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

In the hippocampus, the center for learning and memory, cytochrome P450s (P450scc, P450(17alpha), and P450arom) as well as 17beta-, 3beta-hydroxysteroid dehydrogenases, and 5alpha-reductase participate in the synthesis of brain steroids from endogenous cholesterol. These brain steroids include pregnenolone, dehydroepiandrosterone, testosterone, dihydrotestosterone, and 17beta-estradiol. Both estrogens and androgens are synthesized in the adult male hippocampal neurons. Although the expression levels of steroidogenic enzymes are as low as 1/200 to 1/50,000 of those in testis or ovary, the levels of synthesized steroids are sufficient for the local usage within small neurons (i.e., intracrine system). This intracrine system contrasts with the endocrine system in which high expression levels of steroidogenic enzymes are necessary in endocrine organs in order to supply steroids to many other organs via blood circulation. Endogenous synthesis of sex steroids in the hypothalamus is also discussed. Rapid modulation by estrogens and xenoestrogens is discussed concerning synaptic plasticity such as the long-term potentiation, the long-term depression, or spinogenesis. Synaptic expression of P450(17alpha), P450arom, and estrogen receptors suggests "synaptocrine" mechanisms of brain steroids, which are synthesized at synapses and act as synaptic modulators.
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PMID:Role of cytochrome p450 in synaptocrinology: endogenous estrogen synthesis in the brain hippocampus. 1687 57

Fast inhibitory neurotransmission in the brain is largely mediated by the gamma-aminobutyric acid-type A (GABA(A)) receptor. The 3alpha,5alpha-reduced neurosteroids (e.g., allopregnanolone) are the most potent endogenous modulators of the GABA(A) receptor. Although it is known that 3alpha,5alpha-reduced neurosteroid levels change during stress or depression and over the estrus cycle, a basic physiological role consistent with their pharmacological action remains elusive. We used the unique architecture of the auditory midbrain to reveal a role for 3alpha,5alpha-reduced neurosteroids in regulating inhibitory efficacy. After blocking the massive GABAergic projection from the dorsal nucleus of the lateral lemniscus (DNLL) to the contralateral central nucleus of the inferior colliculus (ICC) in anesthetized rats, a reactive increase in the efficacy of other inhibitory circuits in the ICC (separable because of the dominant ear that drives each circuit) was demonstrated with physiological measures-single-neuron activity and a neural-population-evoked response. This effect was prevented by blocking 3alpha,5alpha-reduced neurosteroid synthesis with a 5alpha-reductase inhibitor: finasteride. Immunohistochemistry confirmed that the DNLL blockade induced an increase in 3alpha,5alpha-reduced neurosteroids in the contralateral ICC. This study shows that when GABAergic inhibition is reduced, the brain compensates within minutes by locally increasing synthesis of neurosteroids, thereby balancing excitatory and inhibitory inputs in complex neural circuits.
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PMID:Neurosteroids involved in regulating inhibition in the inferior colliculus. 1697 75

In neuroendocrinology, it is believed that steroid hormones are synthesized in the gonads and/or adrenal glands, and reach the brain via the blood circulation. In contrast to this view, we are in progress of demonstrating that estrogens and androgens are also synthesized locally by cytochrome P450s in the hippocampus, and that these steroids act rapidly to modulate neuronal synaptic plasticity. We demonstrated that estrogens were locally synthesized in the adult hippocampal neurons. In the pathway of steroidogenesis, cholesterol is converted to pregnenolone (by P450scc), dehydroepiandrosterone [by P450(17alpha)], androstenediol (by 17beta-hydroxysteroid dehydrogenase, 17beta-HSD), testosterone (by 3beta-HSD) and finally to estradiol (by P450arom) and dihydrotestosterone (by 5alpha-reductase). The basal concentration of estradiol in the hippocampus was approximately 1 nM, which was greater than that in blood plasma. Significant expression of mRNA for P450scc, P450(17alpha), P450arom, 17beta-HSD, 3beta-HSD and 5alpha-reductase was demonstrated by RT-PCR. Their mRNA levels in the hippocampus were 1/200-1/5,000 of those in the endocrine organs. Localization of P450(17alpha) and P450arom was observed in synapses in addition to endoplasmic reticulum of principal neurons using immunoelectron microscopy. Different from slow action of gonadal estradiol which reaches the brain via the blood circulation, hippocampal neuron-derived estradiol may act locally and rapidly within the neurons. For example, 1 nM 17beta-estradiol rapidly enhanced the long-term depression (LTD) not only in CA1 but also in CA3 and dentate gyrus. The density of thin spines was selectively increased within 2 h upon application of 1 nM estradiol in CA1 pyramidal neurons. Only ERalpha agonist propyl-pyrazole-trinyl-phenol induced the same enhancing effect as estradiol on both LTD and spinogenesis in the CA1. ERbeta agonist hydroxyphenyl-propionitrile suppressed LTD and did not affect spinogenesis. Localization of estrogen receptor ERalpha in spines in addition to nuclei of principal neurons implies that synaptic ERalpha can drive rapid modulation of synaptic plasticity by endogenous estradiol.
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PMID:Local neurosteroid production in the hippocampus: influence on synaptic plasticity of memory. 1714 99

