Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Various classes of antidepressant drugs with distinct pharmacologic actions are differentially effective in the treatment of classic melancholic depression--characterized by pathological hyperarousal and atypical depression--associated with lethargy, hypersomnia, and hyperphagia. All antidepressant agents exert their therapeutic efficacy only after prolonged administration. In situ hybridization histochemistry was used to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) administration of 3 different classes of activating antidepressant drugs which tend to be preferentially effective in treating atypical depressions, on the expression of central nervous system genes thought to be dysregulated in major depression. Daily administration (5 mg/kg, i.p.) of the selective 5-hydroxytryptophan (5-HT) reuptake inhibitor fluoxetine, the selective alpha 2-adrenergic receptor antagonist idazoxan, and the nonspecific monoamine oxidase A and B inhibitor phenelzine increased tyrosine hydroxylase mRNA levels by 70-150% in the locus coeruleus after 2 weeks of drug and by 71-115% after 8 weeks. The 3 drugs decreased corticotropin-releasing hormone mRNA levels by 30-48% in the paraventricular nucleus of the hypothalamus. The decreases occurred at 8 weeks but not at 2 weeks. No consistent change in steroid hormone receptor mRNA levels was seen in the hippocampus with the 3 drugs, but fluoxetine and idazoxan increased the level of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA, respectively, after 8 weeks of drug administration. Proopiomelanocortin (POMC) mRNA levels in the anterior pituitary and plasma adrenocorticotropic-hormone (ACTH) levels were not altered after 2 or 8 weeks of drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications. 135 83

Previous studies have demonstrated an inverse relationship between estrogen receptor (ER) and epidermal growth factor receptor (EGF-R) gene expression in human breast cancer cells. This relationship was further investigated in MCF 7 cells treated with 12-O-tetradecanoylphorbol-13-acetate (TPA). Exposure to 10 nM TPA resulted in a time-dependent increase in EGF-R mRNA, first apparent at 3 h and maximal between 9 and 24 h. There was a concomitant fall in ER mRNA with a maximum decline to 15-20% of control between 12 and 24 h. Although EGF-R mRNA levels declined between 24 and 72 h, both EGF-R mRNA and EGF-R binding remained above control levels and this was accompanied by a sustained depression of ER mRNA. These data support the view that ER and EGR-R gene expression is inversely regulated in human breast cancer and describe for the first time an inhibitory effect of a phorbol ester on steroid hormone receptor gene expression.
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PMID:Modulation of estrogen receptor and epidermal growth factor receptor mRNAs by phorbol ester in MCF 7 breast cancer cells. 275 60

Sex hormone, an essential hormone in reproduction, acts upon the tissues through binding to its receptors. Thus, the study on the receptors is essential for understanding the reproductive processes, physiologically or pathologically. With the advent of molecular biology, receptorology in our field has rapidly developed. In this lecture, we presented our recent findings on the receptor and its gene expression, together with some brief overview on the development of the receptor study, basically or clinically. I. Basic study. 1) Methology: A specific and highly sensitive quantitative RT-PCR assay for measurement of the steroid hormone receptor (SHR) mRNA was developed. 2) Rat progesterone receptor (PR) cDNA, especially PR-BcDNA, was partially cloned. Using primers designed upon the cloned cDNA, two distinct different promoters was found to exist in PR-A and B gene expression in the rat. 3) Tissue specificity of gene expression of the SHRs in the central and peripheral tissues: The synthesis of the receptor protein was regulated mostly on the level of transcription. In some tissues, however, the receptor synthesis was regulated posttranscriptionally. Gene expression of the SHRs was widely distributed even in non-target tissue, indicating the existence of 'basic action' of SH on the tissues. 4) Primate monkey studies: SHR, especially PR, was localized mostly in the preoptic hypothalamic region and hypophysis in contrast with its wide distribution in the rat brain, suggesting the more limited feedback site of progesterone in women. 5) Brain sex differentiation and acquisition of steroid sensitivity: Region-specific and dynamic appearance of SHRs during peri- and postnatal development seemed to a major determinant of sex differentiation and hormone sensitivity' acquisition in female rats. Based upon analysis of PR-A and B mRNAs, gene expression of PR-B was first 'turn on', followed by PR-B gene expression. Progesterone seemed to be associated with 'termination' of the critical period of sex differentiation in the brain. 6) Thyroid hormone may be a regulator of synthesis and gene expression of the PR in rat cerebral cortex. Arachidonic acid, released from cell membrane, regulated SHRs in a non-competitive way, indicating some 'second messenger' role. Cross-talk might exist between the membrane factor and SHR. 7) Antisense mRNA against GnRHmRNA, SH2RNA, was identified in rat brain. Most interestingly, there was a reciprocal relationship between GnRHmRNA and SH2RNA, suggesting some GnRHmRNA regulatory mechanism other than previously thought. 8) Depression of the GnRH receptor (GnRHR)mRNA level by GnRH agonist indicated another mechanism on down-regulation of GnRHR.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Basic and clinical studies on sex hormone receptors]. 808 3

