Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

OBJECTIVE: To evaluate whether altered levels of progesterone and its main neuroactive metabolite allopregnanolone do occur in premenopausal women. The second part of this study deals with allopregnanolone levels in thyreoidectomized women. METHODS: Allopregnanolone, a neurosteroid acting by its allosteric interaction with GABAA receptors and progesterone, were determined in two groups of patients which have in common certain psychic disorders generally characterized by the depression and anxiety, namely in 23 women with premenstrual syndrome (PMS) and in 52 women after total thyreoidectomy. The control groups consisted of women of the same age without premenstrual complaints and with normal thyroid function, respectively. RESULTS: Significantly lower values of allopregnanolone in PMS patients than in controls have been found in the follicular phase, indicating the lower peripheral activity of 5alpha-reductase of C21-steroids detectable at low progesterone levels only. In the thyroidectomized patients significantly higher values of allopregnanolone have been found in the luteal phase. CONCLUSION: The increase of allopregnanolone level in thyroidectomized patients may represent one of the counterregulatory mechanisms protecting the organism from some consequences of hormonal disbalance after thyroid ablation.
 ...
PMID:Serum Levels of Neurosteroid Allopregnanolone in Patients with Premenstrual Syndrome and Patients after Thyroidectomy. 1033 May 22

Sex steroid hormones exert important influences on neuroendocrine and behavioural brain function. As neuroactive steroids they are able to modify neuronal excitability. Unbalanced synthesis may thus be implicated in pathophysiological conditions, such as epilepsy, migraine, depression and anxiety. In sex steroid metabolism, 17beta-hydroxisteroid dehydrogenases (17beta-HSDs) play a crucial role in catalyzing the final steps of androgen and estrogen biosynthesis. The hippocampus appears to be a major target area of neurosteroidal action. The expression of 17beta-HSD isozymes has not yet been studied in human hippocampus. Therefore, we investigated the expression of 17beta-HSD 1, 2, 3 and 4 mRNAs in hippocampal tissue specimens obtained at neurosurgery from 42 patients with pharmacoresistant temporal lobe epilepsy. A competitive RT-PCR assay was used to quantify the mRNA transcript level. 17beta-HSD 1 mRNA concentrations were 10000 fold lower in the hippocampus compared to placental tissue, whereas 17beta-HSD 3 mRNA concentrations were 50 fold lower than in testis and 17beta-HSD 4 concentrations were in the same order of magnitude as in liver. 17beta-HSD 2 mRNA was not expressed. 17beta-HSD 1, 3 and 4 mRNA concentrations in the hippocampus showed no significant differences between men and women and there were no significant differences in expression levels of these enzymes between patients with Ammon's horn sclerosis (AHS) and those with histopathologically normal hippocampus associated with extrahippocampal lesions. No significant correlation could be detected between duration of epilepsy, individual seizure frequency and expression levels of 17beta-HSDs. In conclusion, the present study is the first to demonstrate mRNA expression of 17beta-HSD 1, 3 and 4 in the epileptic human hippocampus. Together with data on 5alpha-reductase 1, 3alpha-hydroxisteroid oxidoreductase 2 and cytochrome P450scc, previously shown to be expressed in the human hippocampus also, our data provide further evidence for the existence of sex steroid formation and metabolism in this specific brain area.
 ...
PMID:Expression of mRNAs encoding for 17beta-hydroxisteroid dehydrogenase isozymes 1, 2, 3 and 4 in epileptic human hippocampus. 1092 71

