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)

Lithium salts are considered the most effective agents used in treating manic-depression. Previous studies in PC12 pheochromocytoma cells indicate that lithium has a dramatic augmenting effect on expression of the fos proto-oncogene, a component of the AP-1 transcription factor. Although fos expression is activated by agonists that function through different signal transduction pathways, the lithium augmenting effect appears to be specific for receptor and post-receptor stimulators of protein kinase C (PKC). In particular, fos induction mediated by the m1 muscarinic receptor linked to PKC activation was found to be exquisitely sensitive to lithium enhancement. We now show that a similar augmenting effect can be demonstrated in rat brain. Following treatment with the muscarinic agonist pilocarpine, fos mRNA accumulates in the cortex, an effect that is blocked by the m1 antagonist pirenzepine. Rats treated with a single intraperitoneal injection of lithium chloride exhibited a substantial increase in pilocarpine-mediated fos expression. In contrast, fos expression induced in several brain regions by a single electroconvulsive shock is not augmented by lithium. The finding that short-term treatment with lithium enhances fos expression in the brain suggests a mechanism for its therapeutic action.
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PMID:Lithium augments pilocarpine-induced fos gene expression in rat brain. 171 37

Changrolin (CRL) is a new antiarrhythmic drug originated in China in 1970s. The effects of CRL on maximal upstroke velocity (Vmax) of action potentials were studied with standard microelectrode and computer in guinea pig papillary muscles. CRL depressed the Vmax. This effect was dependent on the rate of stimulations. The onset of use-dependent depression was monoexponential and dependent on drug concentration and rate of stimulations. The rate of recovery from use-dependent depression also followed a single exponential time course. CRL shifted the curve relating normalized Vmax to membrane potential in the hyperpolarizing direction. The onset rate was 0.156 +/- 0.025 AP-1 (RDB 50%), and offset rate (tau r) was 4.7 +/- 0.9 s. These suggest that CRL belongs to class Ia antiarrhythmic drugs.
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PMID:[Frequency- and voltage-dependent effects of changrolin on maximal upstroke velocity of action potentials in guinea pig papillary muscles]. 210 85

The in vitro electrophysiological properties of a new class I antiarrhythmic agent, SC-36602, were evaluated by recording action potentials (APs) from guinea pig papillary muscle. SC-36602 and its (+) and (-) enantiomers (10(-6)-10(-4) M) caused a concentration- and only slight frequency-dependent depression of Vmax (maximum rate of rise of the AP). At stimulation rates of 30, 60, 120, and 200 pulses/min, SC-36602 (10(-4) M) reduced Vmax to 64 +/- 2.2, 62 +/- 2.8, 60 +/- 2.4, and 58 +/- 2.7% of control, respectively, and significantly shortened effective refractory period (ERP) (20-40%). The rate constants for onset of block of Vmax during trains of stimuli at 1 or 3.3 Hz were similar (approximately 0.2 AP-1). Slow recovery from Vmax block following a stimulus train recorded in tissue depolarized by 10 mM [K+]o Tyrode's solution was enhanced following exposure to SC-36602. The normalized relationship between Vmax and membrane potential was shifted 3 and 12 mV in the hyperpolarizing direction at stimulation frequencies of 0.2 and 1 Hz, respectively. These results suggest that SC-36602 would preferentially depress conduction in depolarized tissue in vivo.
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PMID:Membrane potential-dependent effects of SC-36602, a new class I antiarrhythmic agent on cardiac action potentials. 243 95

