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)

We have examined the effect of cortical spreading depression (SD) and anoxic depolarization (AD) on the interstitial concentration changes of amino acids (AA) in the neocortex of anesthetized rats using microdialysis and HPLC. Accompanying SD alanine increased to 126 +/- 11%, arginine to 116 +/- 3%, aspartate to 160 +/- 17%, glutamate to 163 +/- 9%, glycine to 158 +/- 21%, serine to 125 +/- 9%, and taurine to 172 +/- 15% (mean +/- 1 S.E.M.). The increases lasted for about 1 min. Histidine decreased to 74% +/- 4% at 1 min following SD, and returned to normal 4 min later. Cardiac arrest triggered AD after approximately 2 min, immediately followed by changes of interstitial AAs. At 5 min after AD alanine had increased to 183 +/- 13%, aspartate to 3,458 +/- 656%, GABA to 338 +/- 35%, glutamate to 1,696 +/- 546%, glycine to 297 +/- 37%, serine to 153 +/- 12%, and taurine to 1721 +/- 98% as compared to control values (mean +/- 1 S.E.M.). Histidine decreased to 78 +/- 2% at 3 min following AD while arginine exhibited insignificant variations around the baseline. The increase of glutamate during SD is consistent with activation of NMDA-receptors as an essential requirement for this reaction. The increase of AAs may also contribute to the sequence of events leading to AD, though the exact mechanism remains unknown. SD is an important pathophysiological mechanism of the ischemic penumbra associated with focal cerebral ischemia, while AD reflects the electrophysiological status of the infarct core.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Microdialysis of interstitial amino acids during spreading depression and anoxic depolarization in rat neocortex. 833 Feb 14

Several analogs of an alanine-rich alpha-helical antifreeze polypeptide were synthesized and studied to evaluate the role of charged amino acids on structure and activity. alpha-Helix content and thermal stability were assessed by circular dichroism spectrometry and antifreeze activity by freezing point depression (thermal hysteresis) and ice crystal growth rate measurements. Rearrangement, deletion and replacement of charged amino acids resulted in reduced helicity and antifreeze activity in some cases, but the effects were not dramatic. We conclude that the i+4 ion pair Lys18/Glu22 helps to stabilize the alpha-helix but is not absolutely essential for activity. NH2-terminal Asp does not contribute significantly to helix stability or activity, but the COOH terminus is sensitive to modification, since replacement of Arg37 can lead to reduced helix content and activity. In general, factors which reduce alpha-helix content also reduce antifreeze activity.
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PMID:Structure-function relationships in an antifreeze polypeptide. The role of charged amino acids. 834 24

Spermatozoa are highly specialized cells, and they offer advantages for studying several basic aspects of metabolic control such as the role of adenosine triphosphate-(ATP)-homeostasis for cell function, the mechanisms of fatigue and metabolic depression, the metabolic channelling through the cytoplasm and the organization and regulation of glycolytic enzymes. Spermatozoa of four species with different reproductive modes are introduced and the first results are presented: Spermatozoa of the marine worm Arenicola marina are well adapted to external fertilization in sea water with fluctuating oxygen tension: they are motile for several hours in oxygen-free sea water, even when the ATP level is dramatically reduced. Anaerobic ATP production occurs by alanine, acetate and propionate fermentation probably by the same pathways known from somatic cells of this species. Under aerobic conditions the phosphagen system might function like a shuttle for energy-rich phosphate from mitochondria to the dynein-ATPases. Storage of turkey and carp spermatozoa for several hours without exogenous substrates and oxygen results in the degradation of phosphocreatine and ATP to inorganic phosphate and adenosine monophosphate (AMP), respectively. Despite low energy charges, stored spermatozoa of both species are capable of progressive movements. In carp spermatozoa fatigue of motility is not accompanied by the dramatic acidosis one discusses as an important effect in muscle fatigue. Energy metabolism of boar spermatozoa is typically based on glycolysis consuming extracellular carbohydrates and producing lactate and protons. The sperm seem to tolerate low intracellular pH (< 6.5). The lack of a phosphagen system (no energy shuttle from mitochondria to the distal dynein-ATPases) is probably compensated by a high glycolytic ATP-production in the mitochondria-free piece of the flagellum.
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PMID:Spermatozoa: models for studying regulatory aspects of energy metabolism. 864 86