This review summarizes the current knowledge of the biosynthesis of neurosteroids in the human brain, the enzymes mediating these reactions, their localization and the putative effects of neurosteroids. Molecular biological and biochemical studies have now firmly established the presence of the steroidogenic enzymes cytochrome P450 cholesterol side-chain cleavage (P450SCC), aromatase, 5alpha-reductase, 3alpha-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase in human brain. The functions attributed to specific neurosteroids include modulation of gamma-aminobutyric acid A (GABAA), N-methyl-d-aspartate (NMDA), nicotinic, muscarinic, serotonin (5-HT3), kainate, glycine and sigma receptors, neuroprotection and induction of neurite outgrowth, dendritic spines and synaptogenesis. The first clinical investigations in humans produced evidence for an involvement of neuroactive steroids in conditions such as fatigue during pregnancy, premenstrual syndrome, post partum depression, catamenial epilepsy, depressive disorders and dementia disorders. Better knowledge of the biochemical pathways of neurosteroidogenesis and their actions on the brain seems to open new perspectives in the understanding of the physiology of the human brain as well as in the pharmacological treatment of its disturbances.
 ...
PMID:Neurosteroid metabolism in the human brain. 1172 Aug 89

Allopregnanolone (3alpha,5alpha-TH PROG) and 5alpha-dihydroprogesterone (5alpha-DH PROG), the two most important neuroactive steroids synthesized in the brain, potently modulate neuronal activity by allosterically regulating GABA action at GABA(A) receptors or by changing specific GABA(A) receptor subunit gene expression, respectively. We recently reported [Proc. Natl. Acad. Sci. USA 95 (1998) 3239] that in patients with severe depression there is a decrease in the CSF levels of 3alpha,5alpha-TH PROG, which is normalized by treatment with drugs (i.e. fluoxetine) that improve psychopathology. The mechanism by which fluoxetine and other selective serotonin reuptake inhibitors normalize 3alpha,5alpha-TH PROG CSF levels appears to involve a direct stimulation of 3alpha-hydroxysteroidoxidoreductase (3alpha-HSD), an enzyme that catalyses the reduction of 5alpha-DH PROG into 3alpha,5alpha-TH PROG. Here, we propose the use of socially-isolated mice that have a downregulation of 3alpha,5alpha-TH PROG and of 5alpha-DH PROG expression to establish a model to study the behavioral consequences of this deficiency. After 4-6 weeks of isolation, these mice exhibit increased anxiety and aggressive behavior and also a decreased response to the administration of GABA-mimetic drugs. In these mice, the decrease in 3alpha,5alpha-TH PROG is selectively normalized by the use of fluoxetine in doses that reduce behavioral abnormalities. In addition, the expression of 5alpha-reductase Type I mRNA and protein was lower in socially-isolated mice than that in group-housed mice whereas 3alpha-HSD mRNA expression remained unchanged. The results of these studies may enable us to design drugs that specifically affect neurosteroidogenic enzymatic activities and may provide an efficacious treatment for the psychopathologies associated with psychiatric disorders.
 ...
PMID:The socially-isolated mouse: a model to study the putative role of allopregnanolone and 5alpha-dihydroprogesterone in psychiatric disorders. 1174 79

The purpose of these experiments was to test the hypothesis that attenuating the endogenous increase of the 5alpha-reduced progesterone metabolite 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) in the hippocampus will alter anxiety and depression behavior of proestrous rats. In Experiment 1, anxiety (open field) and depression (forced swim test) behavior was compared of rats that should have high (proestrous) and low (diestrous and male rats) endogenous hippocampal 3alpha,5alpha-THP. Proestrous rats exhibited more anxiolytic-like (increased central entries in the open field) and anti-depressant-like (less immobility in the forced swim test) behavior than diestrous or male rats. In Experiments 2 and 3, respectively, systemic and intrahippocampal finasteride, a 5alpha-reductase inhibitor which attenuates progesterone's metabolism to 3alpha,5alpha-THP, versus vehicle administration to proestrous rats was compared for effects on open field and forced swim test behavior. Systemic or intrahippocampal finasteride decreased central entries in the open field and increased immobility in the forced swim tests compared to vehicle administration. In Experiment 4, the effects of systemic and intrahippocampal finasteride vs vehicle administration on hippocampal 3alpha,5alpha-THP of proestrous rats was examined. Finasteride, SC or intrahippocampally, reduced 3alpha,5alpha-THP in the hippocampus compared to vehicle administration. Together these data suggest that variations in 3alpha,5alpha-THP levels in the hippocampus may mitigate proestrous changes in anxiety and depressive behavior of cycling rats.
 ...
PMID:Changes in progesterone metabolites in the hippocampus can modulate open field and forced swim test behavior of proestrous rats. 1197 64