ATP-sensitive potassium (K(ATP)) channels are activated during myocardial ischemia. The ensuing potassium efflux leads to a shortening of the action potential duration and depolarization of the membrane by accumulation of extracellular potassium favoring the development of reentrant arrhythmias, including ventricular fibrillation. The sulfonylthiourea HMR 1883 was designed as a cardioselective blocker of myocardial K(ATP) channels for the prevention of arrhythmic sudden death in patients with ischemic heart disease. We investigated the effect of HMR 1883 on sudden cardiac arrhythmic death and electrocardiography (ECG) changes induced by 20 min of left anterior descending coronary artery occlusion in pentobarbital-anesthetized pigs. HMR 1883 (3 mg/kg i.v.) protected pigs from arrhythmic death (91% survival rate versus 33% in control animals; n = 12; p<.05). Ischemic areas were of a similar size. The compound had no effect on hemodynamics and ECG, including Q-T interval, under baseline conditions and no effect on hemodynamics during occlusion. In control animals, left anterior descending coronary artery occlusion lead to a prompt and significant depression of the S-T segment (-0.35 mV) and a prolongation of the Q-J time (+46 ms), the former reflecting heterogeneity in the plateau phase of the action potentials and the latter reflecting irregular impulse propagation and delayed ventricular activation. Both ischemic ECG changes were significantly attenuated by HMR 1883 (S-T segment, -0.14 mV; Q-J time, +15 ms), indicating the importance of K(ATP) channels in the genesis of these changes. In conclusion, the K(ATP) channel blocker HMR 1883, which had no effect on hemodynamics and ECG under baseline conditions, reduced the extent of ischemic ECG changes and sudden death due to ventricular fibrillation during coronary occlusion.
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PMID:ATP-sensitive potassium channel blocker HMR 1883 reduces mortality and ischemia-associated electrocardiographic changes in pigs with coronary occlusion. 1052 61

Depression-like behavior induced by YM643, a consensus interferon-alpha (IFN-alpha), was evaluated with the tail-suspension test in mice and compared with depression-like behavior induced by sumiferon, a natural IFN-alpha. To investigate the mechanism of IFN-alpha-induced depression-like behavior, the effects of the tricyclic antidepressant imipramine, the cyclooxygenase inhibitor indomethacin, the opioid receptor antagonist naloxone, and the selective corticotropin-releasing hormone receptor antagonist CP-154, 526 on IFN-alpha-induced depression-like behavior were evaluated. Intravenously injected YM643 (2 x 10(8)-2 x 10(9) U/kg) and sumiferon (2 x 10(6)-2 x 10(7) I.U./kg) dose-dependently increased immobility time. Repeated s.c. injection of either YM643 (6 x 10(6)-6 x 10(8) U/kg) or sumiferon (6 x 10(4)-6 x 10(6) I.U./kg) for 7 days also dose-dependently increased immobility time. After i.c.v. injection of either YM643 (2 x 10(6) U/mouse) or sumiferon (6 x 10(4) I.U./mouse), significant prolongation of immobility time also was observed. Pretreatment with imipramine (30 mg/kg s.c.) significantly reduced the YM643- or sumiferon-induced increases in immobility time. CP-154,526 (0.3-3 mg/kg s.c.) dose-dependently reduced YM643- or sumiferon-induced increases in immobility time with ID(50) values of 0.6 mg/kg against YM643 and 1.3 mg/kg against sumiferon. However, neither indomethacin (10 mg/kg s.c.) nor naloxone (3 mg/kg s.c.) had any effect on YM643- or sumiferon-induced increases in immobility time. These results suggest that IFN-alpha centrally induces depression-like behavior in mice that can be alleviated with imipramine. The results also suggest that activation of corticotropin-releasing hormone receptors is involved in IFN-alpha-induced depression-like behavior, but the prostaglandin and opioid systems do not participate in this process.
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PMID:Corticotropin-releasing hormone receptors mediate consensus interferon-alpha YM643-induced depression-like behavior in mice. 1060 46

