Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mother-infant relationship is an instinctive phenomenon, and loss of maternal care in early life influences neonatal development, behavior and physiologic responses.(1,2) Furthermore, the early loss may affect the vulnerability of the infant to neuropsychiatric disorders, such as childhood anxiety disorders, personality disorders and depression, over its lifespan.(3,4) Fluoxetine is prescribed worldwide for depression and is often used in the treatment of childhood mental problems related to maternal separation or loss of maternal care.(5,6) In the present study, fluoxetine was administrated to rats with maternal separation to determine its effects on neuronal development, in particular with respect to cell proliferation and apoptosis in the dentate gyrus of the hippocampus. Rat pups were separated from their mothers and socially isolated on postnatal day 14 and were treated with fluoxetine (5 mg kg(-1)) and 5-bromo-2'-deoxyuridine (BrdU) (50 mg kg(-1)) for 7 days, after which immunohistochemistry and a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining were carried out. In the pups with maternal separation treated with fluoxetine, the number of BrdU-positive cells was significantly increased and that of TUNEL-positive cells was significantly decreased in the dentate gyrus compared to pups with maternal separation that did not receive fluoxetine treatment. These findings indicate that fluoxetine affects new cell proliferation and apoptosis, and we propose that fluoxetine may be useful in the treatment of maternal separation-related diseases.
Mol Psychiatry 2001 Nov
PMID:Fluoxetine enhances cell proliferation and prevents apoptosis in dentate gyrus of maternally separated rats. 1167 2

When exposed to prolonged stress, rats develop gastric ulceration, enhanced colon motility with depletion of its mucin content and signs of physiological and behavioral arousal. In this model, we tested whether antidepressants (fluoxetine and bupropion), anxiolytics (diazepam and buspirone) or the novel nonpeptide corticotropin-releasing hormone (CRH) type-1 receptor (CRH-R1) antagonist, antalarmin, modify these responses. Fluoxetine, bupropion, diazepam and antalarmin all suppressed stress-induced gastric ulceration in male Sprague-Dawley rats exposed to four hours of plain immobilization. Antalarmin produced the most pronounced anti-ulcer effect and additionally suppressed the stress-induced colonic hypermotility, mucin depletion, autonomic hyperarousal and struggling behavior. Intraperitoneal CRH administration reproduced the intestinal but not the gastric responses to stress while vagotomy antagonized the stress-induced gastric ulceration but not the intestinal responses. We conclude that brain CRH-R1 and vagal pathways are essential for gastric ulceration to occur in response to stress and that peripheral CRH-R1 mediates colonic hypermotility and mucin depletion in this model. Nonpeptide CRH-R1 antagonists may therefore be prophylactic against stress ulcer in the critically ill and therapeutic for other pathogenetically related gastrointestinal disorders such as peptic ulcer disease and irritable bowel syndrome.
Mol Psychiatry 2002
PMID:Marked suppression of gastric ulcerogenesis and intestinal responses to stress by a novel class of drugs. 1208 65

As rats age, a subgroup will show spatial memory impairments, along with decreased corticosteroid receptors (MR and/or GR) in the hippocampus and a hyperactive hypothalamic-pituitary-adrenal axis. In previous work, we have shown that amitriptyline treatment increases hippocampal MR mRNA and improves spatial memory in young rats but had no effect in aged rats. Here, we examine the effect of 1-month treatment with the selective 5-HT re-uptake inhibitor, fluoxetine (10 mg/kg, p.o.) on hippocampal corticosteroid receptor mRNA and spatial memory in young 4-month-old and aged 24-month-old rats. Aged rats were impaired in spatial memory compared to young controls. MR mRNA expression was reduced with ageing in all hippocampal subfields except CA4 (35% decrease in dentate gyrus (DG) and CA2, P<0.05) and GR mRNA was decreased selectively in CA1 (17% decrease, P<0.05). Fluoxetine treatment increased GR mRNA in the hippocampus of young rats (24 and 46% increase in DG and CA3, respectively, P<0.01) but had no effect on hippocampal MR mRNA expression. In contrast, in aged rats, fluoxetine treatment increased hippocampal MR mRNA selectively in CA2 (43% increase, P<0.05), but had no effect on hippocampal GR mRNA. Fluoxetine treatment did not alter watermaze performance in either young or aged rats. It appears that increased hippocampal MR (at least in the CA2 region) which may underlie the enhancement in memory processing in young rats, is insufficient to improve memory in already cognitively impaired aged rats.
Brain Res Mol Brain Res 2002 Oct 15
PMID:The effect of chronic fluoxetine treatment on brain corticosteroid receptor mRNA expression and spatial memory in young and aged rats. 1239 71

