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)

Positron-emission tomography (PET) provides potential in neuropsychiatric drug development by expanding knowledge of drug action in the living human brain and reducing time consumption and costs. The 5-hydroxytryptamine(1A) (5-HT(1A)) receptor is of central interest as a target for the treatment of anxiety, depression, and schizophrenia. Research on the clinical significance of the 5-HT(1A) receptor now benefits from the highly selective radioligand [carbonyl-(11)C]WAY-100635 (WAY) for quantitative determination of 5-HT(1A) receptors in the primate and human brain in vivo using PET. In this paper, three studies are reviewed to demonstrate the suitability of WAY as radioligand for quantification of central 5-HT(1A) receptors in brain and as an applicable tool for drug development. In the first study a monkey model was used to characterize WAY binding. It was confirmed that the reference ligand 8-OH-DPAT and psychoactive drugs such as buspirone and pindolol occupies 5-HT(1A) receptors in the primate brain. Pindolol is an beta-adrenoreceptor antagonist with a high affinity to 5-HT(1A) receptors. This drug has been suggested in combination with selective serotonin reuptake inhibitors for the treatment of depression and was given to healthy males in the second study. Pindolol induced a marked inhibition of central 5-HT(1A) receptors as calculated by the ratio-analysis method and simplified reference tissue model, 2 h after administration of 10 mg as a single oral dose. This observation suggests that pindolol may have a role for the suggested potentiation of selective serotonin reuptake inhibitor treatment of depression. The third study was on robalzotan (NAD-299), a recently developed 5-HT(1A) receptor antagonist and putative drug with implications for the treatment of depression. In the cynomolgus monkey brain, robalzotan in the dose range 2-100 microg/kg IV occupied 5-HT(1A) receptors in a dose-dependent and saturable manner with a maximal calculated occupancy of 70-80%. The relationship between robalzotan plasma concentration and 5-HT(1A) receptor occupancy could be described by a hyperbolic function that was used to guide the selection of appropriate doses in man. In a subsequent PET study of robalzotan binding to 5-HT(1A) receptors in the living human brain, similar results have been replicated recently. These studies reviewed here illustrate and corroborate that quantitative neuroimaging of receptor binding has potential for the evaluation and dose finding of new central nervous system drugs.
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PMID:Use of PET and the radioligand [carbonyl-(11)C]WAY-100635 in psychotropic drug development. 1096 60

The 5-HT1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy. Here, we review the radioligands which are available for visualisation and quantification of this important neuroreceptor in the human brain, using positron emission tomography (PET) or single-photon emission tomography (SPET). More than 20 compounds have been labelled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogues of the agonist, 8-OH-DPAT, structural analogues of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl-11C] WAY-100635 (WAY), [carbonyl-11C]desmethyl-WAY-100635 (DWAY), p-[18F]MPPF and [11C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT1A receptor distribution in the brain (even the raphe nuclei are visualised), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centres within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) production of a radioiodinated or technetium-labelled ligand for SPET.
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PMID:Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system. 1120 45

Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are two Ca(2+) messengers derived from NAD and NADP, respectively. Although NAADP is a linear molecule, structurally distinct from the cyclic cADPR, it is synthesized by similar enzymes, ADP-ribosyl cyclase and its homolog, CD38. The crystal structure of the cyclase has been solved and its active site identified. These two novel nucleotides have now been shown to be involved in a wide range of cellular functions including: cell cycle regulation in Euglena, a protist; gene expression in plants; and in animal systems, from fertilization to neurotransmitter release and long-term depression in brain. A battery of pharmacological reagents have been developed, providing valuable tools for elucidating the physiological functions of these two novel Ca(2+) messengers. This article reviews these recent results and explores the implications of the existence of multiple Ca(2+) messengers and Ca(2+) stores in cells.
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PMID:Physiological functions of cyclic ADP-ribose and NAADP as calcium messengers. 1126 60

Sepsis depletes intracellular stores of ATP and NAD+, leading to cellular energy failure. Liposome encapsulation improves intracellular delivery of bulky, charged molecules and substrates susceptible to extracellular enzyme degradation. We hypothesized that treatments with liposome encapsulated ATP or NAD+ would protect human endothelial cells exposed to endotoxin (LPS) and interferon-gamma (IFN-gamma) from energy failure. Liposomal ATP and NAD+ were prepared by a modification of the thin film method. Human endothelial cells were exposed to LPS 50 microg/ml and IFN-gamma 50 ng/ml for 72 hours, and liposomal ATP and NAD+ treatments were dosed at 0 and 24 hours. Energy state was determined by rate of mitochondrial respiration as measured by WST-1 assay. Mitochondrial respiration significantly decreased to 57% +/- 3 of control in LPS/IFN-gamma exposed cells after 72 hours. Liposomal ATP (200 microM) and NAD+ (100 microM) completely reversed this respiratory depression while empty liposomes, free ATP (200 microM). and free NAD+ (100 microM) did not. These results support the hypothesis that treatments with liposome encapsulated ATP or NAD+ protect human endothelial cells from energy failure in a cell culture model of sepsis and potentially may provide a novel therapy for use in clinical sepsis.
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PMID:Liposomal atp or NAD+ protects human endothelial cells from energy failure in a cell culture model of sepsis. 1209 Mar 49