Ethanol is known to increase cortical and plasma content of GABAergic neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) which is responsible for some of its behavioral and electrophysiological effects. We have previously demonstrated the antidepressant like effect of 3alpha,5alpha-THP in mice. This study investigated the role of 3alpha,5alpha-THP in acute, chronic and withdrawal effects of ethanol using mouse forced swim test (FST) paradigm. While acute systemic ethanol (2 or 2.5 g/kg) administration exhibited an antidepressant like effect, its prolonged consumption produced tolerance to this effect and its withdrawal, on the other hand, elicited enhanced behavioral despair (depression). The antidepressant like effect of ethanol was potentiated by GABA(A) receptor agonist, muscimol (0.5 mg/kg, i.p.), 3alpha,5alpha-THP (0.5, 1 or 2 microg/mouse, i.c.v.) and by neurosteroidogenic drugs viz. selective serotonin reuptake inhibitor (SSRI), fluoxetine (5 or 20 mg/kg, i.p.), agonist at mitochondrial diazepam binding inhibitor receptor, FGIN 1-27 (0.5 or 1 microg/mouse, i.c.v.), or 11beta-hydroxylase inhibitor, metyrapone (0.5 or 1 microg/mouse, i.c.v.) which are known to increase endogenous 3alpha,5alpha-THP content. Furthermore, inhibition of the endogenous neurosteroid biosynthesis by drugs like 5alpha-reductase inhibitor, finasteride (50 mg/kg, s.c.), 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane (30 mg/kg i.p.) or 3alpha-hydroxysteroid dehydrogenase inhibitor, indomethacin (5 mg/kg, i.p.) and GABA(A) receptor antagonist, bicuculline (1 mg/kg, i.p.) blocked the antidepressant like effect of ethanol. Withdrawal of ethanol from mice consuming it chronically displayed enhanced behavioral despair and elicited tolerance to antidepressant like action of acute ethanol (2.5, 3 or 3.5 g/kg). Moreover, sub-antidepressant doses (0.25 or 0.5 microg/mouse, i.c.v.) of 3alpha,5alpha-THP and fluoxetine (5 mg/kg, i.p.) but not imipramine (1 mg/kg, i.p.) reversed the depression associated with ethanol withdrawal indicating sensitization to their antidepressant action. Thus, 3alpha,5alpha-THP plays a pivotal role in the actions of ethanol and in the depression associated with ethanol withdrawal. These findings may be of potential ramification to contribute to the depression associated with alcoholism and its treatment using neurosteroids.
 ...
PMID:Behavioral action of ethanol in Porsolt's forced swim test: modulation by 3 alpha-hydroxy-5 alpha-pregnan-20-one. 1252 84

The 5alpha-reduced metabolite of progesterone (P), 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), may mediate progestins' effects to reduce depressive behavior of female rats in part through actions in the hippocampus. To investigate, forced swim test behavior and plasma and hippocampal progestin levels were assessed in groups of rats expected to differ in their 3alpha,5alpha-THP levels due to endogenous differences (pregnant and postpartum), administration of a 5alpha-reductase inhibitor (finasteride; 50 mg/kg sc), and/or gestational stress [prenatal stress (PNS)], an animal model of depression. Pregnant rats had higher plasma and hippocampal 3alpha,5alpha-THP levels and less depressive behavior (decreased immobility, increased struggling and swimming) in the forced swim test than did postpartum rats. Finasteride, compared to vehicle-administration, reduced plasma and hippocampal 3alpha,5alpha-THP levels and increased depressive behavior (increased immobility, decreased struggling and swimming). PNS was associated with lower hippocampal, but not plasma, 3alpha,5alpha-THP levels and increased swimming compared to that observed in control rats. Together, these data suggest that 3alpha,5alpha-THP in the hippocampus may mediate antidepressive behavior of female rats.
 ...
PMID:Hippocampal 3alpha,5alpha-THP may alter depressive behavior of pregnant and lactating rats. 1525 Dec 62