The liver is a frequent target of gene-transfer experiments, because of its central role in many metabolic and synthetic pathways. For applications where prolonged expression of genes in the liver is required, adeno-associated virus (AAV) has proven to be an effective tool for in vivo gene transfer. High-level, persistent hepatic expression has been achieved in a number of experimental systems following a single treatment with AAV in murine and larger animal models. This prolonged expression is particularly useful for the treatment of genetic diseases such as the inborn errors of metabolism, where lifelong expression of the deficient enzyme may be required. Therapeutic benefits using AAV vectors have been demonstrated in animal models of amino acid disorders, lysosomal storage diseases, and coagulopathies (3-5), and Phase I clinical trials are proposed for the treatment of hemophilia B (6). Gene transfer to the murine liver using AAV is achieved by intravenous (iv) injection of recombinant virus, either via a peripheral or portal vein. The liver is the primary organ transduced following intravenous injection of AAV, although other tissues such as heart and lung may also take up virus to a lesser extent when peripheral injection sites are used (7). Portal-vein injection can reduce the amount of extra-hepatic transduction, and allows a larger dose of virus to be delivered to the liver. However, this technique requires surgical expertise, and can only be performed on adult mice.
Methods Mol Biol 2004
PMID:AAV-mediated gene transfer to the liver. 1497 May 93

The effect of the selective serotonin uptake inhibitor fluoxetine was examined on prodynorphin gene expression. Fluoxetine or vehicle was infused continuously for 7 d via osmotic minipumps into male rats. Northern blot analysis showed significant increases in prodynorphin gene expression in the hypothalamus (171% of controls) and significant decreases in the caudate putamen and nucleus accumbens (62% and 70% of controls, respectively). There were no significant changes in the hippocampus. Thus, chronic inhibition of serotonin uptake can regulate prodynorphin gene expression in the hypothalamus, caudate putamen, and nucleus accumbens. Fluoxetine effects were also evaluated in rats treated with p-chloroamphetamine (PCA), a neurotoxin that depletes serotonin. Because we previously reported that continuous infusion of cocaine for 7 d (which inhibits dopamine, serotonin, and norepinephrine uptake), or GBR 12909 (a selective dopamine uptake inhibitor), produced significant decreases in the hypothalamus and cocaine also produced a significant increase in prodynorphin gene expression in caudate putamen, regulation of prodynorphin gene expression by fluoxetine is suggested to be different from that by cocaine. Because neither a selective dopamine uptake inhibitor nor a selective serotonin uptake inhibitor produced the same effect as cocaine in the caudate putamen, this effect is likely regulated by the inhibition of norepinephrine uptake, by a combination of effects on two or three neurotransmitter transporters, or by a mechanism unrelated to transporter inhibition.
J Mol Neurosci 2004
PMID:Role of serotonin on cocaine-mediated effects on prodynorphin gene expression in the rat brain. 1499 15

Chronic treatments with antidepressants active on major depressive disorders influence pathways involved in cell survival and plasticity. As astrocytes seem to play a key role in the protection of brain cells, we investigated in these cells the rapid effects of the antidepressant fluoxetine (Prozac) on signaling cascades and gene induction, which probably play a role in neuroprotection. We show here that fluoxetine alone activates the extracellular signal-regulated-protein kinase (Erk) and p38 mitogen-associated protein (MAP) kinase cascades. RT-PCR revealed that genes, modulated in brain by long-term fluoxetine treatment, are rapidly induced by fluoxetine in cultured astrocytes: brain-derived nerve factor (BDNF) and its receptors, glial-derived nerve factor (GDNF) and deiodinase 3 (D3). Induction of D3 by fluoxetine is inhibited by U0126 and SB203580, suggesting that Erk and p38 MAP kinases are involved. Glial-derived nerve factor (GDNF) induction by fluoxetine is prevented by U0126, suggesting that Erk is implicated. Brain-derived nerve factor (BDNF) induction seems mediated by other signaling pathways. In conclusion, we show that fluoxetine alone rapidly activates mitogen activated protein (MAP) kinase cascades in rat astrocytes and that genes involved in neuroprotection are induced in a few hours in a MAP kinase-dependent or -independent manner.
J Mol Neurosci 2004
PMID:MAP kinase activation by fluoxetine and its relation to gene expression in cultured rat astrocytes. 1545 34