Clinical and preclinical studies have gathered substantial evidence that alterations of the stress hormone system play a major, causal role in the development of depression. In this review article, a summary of studies sustaining that view is given and data are presented which demonstrate that depression is associated with an impairment of corticosteroid receptor function that gives rise to an excessive release of neurohormones to which a number of signs and symptoms characteristic of depression can be attributed. The studies referred to in the following unanimously support the concept of an antidepressant mechanism of action that exerts its effects beyond the cell membrane receptors of biogenic amines and particularly includes the improvement of corticosteroid receptor function. When activated by ligands, corticosteroid receptors act as transcription factors in correspondence with numerous other transcription factors already known to be activated by antidepressants. Furthermore, the potential of drugs that interfere more directly with stress hormone regulation, such as corticosteroid receptor antagonists and corticotropin-releasing hormone receptor antagonists, is discussed.
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PMID:Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. 1117 75

Changes in amplitude of the soleus H (S(H))-reflex and its neurographic correlates (P(1) and P(2) waves) after vibration of the soleus muscle have been evaluated as a function of mechanical stimulation frequency, duration of the conditioning train, and test stimulus intensity. Additional experiments aimed at assessing the nervous system mechanisms underlying the postvibration depression (PVD) have been performed. In particular, homonymous (S(HMR) or S(H)) versus heteronymous (S(HTR)) soleus response, evoked respectively by tibial nerve and femoral nerve electrical stimulation, the effectiveness of sub-H threshold tibial nerve conditioning volleys on the S(HTR), and the respective effects of a brief passive stretching of the quadriceps and soleus muscles on the recovery of both the S(HMR) and S(HTR) after vibration of the homologous muscle were investigated under suitable experimental conditions. It was found that PVD occurs in the absence of changes in amplitude of the P(1) wave and the S(HTR), is paralleled by a reduced effectiveness of tibial nerve-conditioning volleys on the S(HTR) and is shortened consistently by brief passive stretching of the homologous muscle. It follows that PVD may be the result of a long-lasting reduction of the transmitter release from Ia presynaptic terminals depending, at least in part, on a protracted postvibration Ia afferent discharge caused by spindles thixotropy. These findings may provide a better understanding of the pathophysiologic mechanisms underlying spasticity in humans.
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PMID:Postvibration depression of the H-reflex as a result of a dual mechanism: an experimental study in humans. 1170 52

Inhibition of cardiomyocyte-specific ATP-sensitive potassium (K(ATP)) channels prolongs the action potential during intense ischaemia with attendant antiarrhythmic effects. However, this is accompanied by contractile depression in some models. These changes may be particularly troublesome in dilated cardiomyopathic hearts that display basal systolic dysfunction, limited energy reserve, and prolonged repolarization favouring arrhythmia. Mechanical effects of selective myocyte K(ATP) channel blockade on basal, beta-adrenergic stimulated, and ischemic responses were therefore tested in dogs with cardiac failure induced by tachypacing. Cardiovascular function was assessed by pressure - dimension relationships in 10 conscious, chronically instrumented dogs (sonomicrometry/micromanometry), with or without cardiac failure. Cardiomyocyte K(ATP) channels were inhibited by HMR 1098, and data obtained under basal conditions, during epinephrine infusion to raise metabolic demand, during regional ischaemia, and with combined ischaemia+epinephrine. HMR 1098 had no effect on baseline cardiac function nor did it induce arrhythmia in normal or failing hearts. Epinephrine raised cardiac work 65% and oxygen consumption 55%, yet HMR 1098 had no functional effect in either heart condition. Regional ischaemia with or without epinephrine co-stimulation depressed regional and global function, yet both were also unaffected by HMR 1098. There was minimal arrhythmia without HMR 1098, and drug infusion did not alter this. Thus, myocyte-K(ATP) channels play a negligible role modulating intact in vivo cardiac contraction or arrhythmia in normal and failing heart with and without increased metabolic demand and/or regional ischaemia. This supports the feasibility of administering such agents to depressed hearts, despite underlying contractile and electrophysiologic abnormalities.
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PMID:Effects of cardioselective KATP channel antagonism on basal, stimulated, and ischaemic myocardial function in in vivo failing canine heart. 1183 13