Increases in plasma free fatty acids (FFA) inhibit the GH response to a variety of stimuli; however, the role of FFA depression in GH control is far from understood. In the present work, FFA reduction was obtained by the administration to normal subjects of acipimox, a lipid-lowering drug devoid of side-effects. Each subject tested underwent two paired tests. In one, acipimox was administered orally at a dose of 250 mg at -270 min and at a dose of 250 mg at -60 min; in the matched test, placebo was given at similar intervals. To induce GH release, four stimuli acting through different mechanisms were used: pyridostigmine (120 mg, orally) at -60 min, GHRH (1 microgram/kg, iv) at 0 min, GH-releasing peptide (GHRP-6; His-D-Trp-Ala-Trp-D-Phe-Lys-NH2; 1 microgram/kg, iv) at 0 min, and finally, GHRH plus GHRP-6 at the same doses at 0 min. GH secretion was analyzed as the area under the secretory curve (AUC; mean +/- SE, micrograms per L/120 min). Acipimox pretreatment alone (n = 6) induced a reduction in FFA levels compared with placebo treatment. The FFA reduction led to a sustained GH secretion that increased from 2.4 +/- 1.8 micrograms/L at -120 min to 14.2 +/- 4.0 at 120 min. The GH AUC for placebo was 266 +/- 100, and that for acipimox was 1781 +/- 408 (P < 0.05). In the pyridostigmine-treated group (n = 6), the acipimox-pyridostigmine AUC (2046 +/- 323) was higher (P < 0.05) than the placebo-pyridostigmine AUC (764 +/- 101), but was not different from the AUC of acipimox alone. Previous FFA reduction nearly doubled the GHRH-mediated GH secretion (n = 6; placebo-GHRH AUC, 1817 +/- 365; acipimox-GHRH test, 3228 +/- 876; P < 0.05). A similar enhancement was observed when the stimulus employed was GHRP-6 (n = 6; placebo-GHRP-6 AUC, 2034 +/- 295; acipimox-GHRP-6, 4827 +/- 703; P < 0.05). Furthermore, even the most potent GH stimulus known to date, i.e. GHRH plus GHRP-6, was enhanced by the FFA suppression (placebo-GHRH-GHRP-6 AUC, 2034 +/- 277; acipimox-GHRH-GHRP-6, 5809 +/- 758; P < 0.05). The enhancing effect of lowering FFA levels was additive regardless of the stimulus employed. These results indicate that 1) FFA reduction per se stimulates GH secretion with a delayed time of action; 2) FFA reduction enhanced in an additive manner the GH secretion elicited by such different stimuli as pyridostigmine, GHRH, and GHRP-6; and 3) the observation that FFA reduction enhanced the response to the most potent GH stimulus, GHRH plus GHRP-6, suggests that FFA suppression acts by a separate mechanism. FFA reduction may have value in the clinical setting for assessing GH reserve.
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PMID:Acipimox-mediated plasma free fatty acid depression per se stimulates growth hormone (GH) secretion in normal subjects and potentiates the response to other GH-releasing stimuli. 877 49

The chromogranins comprise a class of acidic proteins that are secreted from large dense core vesicles and expressed in neuronal and endocrine tissues. We describe here the molecular characterization of NESP55 (neuroendocrine secretory protein of Mr 55,000), a novel member of the chromogranins. Several NESP55 cDNA clones were isolated from bovine chromaffin cell libraries. The cDNA sequence of NESP55 totals 1499 nucleotides. All of the clones that were isolated contained in their 3'-untranslated mRNA a sequence that was homologous to exon 2 of the G-protein Gsalpha. The open reading frame encodes for an acidic and hydrophilic protein of 241 amino acids with a predicted molecular mass of 27,494 Da. An antiserum directed against the C terminus of NESP55 labeled a band of Mr 55,000 with an acidic pI ranging from 4.4 to 5.2 in one- and two-dimensional immunoblots of secretory proteins from chromaffin granules. NESP55 is localized within the cell to the large dense secretory vesicles and is expressed, apart from the adrenal medulla, in the anterior and posterior pituitary and various regions of the brain. For the physiological function, one interesting factor has emerged. NESP55 is proteolytically processed within the chromaffin granule to smaller peptides that might be physiologically active. One tetrapeptide, Leu-Ser-Ala-Leu (LSAL), present in the NESP55 sequence and flanked by arginine residues suitable for cleavage by prohormone convertases, has been identified recently as an endogenous antagonist of the serotonergic 5-HT1B receptor subtype. Alterations in the serotonergic system are thought to play an important role in mental disorders, especially depression, and might be related to abnormal ethanol consumption. It is tempting to speculate that increased expression of NESP55 or its proteolytically derived peptide LSAL might contribute to the pathophysiology of the serotonergic transmission.
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PMID:Molecular cloning and characterization of NESP55, a novel chromogranin-like precursor of a peptide with 5-HT1B receptor antagonist activity. 911 Oct 83