Cyclosporine protects the heart against ischemia/reperfusion injury, but its effect on cardiac metabolism is largely unknown. We assessed cyclosporine-induced metabolic changes in the rat heart prior to occlusion using magnetic resonance spectroscopy (MRS) and correlated effects with infarct size in a coronary occlusion/reperfusion model. The two study groups were cyclosporine and cyclosporine + coronary occlusion (n = 20/group). Rats were pretreated with cyclosporine (5, 10, 15, and 25 mg/kg/day) or the vehicle by oral gavage for 3 days (n = 4/dose). On day 4, hearts of rats in the cyclosporine group were excised, and extracted cell metabolites were measured using (1)H and (31)P MRS. The second group was subjected to 30 min of coronary artery occlusion followed by 24 h of reperfusion. Infarct size and area at risk were measured using a double staining method. In the cyclosporine group, cyclosporine reduced cardiac energy metabolism (ATP: r = -0.89, P < 0.001) via depression of oxidative phosphorylation and the Krebs' cycle in a dose-dependent manner. The decrease of ATP levels was positively correlated with changes of NAD(+) (r = 0.89), glutamate (r = 0.95), glutamine (r = 0.84), and glucose concentrations (r = 0.92, all P < 0.002). It was inversely correlated with lactate (r = -0.93, P < 0.001). In the coronary occlusion group, cyclosporine dose dependently reduced the ratio [area of infarct/area of the left ventricle] (r = -0.86, P < 0.01), with 15 mg/kg/day being the most effective cyclosporine dose. The reduction in infarct size correlated with the reduction in oxidative phosphorylation (ATP: r = 0.97; NAD(+): r = 0.82, P < 0.01). The reduction in cardiac energy metabolism before occlusion may be the cause of myocardial preservation during ischemia/reperfusion.
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PMID:Close association between the reduction in myocardial energy metabolism and infarct size: dose-response assessment of cyclosporine. 1218 71

We described the effects of nimesulide (N-[4-nitro-2-phenoxyphenyl]-methanesulfonamide) and its reduced metabolite in isolated rat hepatocytes. Nimesulide stimulated the succinate-supported state 4 respiration of mitochondria, indicating an uncoupling effect of the drug. Incubation of hepatocytes with nimesulide (0.1-1 mM) elicited a concentration- and time-dependent decrease in cell viability as assessed by lactate dehydrogenase leakage, a decrease of mitochondrial membrane potential as assessed by rhodamine 123 retention, and cell ATP depression. Nimesulide also decreased the levels of NAD(P)H and glutathione in hepatocytes, but the extent of the effects was less pronounced in relation to the energetic parameters; in addition, these effects did not imply the peroxidation of membrane lipids. The decrease in the viability of hepatocytes was prevented by fructose and, to a larger extent, by fructose plus oligomycin; it was stimulated by proadifen, a cytochrome P450 inhibitor. In contrast, the reduced metabolite of nimesulide did not present any of the effects observed for the parent drug. These results indicate that: 1) nimesulide causes injury to the isolated rat liver cells, 2) this effect is mainly mediated by impairment of ATP production by mitochondria due to uncoupling, and 3) on account of the activity of its nitro group, the parent drug by itself is the main factor responsible for its toxicity to the hepatocytes.
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PMID:The critical role of mitochondrial energetic impairment in the toxicity of nimesulide to hepatocytes. 1238 41

Previous work has shown that niacin deficiency in rats increases the severity of ethylnitrosourea (ENU)-induced anemia and leukopenia and the long-term development of cancer. The current study was initially designed to characterize changes in bone marrow cell populations during ENU treatment in this model. Weanling Long-Evans rats were fed diets containing 0 or 30 mg/kg of added niacin for a period of 2-3 wk. ENU treatment started after 1 wk of feeding and consisted of either 4 or 8 doses of ENU delivered by gavage, every other day. Niacin deficiency (ND) alone caused a significant depression in nucleated red blood cells (30%), and a sporadic effect on granulocytes (+23% after 4 doses of vehicle, -29% after 8 doses of vehicle). ENU treatment, after only 4 doses, caused a large decline in the numbers of bone marrow cells, and this effect was enhanced by ND (ENU decreased lymphocytes by 66% in pair-fed (PF) and 86% in ND, granulocytes by 41% in PF and 64% in ND, and nucleated red blood cells by 63% in PF and 71% in ND). Cell cycle distribution suggested that bone marrow cells in niacin-adequate rats, but not ND rats, mounted a compensatory proliferative response during chronic ENU exposure. ND alone caused an 80% decrease in bone marrow NAD+ levels at all time points. Surprisingly, chronic exposure to ENU (which should cause DNA damage and NAD+ utilization) led to a 2.8-fold increase in NAD+ content in ND marrow cells. This finding led to a second study in which ND and niacin-adequate PF control rats received 7 doses of ENU or vehicle (CON), after which all rats received 1 dose of ENU. In this study, modestly enhanced bone marrow NAD+ in chronically treated PF rats was used to synthesize 2-fold greater amounts of poly(ADP-ribose) than seen after one acute dose of ENU, while this did not occur in chronically treated ND rats, in spite of a 2.8-fold increase in bone marrow NAD+. This study has shown that bone marrow cell populations are sensitized to ENU treatment by ND, that NAD+ pools are regulated in response to DNA damage, and that NAD+ localization and/or utilization in the nucleus is altered during ND and chronic DNA damage.
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PMID:Chronic DNA damage and niacin deficiency enhance cell injury and cause unusual interactions in NAD and poly(ADP-ribose) metabolism in rat bone marrow. 1279 12