Effects of SUN 1165, disopyramide, lorcainide, and mexiletine were studied either on the kinetics of onset of and recovery from rate-dependent depression of maximum rate of rise of phase 0 action potential (Vmax) in isolated guinea pig papillary muscles using standard microelectrode techniques or on intraventricular conduction time of extrasystoles evoked at varied coupling intervals in anesthetized dogs. SUN 1165 and lorcainide produced a slow-developing rate-dependent block of Vmax with the rate constant of 0.12 AP-1 and 0.09 AP-1, respectively. Mexiletine also produced a rate-dependent block of Vmax, but with very rapid onset so as not to be fitted by a single exponential curve. Disopyramide produced an intermediate rate-dependent block of Vmax with the rate constant of 0.46 AP-1. The time constants for recovery from the rate-dependent block for SUN 1165, lorcainide and disopyramide were 27.3-28.2, 23.2, and 17.0 s, respectively, while that for mexiletine was 0.118 s. SUN 1165, lorcainide, and disopyramide slowed ventricular conduction time of extrasystoles at all coupling intervals of 800-250 ms. On the other hand, mexiletine slowed conduction time at short coupling intervals of 500-250 ms. These findings suggest that, like lorcainide, SUN 1165 belongs to class Ic antiarrhythmic agents, and that SUN 1165 and lorcainide as well as disopyramide with slow and intermediate kinetics and mexiletine with fast kinetics may inhibit ventricular extrasystoles conducted at long and short range of coupling intervals, respectively.
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PMID:Effect of SUN 1165, a new potent antiarrhythmic agent, on the kinetics of rate-dependent block of Na channels and ventricular conduction of extrasystoles. 245 43

Frequency- and voltage-dependent electrophysiologic effects of a chemically novel compound, nicainoprol, were evaluated by recording transmembrane action potentials (APs) from papillary muscles and electrograms (EGs) from isolated perfused hearts of guinea pigs. At 0.2 Hz stimulation, nicainoprol (3.3 x 10(-6) M and 10(-5) M) significantly reduces the maximal upstroke velocity (Vmax) of APs without significant change in resting membrane potential (RMP), functional refractory period (FRP), and action potential duration. Nicainoprol prolongs the spread of excitation but has little effect on the duration of the ventricular EG. The Vmax depression is frequency dependent in the range of 0.02-2.5 Hz, showing saturation at higher frequencies. Under resting conditions, nicainoprol (3.3 x 10(-6) M and 10(-5) M) has no effect on Vmax. The onset of frequency-dependent Vmax reduction follows monoexponential time courses with rate constants of 0.053 +/- 0.007 AP-1 (3.3 x 10(-6) M) and of 0.066 +/- 0.005 AP-1 (10(-5) M) at 1 Hz. Vmax recovers from frequency-dependent depression with time constants of 45.4 +/- 3.2 s (3.3 x 10(-6) M) and 48.4 +/- 3.5 s (10(-5) M). Nicainoprol significantly shifts the Vmax-RMP relation in hyperpolarizing direction by 2.6 +/- 1.1 mV (3.3 x 10(-6) M) and 5.4 +/- 1.3 mV (10(-5) M) at membrane potentials where Vmax is half maximal. It is concluded that nicainoprol can be classified as a class 1C drug and does preferentially bind to inactivated sodium channels with a dissociation constant of about 10(-5) M.
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PMID:Evaluation and interpretation of voltage- and frequency-dependent electrophysiologic effects of a new class I antiarrhythmic agent (nicainoprol) on guinea pig papillary muscle and isolated heart. 246 84

Expression of immediate early genes (IEGs) was examined following long-term desensitization of cerebellar Purkinje cells. This form of desensitization, which may underlie synaptic long-term depression (LTD), was evoked by co-administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and 8-bromo cGMP (8-Br-cGMP). Among the IEGS examined with in situ hybridization and immunohistochemistry, combined application of 8-Br-cGMP and AMPA synergistically enhanced the expression of c-Fos and Jun-B in Purkinje cells. This may suggest a role for active transcriptional complexes such as AP-1 (c-Fos/Jun-B), which could be formed following conjoint inputs to Purkinje cells and which may help to establish cerebellar long-term plasticity.
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PMID:The conjunctive stimuli that cause long-term desensitization also predominantly induce c-Fos and Jun-B in cerebellar Purkinje cells. 769 17