5-HT-moduline (Leu-Ser-Ala-Leu, LSAL) is a novel endogenous peptide isolated from rat brain which interacts in vitro specifically with 5-HT(1B) receptors by a non-competitive mechanism. In the present study, we demonstrate that the efficacy of the selective 5-HT(1B) receptor agonist CP 93 129 in inhibiting the forskolin-stimulated adenylyl cyclase activity in the rat substantia nigra was reduced 15 min after intracerebral injection of LSAL compared to vehicle or ALLS (scrambled peptide) injected rats. Accordingly, the concentration-response curve of the agonist is shifted to the right with a 3.5-fold increase of the half-maximal inhibitory concentration compared to vehicle injected rats. Thus, the in vivo desensitization of serotonergic autoreceptors strongly strengthens the important role of 5-HT-moduline in the rapid adaptative control of the serotonergic system, implicated in numerous pathological events as anxiety and depression.
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PMID:The endogenous cerebral tetrapeptide 5-HT-moduline reduces in vivo the functional activity of central 5-HT1B receptors in the rat. 912 86

Milacemide or 2-n-pentylaminoacetamide hydrochloride, a new glycine derivative, was found to cause elevations of plasma transaminases in patients suffering from severe depression and Alzheimer's disease. However, no signs of liver toxicity were observed during the course of earlier conducted subchronic and chronic in vivo studies in rodents and cynomolgus monkeys. In this study an in vivo/in vitro approach has been proposed to detect early alterations in key metabolic and functional liver capacities. Milacemide was administered by continuous i.v. infusion for 7 days to male Sprague-Dawley rats using subcutaneously implanted osmotic pumps. Doses were given of 0, 250 and 500 mg/kg per day. Body weight and food intake were recorded and at day 7 of exposure, Milacemide concentration, glucose, urea, triglycerides and cholesterol levels and alanine (ALT) and aspartate aminotransferase (AST) activities were measured in plasma. Non-esterified fatty acids were determined in serum. On day 8, after overnight fasting, hepatocytes were isolated. A portion of the cells derived from untreated animals (no osmotic pumps) were cultured in a primary monolayer and exposed in vitro to different Milacemide concentrations. The xenobiotic biotransformation capacity of the isolated hepatocytes was studied by measuring the cytochrome P450 content, ethoxycoumarin-O-deethylase (ECOD), pentoxyresorufin-O-deethylase (PROD), ethoxyresorufin-O-deethylase (EROD), aldrin epoxidase (AE), epoxide hydrolase (EH) and glutathione S-transferase (GST) enzyme activities. Triglycerides, cholesterol and phospholipid contents were measured on the isolated cells. At plasma concentrations of 43 and 130 microM Milacemide, the ALT activity was unchanged or significantly decreased, whereas the AST activity was increased in both cases. Other clinical chemistry parameters remained unchanged. Weight gain was significantly lower in rats treated with the high Milacemide dose. In addition, decreased food consumption was observed in all treated animals leading to significantly lower food efficiency factors for the rats treated with the high dose. Milacemide had a specific inhibitory effect on xenobiotic biotransformation: ECOD activity decreased to 60% of the control value for both Milacemide doses, PROD activity remained unaffected whereas EROD activity decreased to 65% of the control value. A decrease was also observed at the highest drug concentration for AE (to 41%), EH (to 65%), cytochrome P450 content (to 80%) and GST (to 85%). At 500 mg Milacemide kg/day, hepatocyte triglycerides levels increased 3.1-fold while cholesterol and phospholipid levels remained unaffected. Electron and light microscopy on total liver and isolated hepatocytes indicated a concentration-dependent accumulation of lipid droplets, the occurrence of numerous vacuoles in the cytoplasm and other structural abnormalities. When the cultured hepatocytes of control animals (without osmotic pumps) were exposed to Milacemide, the appearance of vacuoles and myeloid bodies could be confirmed in vitro. The results of this study using an in vivo/in vitro approach clearly show potential hepatotoxic properties of Milacemide, an effect not observed in conventional toxicity studies.
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PMID:Observation of hepatotoxic effects of 2-n-pentylaminoacetamide (Milacemide) in rat liver by a combined in vivo/in vitro approach. 913 5