Withdrawal from high levels of progesterone in rodents has been proposed as a model for premenstrual syndrome or postpartum depression. Forced swim test (FST) immobility, used to model depression, was assessed in intact female DBA/2J mice following progesterone withdrawal (PWD) or treatment with the 5alpha-reductase inhibitor finasteride. Following 5 daily progesterone injections (5 mg/kg IP) FST immobility increased only in mice withdrawn for 3 days (p<.05). In another experiment, 3 days of PWD significantly decreased levels of progesterone compared to 0 days of withdrawal, but progesterone levels at 3 days of PWD did not differ from vehicle-treated controls. In a final study, mice received daily injections of progesterone (5 mg/kg IP) for 8 days, with 0 mg/kg, 50 mg/kg, or 100 mg/kg finasteride co-administered for the last three days. Mice that received 100 mg/kg finasteride, but not 50 mg/kg finasteride, displayed increased FST immobility. PWD and finasteride treatment, both of which reduce allopregnanolone levels, were associated with increased FST immobility in female DBA/2J mice. These findings suggest that decreased levels of the GABAergic neurosteroid allopregnanolone contribute to symptoms of PWD. Future studies of PWD may provide information about human conditions that are associated with hormone changes such as premenstrual syndrome or postpartum depression.
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PMID:Inhibition of progesterone metabolism mimics the effect of progesterone withdrawal on forced swim test immobility. 1759 97

The neurosteroid allopregnanolone is a potent positive allosteric modulator of GABA action at GABA(A) receptors. Allopregnanolone is synthesized in the brain from progesterone by the sequential action of 5alpha-reductase type I (5alpha-RI) and 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD). 5alpha-RI and 3alpha-HSD are co-expressed in cortical, hippocampal, and olfactory bulb glutamatergic neurons and in output neurons of the amygdala, thalamus, cerebellum, and striatum. Neither 5alpha-RI nor 3alpha-HSD mRNAs is expressed in glial cells or in cortical or hippocampal GABAergic interneurons. It is likely that allopregnanolone synthesized in principal output neurons locally modulates GABA(A) receptor function by reaching GABA(A) receptor intracellular sites through lateral membrane diffusion. This review will focus on the behavioral effects of allopregnanolone on mouse models that are related to a sexually dimorphic regulation of brain allopregnanolone biosynthesis. Animal models of psychiatric disorders, including socially isolated male mice or mice that receive a long-term treatment with anabolic androgenic steroids (AAS), show abnormal behaviors such as altered fear responses and aggression. In these animal models, the cortico-limbic mRNA expression of 5alpha-RI is regulated in a sexually dimorphic manner. Hence, in selected glutamatergic pyramidal neurons of the cortex, CA3, and basolateral amygdala and in granular cells of the dentate gyrus, mRNA expression of 5alpha-RI is decreased, which results in a downregulation of allopregnanolone content. In contrast, 5alpha-RI mRNA expression fails to change in the striatum medium spiny neurons and in the reticular thalamic nucleus neurons, which are GABAergic.By manipulating allopregnanolone levels in glutamatergic cortico-limbic neurons in opposite directions to improve [using the potent selective brain steroidogenic stimulant (SBSS) S-norfluoxetine] or induce (using the potent 5alpha-RI inhibitor SKF 105,111) behavioral deficits, respectively, we have established the fundamental role of cortico-limbic allopregnanolone levels in the sexually dimorphic regulation of aggression and fear. By selectively targeting allopregnanolone downregulation in glutamatergic cortico-limbic neurons, i.e., by improving the response of GABA(A) receptors to GABA, new therapeutics would offer appropriate and safe management of psychiatric conditions, including impulsive aggression, irritability, irrational fear, anxiety, posttraumatic stress disorders, and depression.
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PMID:Neurosteroid biosynthesis regulates sexually dimorphic fear and aggressive behavior in mice. 1847 73