N-terminal peptides of parathyroid hormone (PTH) and PTH-related peptide (PTHRP) elicit a wide variety of biological responses in target cells, including the inhibition of Na+/H+ exchanger NHE3 activity in renal cells. This response is believed to be mediated by ligand binding to a common receptor (i.e. PTH/PTHRP receptor type I) and activation of cAMP-dependent and/or Ca2+/phospholipid-dependent protein kinases (PKA and PKC, respectively). However, the mechanism of action of these N-terminal peptides is now unclear because of recent data reporting the existence of additional receptor isoforms. Therefore, to directly examine the ligand binding and signaling characteristics of the PTH/PTHRP receptor type I and its ability to elicit a biological response, cDNAs encoding the rat type I receptor and the rat NHE3 isoform were transfected into Chinese hamster ovary (AP-1) cells that lack endogenous expression of these proteins. Competition binding assays using [125I-Tyr36]PTHRP-(1-36)-NH2 radioligand indicated that several biologically active human N-terminal PTH and PTHRP fragments (PTH-(1-34), PTH-(3-34), PTH-(28-42), PTH-(28-48), and PTHRP-(1-34)) were capable of binding to the type I receptor. Both PTH-(1-34) and PTHRP-(1-34) stimulated adenylate cyclase and PKC activities in these cells, whereas PTH-(3-34), PTH-(28-42), and PTH-(28-48) selectively enhanced only PKC activity. PTHRP-(1-16), a biologically inert fragment, was incapable of binding to this receptor and influencing either the PKA or PKC pathway. Furthermore, all the analogues with the exception of PTHRP-(1-16) inhibited NHE3 activity. Inhibition of PKC by the potent antagonist chelerythrine chloride abolished the depression of NHE3 activity by PTH-(3-34), PTH-(28-42), and PTH-(28-48) but did not alleviate the effects of PTH-(1-34). Likewise, antagonism of PKA by H-89 was unable to prevent the inhibition caused by PTH-(1-34). However, inhibition of both PKA and PKC by the nonselective protein kinase antagonist H-7 abolished the reduction of NHE3 activity by PTH-(1-34). These data indicate that discrete N-terminal analogues of PTH and PTHRP can interact with the classical PTH/PTHRP receptor type I and activate PKA and/or PKC. Activation of either signaling pathway independently leads to inhibition of NHE3.
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PMID:Structurally diverse N-terminal peptides of parathyroid hormone (PTH) and PTH-related peptide (PTHRP) inhibit the Na+/H+ exchanger NHE3 isoform by binding to the PTH/PTHRP receptor type I and activating distinct signaling pathways. 866 42

The induction of the heme oxygenase-1 (HO-1) protein, also called HSP32, was compared to HSP70 heat shock protein induction following focal ischemia. Adult Sprague-Dawley male rats (n = 14) were subjected to either 30 min or 2 h of focal cerebral ischemia using the suture, middle-cerebral-artery (MCA) occlusion model. Controls (n = 4) had sham surgery. Following 24 h of reperfusion, subjects were killed and their brains stained immunocytochemically for HO-1 and the HSP70 heat shock proteins. One day following 30 min of ischemia, HO-1 and HSP70 staining in striatum occurred mainly in endothelial cells in infarcts and in glial cells surrounding the areas of infarction. Following the 30 min ischemia HO-1 was not induced in cortex whereas HSP70 was induced in cortical neurons in the MCA distribution. One day following 2 h of MCA ischemia, both HO-1 and HSP70 were induced in neurons in cortex in the MCA distribution. HO-1, however, was induced in glial cells throughout ipsilateral cortex, inside as well as outside the MCA distribution. This suggests that translation and/or transcription of the HO-1 and HSP70 genes are blocked in neurons and glia destined to die within infarcts, whereas translation of these stress genes continues in the endothelial cells. The duration of ischemia required to induce HSP70 in cortical neurons appears to be less than that required to induce HO-1 in cortical glia. Prolonged spreading depression and/or diffuse hemispheric ischemia may induce HO-1 in glia throughout the ipsilateral cortex via immediate early gene activation of the AP-1 site in the HO-1 promoter. Since HO-1 degrades heme, a pro-oxidant, to antioxidant molecules, the induction of HO-1 may augment oxidative defense mechanisms compromised by cerebral ischemia.
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PMID:Heme oxygenase-1 (HO-1) protein induction in rat brain following focal ischemia. 873 52

