly depression. The crucial interaction between these two systems may occur, at least in part, at the level of regulation of hippocampal corticosteroid receptor expression.

5,7-Dihydroxytryptamine↗

PubMed1991

Glycyrrhetinic acid, an inhibitor of 11 beta-hydroxysteroid dehydrogenase, alters local cerebral glucose utilization in vivo.

11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) metabolizes corticosterone (B) to inactive 11-dehydrocorticosterone and thus protects the non-specific renal mineralocorticoid receptor from exposure to B in vivo. There is regional 11 beta-OHSD mRNA expression and bioactivity in brain in vitro, but any in vivo function is unknown. We used the [14C]2-deoxyglucose technique in conscious rats to investigate whether 11 beta-OHSD inhibition with glycyrrhetinic acid alters local cerebral metabolic activity. We found increased glucose use in subregions of the hypothalamus, hippocampus, neocortex and subthalamus. Thus, 11 beta-OHSD may play a role in regulating the effects of B in the brain, in vivo.

11-beta-Hydroxysteroid Dehydrogenases↗