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)

The physiological imbalances associated with organ insufficiency and the complexity of organ transplant surgery and postoperative care puts patients at risk for psychiatric disorders. The brain is susceptible to a variety of insults as a result of these complex processes, including those secondary to medications and infections. We review literature relevant to organ transplant patients and also include empirical knowledge based on clinical practice. We first describe the physiologic and psychiatric issues for each major organ that is commonly transplanted, including liver, kidney, heart, bone marrow, and pancreas, as well as multiple organ transplantation. We then discuss the pharmacologic treatment and neuropsychiatric side effects of rejection with various immunosuppressants, including cyclosporine, azathioprine, OKT3, FK506, and corticosteroids. Certain bacterial, fungal, viral, and protozoal infections occur more frequently in the transplant population; their relationship to neuropsychiatric dysfunction is discussed. We then present details of psychopharmacotherapy of delirium, other organic mental disorders, depression, mania, anxiety, and insomnia, with attention to drug interactions and differential diagnosis. Particularly cautious monitoring of medication doses and serum levels is recommended in these patients.
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PMID:Psychopharmacology and neuropsychiatric syndromes in organ transplantation. 187 24

Whole-cell recordings were made from dorsomedial nucleus tractus solitarii neurons in thin coronal medullary slices of the rat, at the level of the area postrema. Monosynaptic excitatory postsynaptic currents (EPSCs) were evoked in the tractus solitarius by electrical stimulation in the presence of D-2-amino-5-phosphonopentanoic acid (AP5) and bicuculline. Currents were also evoked by pressure ejection of (S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) in the presence of AP5, bicuculline, and tetrodotoxin or muscimol in the presence of 6,7-dinitroquinoxaline-2,3-dione and AP5. The metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate [(1S,3R)-ACPD] reversibly depressed the EPSC and muscimol currents and reversibly potentiated AMPA currents. The effects of (1S,3R)-ACPD were blocked in the presence of a low concentration of the phosphoprotein phosphatase (PP)1 and PP2A inhibitor okadaic acid (OA) but not by a low concentration of the PP inhibitor calyculin A. The immunosuppressant agent FK506 failed to block (1S,3R)-ACPD effects on AMPA currents. However, (1S,3R)-ACPD applied in the presence of FK506 produced a reversible potentiation of muscimol currents. We previously demonstrated that the cell-permeant cGMP analog 8-Br-cGMP can mimic many of the effects of (1S,3R)-ACPD. OA antagonized the effects of 8-Br-cGMP in the present investigation. Finally, we previously demonstrated that brief tetanic stimulation results in the activation of a presynaptic mGluR autoreceptor and depression of subsequently evoked EPSCs. OA similarly blocked tetanus-induced depression of EPSCs. These findings suggest that mGluRs on tractus solitarius afferents and first-order nucleus tractus solitarii neurons may modulate glutamate release and AMPA and gamma-aminobutyric acid type A receptor activity via activation of one or more PPs, such as PP2A and/or calcineurin.
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PMID:Inhibition of phosphoprotein phosphatases blocks metabotropic glutamate receptor effects in the rat nucleus tractus solitarii. 751 97

Long-term depression (LTD) of synaptic transmission, often used as an essential component in synaptic models for learning, memory and forgetting, can be produced in layer II/III of the visual cortex by a prolonged, low-frequency stimulation (LFS) of layer IV. The activation of Ca2+/calmodulin-dependent protein phosphatase, calcineurin, has been postulated to play a role in the induction of LTD. The recent introduction of a specific inhibitor for calcineurin, FK506, prompted the investigation of the involvement of this phosphatase in the induction of LTD in visual cortex. Thus, we administered FK506 at 1 microM to visual cortical slices of young rats, and found that it did not significantly affect field responses of layer II/III evoked by test stimulation of layer IV at 0.1 Hz, but prevented LTD of the responses from being induced by LFS (1 Hz for 15 min) in all the 10 slices tested. Without FK506, significant LTD was induced by the same parameters of LFS in 8 of the 12 slices. These results suggest the critical involvement of calcineurin in producing LTD in visual cortex.
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PMID:An inhibitor for calcineurin, FK506, blocks induction of long-term depression in rat visual cortex. 753 57