The neuromodulator systems mediating the central component of the hypoxic ventilatory response (HVR) during development are complex and diverse. The early component of the HVR is mediated through N-methyl-D-aspartate (NMDA) glutamate receptors in the caudal brainstem. The intracellular downstream signal transductions of the NMDA receptors involve protein kinase C (PKC), neuronal nitric oxide synthase (nNOS) and tyrosine kinase (TK). Activation of NMDA receptors will also lead to activation of the early gene transcription factors including AP-1 (c-fos, c-jun) and NF-kappaB which may play a role in modulation of the subsequent response to hypoxia. NMDA receptors in the caudal brainstem play a critical role in the development of the HVR and increasing dependency on NMDA receptors emerges over time. Similarly, hypoxia-induced PKC, NOS and c-Fos activation in the caudal brainstem is relatively weak in the immature animals, but this activation increases with age and the strength of the response appears to increase concomitantly with the appearance of NMDA expression. Several neurotransmitters including adenosine, gamma-aminobutyric acid (GABA), serotonin and opioids are involved in the late component of the HVR. In addition, the late phase of the HVR is mediated in part through platelet-derived growth factor (PDGF)-beta receptors. PDGF-beta receptor activation is an important contributor of the hypoxic ventilatory depression at all postnatal ages, but its role is more critical in the developing animals. Maturation of these neuromodulators, especially the NMDA and PDGF-beta receptors-mediated pathways, occurs primarily during the early postnatal period. Perturbation of these developmental processes may result in short-term or sustained alterations to the HVR and may also affect neuronal survival during hypoxia.
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PMID:Maturational changes in neuromodulation of central pathways underlying hypoxic ventilatory response. 1595 May 54

In the present study, we first observed up-regulation in preproenkephalin (PPE)-like immunoreactivity (-LIR), a precursor of Met- and Leu-enkephalin, in the rat ipsilateral medial vestibular nucleus (ipsi-MVN) after unilateral labyrinthectomy (UL). By means of double-staining immunohistochemistry with PPE and Fos, a putative regulator of PPE gene expression, we revealed that some of these PPE-LIR neurons were also Fos immunopositive. The time course of decay of these double-stained neurons was quite parallel to that of UL-induced behavioral deficits. This suggests that these double-labeled neurons could have something to do with development of vestibular compensation. We next examined correlation between Fos and PPE expression in the ipsi-MVN by means of a 15-min pre-UL application of antisense oligonucleotide probes against c-fos mRNA into the ipsi-MVN. Gel shift assay and Western blotting revealed that elimination of Fos expression significantly reduced both AP-1 DNA binding activity and PPE expression in the ipsi-MVN after UL. C-fos antisense study also revealed that depression of Fos-PPE signaling in the ipsi-MVN caused significantly more severe behavioral deficits during vestibular compensation. Furthermore, studies with PPE antisense and naloxone, an opioid receptor antagonist, demonstrated that specific depression of enkephalinergic effects in the ipsi-MVN significantly delayed vestibular compensation. All these findings suggest that, immediately after UL, Fos induced in some of the ipsi-MVN neurons could regulate consequent PPE expression via the AP-1 activation and facilitate the restoration of balance between bilateral MVN activities via the opioid receptor activation, resulting in progress of vestibular compensation.
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PMID:Fos-enkephalin signaling in the rat medial vestibular nucleus facilitates vestibular compensation. 1654 69


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