Estrogen and androgen are synthesized from cholesterol locally in hippocampal neurons of adult animals. These neurosteroids are synthesized by cytochrome P450s and hydroxysteroid dehydrogenases (HSDs) and 5alpha-reductase. The expression levels of enzymes are as low as 1/200-1/50,000 of those in endocrine organs, however these numbers are high enough for local synthesis. Localization of P450(17alpha), P450arom, 17beta-HSD and 5alpha-reductase is observed in principal glutamatergic neurons in CA1, CA3 and the dendate gyrus. Several nanomolar levels of estrogen and androgen are observed in the hippocampus. Estrogen modulates memory-related synaptic plasticity not only slowly but also rapidly in the hippocampus. Rapid action of 17beta-estradiol via membrane receptors is demonstrated for spinogenesis and long-term depression (LTD). The enhancement of LTD by 1-10nM estradiol occurs within 1 h. The density of spine is increased in CA1 pyramidal neurons within 2h after application of estradiol. The density of spine-like structure is, however, decreased by estradiol in CA3 pyramidal neurons. ERalpha, but not ERbeta, induces the same enhancement/suppression effects on both spinogenesis and LTD.
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PMID:Estrogen synthesis in the brain--role in synaptic plasticity and memory. 1854 62

Finasteride is a potent drug which has been prescribed for the management of benign prostatic hyperplasia (BPH) for more than 20 years. Recent studies indicate that finasteride, as 5alpha-reductase inhibitor, can influence some central effects such as analgesia, neurosteroidogeneses and behavior. The purpose of this study was to investigate the analgesic effect of finasteride, to determine whether finasteride interact with morphine analgesia in tail-flick test and to examine the anti-inflammatory effect of this drug. Adult male Wistar rats (280-330 g) were used for the both of experiments. Tests were assessed on groups of 6 animals. The first control group (O) received water (1 ml/kg, p.o.), the second control group (OO) received the vehicle (olive oil, 1 ml/kg, p.o.) and the third group (F) received finasteride (0.5 mg/kg, p.o.) suspended in olive oil, every morning for 30 days. After 30 days of treatment, tail-flick test and formalin-induced foot paw edema test were performed. Finasteride increased the average latency in seconds in comparison to both controls (10.06 vs. 9.16 and 8.66 s). It was 9.83% higher depression of pain in group F in comparison to O and 16.17% in comparison to OO, but the anti-nociceptive effect of finasteride at applied dose didn't significantly differ compared to both controls (p > 0.05). Chronic pre-treatment with finasteride didn't interact with analgesic effect of morphine compared to O (p > 0.05), but compared to OO finasteride fastened, increased and prolonged the analgesic effect of morphine at all measuring intervals, achiving statistical significance in 60 min (p < 0.01). Finasteride also exhibited significant anti-inflammatory action (p < 0.05) in comparison to OO, but It was not significantly different from the control O. Finasteride didn't exert analgesic action, it increased morphine antinociception and showed chronic anti-inflammatory effect to some extent. This might be a useful contribution to highlight the pathogenesis of BPH. There is the need for further studies in order to confirm these results with more details.
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PMID:Anti-nociceptive and anti-inflammatory properties of 5alpha-reductase inhibitor finasteride in experimental animals. 1900 44

Finasteride is the 5alpha-reductase inhibitor that received clinical approval for the treatment of human benign prostate hyperplasia and androgenetic alopecia. The 5alpha-reductase is enzyme responsible for the reduction of testosterone to dihydrostestosterone, progesterone to dihydroprogesterone and deoxycorticosterone to dihydrodeoxycorticosterone, steroids modulating the action of gamma-aminobutyric acid on GABA receptors. These neuroactive steroids possess anticonvulsant, antidepressant and anxiolytic effects. The objective of the study was to determine the effect of finasteride therapy on a broad steroid spectrum in men with benign prostate hyperplasia. A group of 20 men with benign prostate hyperplasia was involved in the present study. Finasteride in the daily dose of 5 mg/day was administrated for 4 months. In all individuals, their hormonal profile of steroid hormones was determined before and after 4 months lasting finasteride treatment. Finasteride treatment resulted in a significant decrease all alpha-reduced and increase of most 5beta-reduced metabolites of testosterone and progesterone as well as in an increase of 7alpha-hydoxyderivatives, which are known as neuroactive steroids acting by modulation of GABAA and NMAD receptors in the brain. In the course of finasteride treatment the decrease of the concentration of circulating steroids with known inhibitory activity on GABA-ergic excitation in the brain is very probably an important factors contributing to the development of the symptoms of depression seen in some isolated cases of finasteride administration.
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PMID:Finasteride treatment and neuroactive steroid formation. 1965 98


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