Previous research in this laboratory has shown that major depression is accompanied by decreased serum activity of dipeptidyl peptidase IV (DPP IV), a serine protease that cleaves N terminal dipeptides from peptides with penultimate proline or alanine. DPP IV is involved in the metabolism of peptides, T cell activation and proliferation, including the production of cytokines, such as interleukin-1 (IL-1) and IL-2. The aim of this study was to examine (i) serum DPP IV activity in major and treatment resistant depression (TRD) in relation to other established immune and inflammatory markers of that illness, and (ii) the effects of antidepressive treatment on DPP IV activity. Serum DPP IV activity was significantly lower in major depression and TRD than in normal controls. In normal and major depressed subjects, there were significant and positive relationships between serum DPP IV activity and total serum protein, serum albumin, zinc, iron and transferrin. In the group of depressed subjects, there were significant and positive relationships between serum DPP IV activity and number of CD4+T cells and CD4+/CD8+ T cell ratio. There were no significant effects of subchronic treatment with antidepressants on serum DPP IV activity. The findings suggest that: (i) lower serum DPP activity may occur in chronic depression, TRD as well as in the acute phase of major depression; (ii) lower serum DPP IV accompanies the 'chronic' acute phase response in depression; and (iii) serum DPP IV activity is tightly coupled to increased number of CD4+ T cells in depressed subjects, but not in normal controls. Our results do not exclude the possible effects of longer-term treatment with antidepressants on serum DPP-IV activity.
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PMID:Lower serum dipeptidyl peptidase IV activity in treatment resistant major depression: relationships with immune-inflammatory markers. 914 29

Cytoprotection or metabolic modulation is a new principle in the treatment of angina pectoris. The effect of ranolazine (a cytoprotective drug) on ischemic threshold, coronary sinus blood flow, and myocardial metabolism was evaluated by means of two pacing sequences in nine male patients with coronary artery disease (CAD) and in eight male controls. Ranolazine was given as an intravenous bolus followed by continuous infusion; the mean total dose was 32.7 mg and 31.7 mg in patients and controls, respectively. Angina pectoris was relieved in two patients after ranolazine but pacing time to pain was unchanged in the remaining patients. Maximal ST depression was lower (p = 0.02), but pacing time to maximal and to 1-mm ST depression remained unchanged after the drug. Ranolazine had no overall influence on coronary sinus blood flow, cardiac oxygen consumption, blood pressure, and heart rate. Cardiac uptake of free fatty acids (FFA) was reduced (p = 0.01), and net uptakes of glucose (p = 0.07) and lactate (p = 0.06) tended to be lower after ranolazine in CAD patients and controls. Ranolazine had no direct influence on cardiac exchange of glutamate, alanine, and citrate or on the arterial concentration of any metabolite. In the present study ranolazine had minimal clinical effects. A decrease in myocardial FFA utilization, however, allows greater myocardial glucose oxidation, which may increase the energy production in relation to oxygen availability.
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PMID:Effects of ranolazine on ischemic threshold, coronary sinus blood flow, and myocardial metabolism in coronary artery disease. 931 Feb 77

Patients with methylenetetrahydrofolate reductase (MTHFR) deficiency often show psychiatric manifestations. Since a common variant of the MTHFR gene, T677(Ala), responsible for the thermolabile MTHFR with less than 50% specific MTHFR activity, has been reported, we examined whether the T677 allele is associated with psychiatric disorders in an unrelated Japanese population consisting of 297 schizophrenics, 32 patients with major depression, 40 patients with bipolar disorder, and 419 controls. The genotype homozygous for the T677 allele was significantly frequently observed in schizophrenics with an odds ratio of 1.9 (P = 0.0006), and in patients with major depression with an odds ratio of 2.8 (P = 0.005). Our data suggest associations of the MTHFR gene variant with schizophrenia and depression in the Japanese.
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PMID:Methylenetetrahydrofolate reductase variant and schizophrenia/depression. 934 5


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