Long-term social isolation of laboratory animals is a model to study the behavioral and neurochemical consequences of the absence of social interaction in rodents. Many of the symptoms induced by isolation resemble depression and anxiety disorder symptomatology. Our studies have revealed that male mice socially isolated for more than 4 weeks, exhibit increased aggressiveness, a reduced responsiveness to GABA(A) receptor acting drugs, and a downregulation of brain levels of 3alpha,5alpha-tetrahydroprogesterone (allopregnanolone: 3alpha,5alpha-THP), a neurosteroid endowed with potent positive allosteric modulatory activity of the action of GABA at various GABA(A) receptor subtypes. This downregulation of 3alpha,5alpha-THP appeared to be associated with the reduction of brain type I 5alpha-reductase mRNA and protein expression. Systemic administration of the selective serotonin reuptake inhibitor fluoxetine and its metabolite norfluoxetine normalized brain 3alpha,5alpha-THP content and reduced responsiveness to GABA(A) mimetic drugs in a stereospecific manner. These drugs in nanomolar doses also reduced social isolation-induced aggressiveness with the same stereospecificity as detected in their action on 3alpha,5alpha-THP brain content, while their ex vivo inhibition of serotonin reuptake occurred at high micromolar doses and lacked stereospecificity. From these results we infer that the brain 3alpha,5alpha-THP content physiologically upregulates GABA(A) receptor responsiveness to GABA and that social isolation induces a reduction of brain 3alpha,5alpha-THP content that is probably causally related to the onset of aggression.
 ...
PMID:Social isolation stress-induced aggression in mice: a model to study the pharmacology of neurosteroidogenesis. 1601

Previous studies using the 5alpha-reductase inhibitor finasteride suggest that progesterone metabolites, particularly the endogenous neurosteroid allopregnanolone, mediate some of the effects of ethanol. Consequently, we studied the effect of finasteride (2 x 25 mg/kg s.c., 12 h apart) pretreatment on the acquisition and expression of ethanol (2 g/kg i.p.) induced conditioned place preference and c-fos expression in DBA/2 mice; a strain known to be particularly sensitive to ethanol. Ethanol administration induced a clear conditioned place preference and widespread c-fos expression, with elements of the extended amygdala, Edinger-Westphal nucleus and paraventricular nucleus being especially sensitive. However, despite an approximately 99% decrease in whole brain allopregnanolone content, finasteride pretreatment had remarkably little effect on either ethanol-induced conditioned place preference or ethanol-induced c-fos expression. Thus, aside from a general stimulatory effect on c-fos expression in the ventral tegmental area, and generally mild depression of locomotor activity, no other effects of finasteride or interaction with ethanol effects were identifiable. Together, these studies suggest that endogenous allopregnanolone plays little part in mediating acute ethanol-induced reward or neural activation in DBA/2 mice.
 ...
PMID:Lack of evidence of a role for the neurosteroid allopregnanolone in ethanol-induced reward and c-fos expression in DBA/2 mice. 1675 Jan 78

Finasteride is the first 5alpha-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to inhibit the Type II isoform of the 5alpha-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihydrotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms of the 5alpha-reductase enzyme are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC), respectively. Recent preclinical data indicate that the subsequent 3alpha-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of gamma-aminobutyric acid (GABA)ergic inhibitory neurotransmission. Consistent with their ability to enhance the action of GABA at GABA(A) receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual- and alcohol-related behaviors. Thus, finasteride, which inhibits both isoforms of 5alpha-reductase in rodents, has been used as a tool to manipulate neuroactive steroid levels and determine the impact on behavior. Results of some preclinical studies and clinical observations with finasteride are described in this review article. The data suggest that endogenous neuroactive steroid levels may be inversely related to symptoms of premenstrual and postpartum dysphoric disorder, catamenial epilepsy, depression, and alcohol withdrawal.
 ...
PMID:A new look at the 5alpha-reductase inhibitor finasteride. 1683 58


1 2 Next >>