Ryanodine receptors (RyRs) are intracellular channels that regulate the release of Ca2+ from the endoplasmic reticulum of many cell types. The RyRs are physically associated with FK506-binding proteins (FKBPs); immunophilins, with cis-trans peptidyl-prolyl isomerase activity. FKBP12 copurifies with RyR1 (skeletal isoform) and modulates its gating. A different form of FKBP with a slightly higher molecular weight copurifies with RyR2 (cardiac isoform). Previous studies have demonstrated that FKBP stablizes gating of the skeletal Ca(2+)-release channel. In the present study, we measured the activity of cardiac RyRs incorporated into planar lipid bilayers to show that rapamycin, a drug that inhibits the prolyl isomerase activity of FKBP and dissociates FKBP from the RyR, increases the open probability and reduces the current amplitude of cardiac muscle Ca(2+)-release channels. These experiments show for the first time that submicromolar concentrations of rapamycin can alter channel function. Our results provide support for the hypotheses that FKBP functionally associates with the RyR and that the immunosuppressant drug, rapamycin, alters the function of both cardiac and skeletal muscle isoforms of the Ca(2+)-release channel. Our findings suggest that FKBP-dependent modulation of channel function may be generally applicable to all members of the intracellular Ca(2+)-release channel family and that FKBPs may play important regulatory roles in many cell processes, ranging from long-term depression in neurons to contractility in cardiomyocytes.
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PMID:Effects of rapamycin on ryanodine receptor/Ca(2+)-release channels from cardiac muscle. 863 49

It has been proposed that the long-term depression (LTD) seen following low frequency stimulation (LFS) in the rat hippocampus involves calcineurin. We have tested this by examining the effect of FK506, a macrolide which blocks calcineurin at nanomolar concentrations, on synaptic transmission in the rat hippocampal slice at a concentration of 1 microM which has been shown to block LTD in the visual cortex. The effect of FK506 on long-term potentiation (LTP) and spontaneous transmitter release was also studied. The magnitude of LTD induced by LFS was 16.7 +/- 2.4% in control which was not significantly different from the 22.3 +/- 3.0% seen in the same preparations after exposure to FK506 for 25-30 min. In contrast the magnitude of LTD induced 'de novo' in preparations exposed to FK506 was significantly reduced. FK506 had no significant effect on LTP, miniature EPSP frequency, miniature EPSP amplitude, resting membrane potential or input resistance. These results, therefore, support the hypothesis that calcineurin is involved in 'de novo' LTD but it appears that an event is triggered by LFS whereby FK506-insensitive LTD can subsequently be activated by a second episode of LFS.
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PMID:Only 'de novo' long-term depression (LTD) in the rat hippocampus in vitro is blocked by the same low concentration of FK506 that blocks LTD in the visual cortex. 882 55

A rise in Ca2+ concentration at postsynaptic sites provides an initial step in inducing both the long-term potentiation (LTP) and long-term depression (LTD) in the CA1 region of the hippocampus. LTP induction requires the activation of Ca(2+)-sensitive protein kinases following the rise in Ca2+. By contrast, the activity of protein phosphatase(s) appears to be critical to induce LTD. Here we demonstrate that inhibition of the synthesis of calcineurin A alpha and A beta, catalytic subunits of Ca2+/calmodulin- (CaM) dependent protein phosphatase, reduces the threshold of induction for commissural-CA1 LTP in anesthetized rats. In rats administered antisense oligodeoxynucleotides (ODNs) against calcineurin A alpha and A beta intraventricularly for 7 days, a brief tetanic stimulation to the CA3 region, which in the control case was below threshold for the induction of LTP, now produced a long-lasting increase in both the EPSP slope and the amplitude of population spike recorded from the commissural-CA1 pathway. Western blot analysis of calcineurin showed that the threshold reduction was accompanied by a selective decrease in the protein levels in the hippocampus. Thus our study provides direct evidence that calcineurin per se has an antagonizing role in LTP induction. Complementary experiments with the selective calcineurin inhibitor, FK506, also showed the reduction of LTP threshold in a dose-dependent manner. These results, together with previous studies, support the hypothesis that the quantitative phosphorylation level of critical intracellular proteins determines whether the synaptic efficacy will increase or decrease after the activity-dependent rise in postsynaptic Ca2+.
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PMID:A facilitatory effect on the induction of long-term potentiation in vivo by chronic administration of antisense oligodeoxynucleotides against catalytic subunits of calcineurin. 888 51

Cerebellar long-term depression (LTD), a candidate cellular mechanism of motor learning, is induced by conjunctive activation of parallel fibres and a climbing fibre. Previous studies have shown that combinatorial application of high potassium and glutamate (K/glu) to cultured cerebellar neurons can mimic this conjunctive stimulation of presynaptic fibres and induces the LTD of miniature excitatory postsynaptic current (mEPSC) amplitudes lasting for more than 24 h. The late phase of this LTD (LLTD, > 3 h) depends on de novo transcription induced by prolonged conditioning. Here, the role of Calcineurin in the LLTD induction was examined. Application of a Calcineurin inhibitor FK506 mimicked the effect of K/glu-treatment by decreasing mEPSC amplitudes for more than 24 h. FK506-induced depression, as well as the K/glu-induced LLTD, was blocked by inhibitors of either mRNA synthesis or Ca/Calmodulin dependent kinase. In addition, the FK506-induced depression and K/glu-induced LLTD occluded each other, suggesting that they share the same mechanism. On the other hand, misexpression of the constitutively active form of Calcineurin in the Purkinje neuron nucleus blocked the LLTD induction by the K/glu-treatment. These results suggest that Calcineurin is involved in the induction of LLTD as a negative regulator. Furthermore, it was found that trapping superoxide, which is increased by neuronal activity and inactivates Calcineurin, suppressed the LLTD induction. Taken together, these results suggest that the LLTD might be induced by down-regulation of Calcineurin activity through superoxide in cultured Purkinje neurons.
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PMID:Calcineurin regulates induction of late phase of cerebellar long-term depression in rat cultured Purkinje neurons. 1243 Dec 31