Adult rats were given antidepressant drugs orally. Fluoxetine, but not moclobemide, venlafaxine, tianeptine or desipramine, increased total glucocorticoid receptor (GR) mRNA in the hippocampus after 4 weeks. Further examination revealed that GR mRNA containing the brain-specific exon 1(7) was increased across all hippocampal subregions. In contrast, expression of the major exon 1(10) and another brain-specific exon 1(5)-containing GR mRNAs were unchanged. Tissue-specific first exon usage may contribute to the differential regulation of GR by fluoxetine in brain subregions.
Brain Res Mol Brain Res 2004 Oct 22
PMID:Differential regulation of variant glucocorticoid receptor mRNAs in the rat hippocampus by the antidepressant fluoxetine. 1546 96

The introduction of novel molecular tools in research and clinical medicine has created a need for more refined information management systems. This article describes the design and implementation of such a new information platform: the Molecular Imaging Portal (MIPortal). The platform was created to organize, archive, and rapidly retrieve large datasets using Web-based browsers as access points. The system has been implemented in a heterogeneous, academic research environment serving Macintosh, Unix, and Microsoft Windows clients and has been shown to be extraordinarily robust and versatile. In addition, it has served as a useful tool for clinical trials and collaborative multi-institutional small-animal imaging research.
Mol Imaging
PMID:MIPortal: a high capacity server for molecular imaging research. 1628 4

1. Neurotrophins and serotonin have both been implicated in the pathophysiology of depression and in the mechanisms of antidepressant treatments. 2. Brain-derived neurotrophic factor (BDNF) influences the growth and plasticity of serotonergic (5-HT) neurons via the activation of trkB receptor. 3. Transgenic mice overexpressing the full-length trkB receptor (TrkB.TK+) and showing increased trkB activity in brain, and their wild type (WT) littermates, were injected with the antidepressant fluoxetine or saline, and analyzed behaviorally in the forced swimming test paradigm and biochemically for the concentrations of brain monoamines and their metabolites. 4. The TrkB.TK+ mice displayed increased latency to immobility in the forced swim test, suggesting resistance to behavioral despair. 5. Fluoxetine increased the latency to immobility in wild-type mice to a similar level as seen in the trkB.TK+ mice after saline treatment, but had no further behavioral effect in the swimming behavior of the trkB.TK+ mice. 6. Only minor differences in the levels of brain monoamines and their metabolites were observed between the transgenic and wild-type mice. 7. These data, together with other recent observations, suggest that trkB activation may play a critical role in the behavioral responses to antidepressant drugs in mice.
Cell Mol Neurobiol 2005 Sep
PMID:Enhanced BDNF signaling is associated with an antidepressant-like behavioral response and changes in brain monoamines. 1639 30

Fluoxetine, a widely used antidepressant that primarily acts as a selective serotonin reuptake inhibitor, also inhibits various neuronal ion channels. Using the whole-cell patch-clamp technique, we have examined the effects of fluoxetine and norfluoxetine, its major active metabolite, on cloned low-voltage-activated T-type calcium channels (T channels) expressed in tsA 201 cells. Fluoxetine inhibited the three T channels Ca(V)3.1, Ca(V)3.2, and Ca(V)3.3 in a concentration-dependent manner (IC(50) = 14, 16, and 30 microM, respectively). Norfluoxetine was a more potent inhibitor than fluoxetine, especially on the Ca(V)3.3 T current (IC(50) = 5 microM). The fluoxetine block of T channels was voltage-dependent because it was significantly enhanced for T channels in the inactivated state. Fluoxetine caused a hyperpolarizing shift in steady-state inactivation, with a slower rate of recovery from the inactivated state. These results indicated a tighter binding of fluoxetine to the inactivated state than to the resting state of T channels, suggesting a more potent inhibition of T channels at physiological resting membrane potential. Indeed, fluoxetine and norfluoxetine at 1 microM strongly inhibited cloned T currents (approximately 50 and approximately 75%, respectively) in action potential clamp experiments performed with firing activities of thalamocortical relay neurons. Altogether, these data demonstrate that clinically relevant concentrations of fluoxetine exert a voltage-dependent block of T channels that may contribute to this antidepressant's pharmacological effects.
Mol Pharmacol 2006 Jun
PMID:T-type calcium channels are inhibited by fluoxetine and its metabolite norfluoxetine. 1651 May 61


<< Previous 1 2 3 4 5 6 7 8 9 Next >>