Neurophysiological study of all links of afferent somatosensory systems in neuropathies of different genesis was conducted. Patients with alcoholic (APN) and diabetic (DNP) polyneuropathies have been examined and selected as follows: 19 patients with intensive spontaneous pain syndrome (scoring over 6 on VAS); 20--without pain; 22 patients with allodiny caused by neuropathic pain and 38--without allodiny. Control group included 20 healthy subjects. Symptom complex of pain syndrome encompassed pronounced disorders of cutaneous sensitivity, minus symptoms in deep sensory sphere and high depression level. Neurophisiological appearances of spontaneous pain syndrome in APN and DPN are characterized by generalized mixed damage of peripheral sensible nerves and of 1 beta-afferents of H-reflex arch. Insufficiency of function of pain control system was mainly of deafferent character. Allodiny and spontaneous pain syndrome are reciprocally combined, the former being distinguished by involvement in pathology of 1-[symbol: see text] fibers (motor nerves and efferent links of H-reflex).
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PMID:[Neuropathic pain syndrome: clinico-neurophysiological analysis]. 1462 81

Urocanase (EC 4.2.1.49) from Pseudomonas putida was crystallized after removing one of the seven free thiol groups. The crystal structure was solved by multiwavelength anomalous diffraction (MAD) using a seleno-methionine derivative and then refined at 1.14 A resolution. The enzyme is a symmetric homodimer of 2 x 557 amino acid residues with tightly bound NAD+ cofactors. Each subunit consists of a typical NAD-binding domain inserted into a larger core domain that forms the dimer interface. The core domain has a novel chain fold and accommodates the substrate urocanate in a surface depression. The NAD domain sits like a lid on the core domain depression and points with the nicotinamide group to the substrate. Substrate, nicotinamide and five water molecules are completely sequestered in a cavity. Most likely, one of these water molecules hydrates the substrate during catalysis. This cavity has to open for substrate passage, which probably means lifting the NAD domain. The observed atomic arrangement at the active center gives rise to a detailed proposal for the catalytic mechanism that is consistent with published chemical data. As expected, the variability of the residues involved is low, as derived from a family of 58 proteins annotated as urocanases in the data banks. However, one well-embedded member of this family showed a significant deviation at the active center indicating an incorrect annotation.
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PMID:Structure and action of urocanase. 1531 16

The oxidation level of P700 induced by far-red light (DeltaA(FR)) in briefly dark-treated leaves of some sun plants decreased during the daytime and recovered at night. The dark recovery of decreased DeltaA(FR) proceeded slowly, with a half-time of about 5 h. We propose that stromal over-reduction induced by sunlight was the direct cause of the depression of DeltaA(FR). The depression of DeltaA(FR) found during the daytime was reproduced by controlled illumination with saturating light of fully dark-treated leaves. Simultaneous measurement of P700 redox and chlorophyll fluorescence showed that the depression of DeltaA(FR) was associated with dark reduction of the plastoquinone pool, which represented cyclic electron transport activity. The decrease of DeltaA(FR) in the light-stressed chloroplasts was partly reversed by treatment with 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone, an inhibitor of electron transport at the cytochrome b6/f complex, and the subsequent addition of methyl viologen, an efficient electron acceptor from photosystem I (PSI), stimulated further recovery, showing that both cyclic electron flow around PSI and the charge recombination within PSI were responsible for the light-induced depression of DeltaA(FR). The dark level of blue-green fluorescence, an indicator of NAD(P)H concentration, from intact chloroplasts was increased by high-light stress, suggesting that NADPH accumulated in stroma as a result of the high-light treatment. Possible effects on photosynthetic activity of over-reduction and its physiological relevance are discussed.
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PMID:Stromal over-reduction by high-light stress as measured by decreases in P700 oxidation by far-red light and its physiological relevance. 1578 24


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