Unlike the proposed role of reactive oxygen species in neurodegeneration, acute effects of reactive oxygen on synaptic plasticity are poorly understood. Using rat hippocampal slices, we found that exposure to a high concentration (0.5-5 mm) of H(2)O(2) reduces EPSPs in both potentiated and nonpotentiated synapses. Exposure of the slices to 20 microm H(2)O(2) did not affect expression of preestablished long-term potentiation (LTP) but prevented induction of new LTP and enhanced long-term depression (LTD). Surprisingly, 1 microm H(2)O(2) caused a twofold increase in LTP compared with controls, and it further enhanced NMDA-independent LTP. A low concentration of H(2)O(2) also suppressed LTD. Nifedipine, an L-type calcium channel blocker, did not affect control LTP but blocked effects of both 1 and 20 microm H(2)O(2). Calcineurin inhibitors [FK506 (FR900506) and cyclosporin A but not rapamycin] acted similarly and also restored LTP in the presence of 20 microm H(2)O(2). These results suggest that H(2)O(2) alters NMDA-independent, voltage-gated calcium channel-mediated LTP by activating calcineurin.
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PMID:Hydrogen peroxide modulation of synaptic plasticity. 1251 24

We have previously reported that varying stimulus intensity produces qualitatively different types of synaptic plasticity in area CA1 of hippocampal slices: brief low-intensity (LI) theta-burst (TB) stimuli induce long-term potentiation (LTP), but if the stimulus intensity is increased (to mimic conditions that may exist during seizures), LTP is not induced; instead, high-intensity (HI) TB stimuli erase previously induced LTP ("TB depotentiation"). We now have explored the mechanisms underlying TB depotentiation using extracellular field recordings with pharmacological manipulations. We found that TB depotentiation was blocked by okadaic acid and calyculin A (inhibitors of serine/threonine protein phosphatases PP1 and PP2A), FK506 (a specific blocker of calcineurin, a Ca(2+)/calmodulin (CaM) protein phosphatase), and 8-Br-cAMP (an activator of protein kinase A) with 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor). These results suggest that protein phosphatase pathways are involved in the TB depotentiation similar to other type of down-regulating synaptic plasticity such as low-frequency stimulation (LFS)-induced long-term depression (LTD) and depotentiation in the rat hippocampus. However, TB depotentiation and LFS depotentiation could have differential functional significance.
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PMID:Protein phosphatases mediate depotentiation induced by high-intensity theta-burst stimulation. 1257 46

We report here evidence for endogenous NO signalling in long-term (>1 h) synaptic depression at the neuromuscular junction induced by 20 min of 1 Hz nerve stimulation. Synaptic depression was characterized by a 46% reduction in the end-plate potential (EPP) amplitude and a 21% decrease in miniature EPP (MEPP) frequency, but no change to MEPP amplitude, indicating a reduction in evoked quantal release. Both the membrane-impermeant NO scavenger cPTIO and the NOS inhibitor L-NAME blocked depression, suggesting that it is induced by NO originating from a source outside the terminal. The depression was dependent on activation of muscle-type, but not neuronal-type, nAChRs and was still observed when Ca2+ release from the sarcoplasmic reticulum and muscle contraction were blocked with dantrolene. These data suggest that the depression depends on transmission, but not muscle contraction. The calcineurin inhibitors cyclosporin A and FK506, as well as ODQ, an inhibitor of NO-sensitive soluble guanylyl cyclase, Rp-8-pCPT-cGMPS, an inhibitor of cGMP-dependent protein kinase, and the calmodulin antagonist phenoxybenzamine also blocked depression. We propose that low frequency synaptic transmission leads to production of NO at the synapse and depression of transmitter release via a cGMP-dependent mechanism. The NO could be generated either directly from the muscle, or possibly from the Schwann cell in response to an unidentified muscle-derived messenger. We showed that the long-lasting depression of transmitter release was due to sustained activity of the NO signalling pathway, and suggest dephosphorylation of NOS by calcineurin as the basis for continued NO production.
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PMID:Postsynaptic production of nitric oxide implicated in long-term depression at the mature amphibian (Bufo marinus) neuromuscular junction. 1524 35


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