A benzoflavone moiety (BZF) has recently been reported to be liable for many of the biological effects of the plant Passiflora incarnata Linneaus. In light of various reports mentioning the usefulness of P. incarnata in tobacco addiction, studies have been performed using four doses (1, 5, 10 and 20 mg/kg) of the bioactive BZF moiety isolated from the aerial parts of P. incarnata. In a 7-day experimental regimen, mice (n = 5) were given nicotine hydrogen tartrate (2 mg/kg), and combinations of nicotine with four doses of BZF (NnP-1, NnP-5, NnP-10 and NnP-20) q.i.d. by the s.c. route. At the end of the 7 days of treatment, naloxone was given to the mice from all groups to induce a nicotine withdrawal syndrome. The mice that had been treated with 10 and 20 mg/kg dose of BZF concurrently with nicotine showed a significantly fewer number of withdrawal jumps relative to the group treated with nicotine alone (Nn group). Separately, in a 14-day treatment regimen, mice (n = 10; for the N group, n = 12) were administered nicotine (2 mg/kg) and combinations of nicotine with four doses of BZF (NP-1, NP-5, NP-10, NP-20 groups) q.i.d. by the s.c. route. Spontaneous physical and behavioural signs of nicotine dependence were observed 3 hours after cessation of treatments on the 14th day. Mice administered with combinations of nicotine and 5, 10 and 20 mg/kg doses of BZF (i.e. NP-5, NP10 and NP-20 groups), exhibited less intensity and severity of withdrawal effects compared to the mice treated with nicotine alone. Those mice treated with the two highest doses of BZF,in combination with nicotine (NP-10 and NP-20), showed significantly fewer nicotine-abstinence withdrawal jumps and normal ambulatory behaviour. BZF treatment prevented weight loss and resulted in normal performance in the swimming endurance test, which may be a measure of stress and/or depression. Similarly, acute administration of a single 20 mg/kg dose of BZF prevented some of the nicotine-withdrawal effects; lower doses were almost inert. These studies, although preliminary, suggest that the BZF may have value in treating nicotine addiction.
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PMID:Nicotine reversal effects of the benzoflavone moiety from Passiflora incarnata Linneaus in mice. 1457 21

Long-term potentiation (LTP) and long-term depression of synaptic transmission in the hippocampus are widely studied models of learning and memory processes. The role of ATP-regulated K+ channels (K(ATP)+ channels), which are abundant in the brain, has not yet been studied in long-term potentiation or long-term depression. We investigated whether K(ATP)+ channel inhibition by the highly selective K(ATP)+-channel blocker 1-[[5-[2-(5-tert-butyl-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea (HMR-1372), a novel putative class III antiarrhythmic, affects long-term potentiation or the long-term depression induced by 3,5-dihydroxyphenylglycine (30 microM) in submerged rat hippocampal slices. HMR-1372 (10 microM) did not affect basal synaptic transmission, paired pulse inhibition, long-term depression or long-term potentiation elicited by a weak (weak long-term potentiation) tetanus, but significantly amplified the long-term efficacy of long-term potentiation elicited by a strong tetanus (strong long-term potentiation). The K(ATP)+-channel inhibitor glibenclamide (20 microM) also ameliorated only strong long-term potentiation. Our data suggest that K(ATP)+ channels are activated during or after induction of long-term potentiation and play a role in controlling synaptic excitability.
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PMID:The ATP-regulated K+-channel inhibitor HMR-1372 affects synaptic plasticity in hippocampal slices. 1546 94


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