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 short-term cardiac side effects of 2',3'-dideoxycytidine (ddC, zalcitabine) were studied in rats in order to understand the biochemical events contributing to the development of ddC-induced cardiomyopathy. In developing animals, ddC treatment provoked a surprisingly rapid appearance of cardiac malfunctions characterized by prolonged RR, PR, and QT intervals and J point depression. The energy metabolism in the heart was compromised, characterized by a decreased creatine phosphate/creatine ratio (from 2.05 normal value to 0.75) and a decreased free ATP/ADP ratio (from 332 normal value to 121). The activity of respiratory complexes (NADH: cytochrome c oxidoreductase and cytochrome oxidase) also decreased significantly. Southern blot and polymerase chain reaction analysis did not show deletions or a decrease in the quantity of mitochondrial DNA (mtDNA) deriving from ddC-treated rat hearts, indicating that under our experimental conditions, ddC-induced heart abnormalities were not the direct consequence of mtDNA-related damage. The ddC treatment of rats significantly increased the formation of reactive oxygen species (ROS) in heart and skeletal muscle as determined by the oxidation of non-fluorescent dihydrorhodamine123 to fluorescent rhodamine123 and the oxidation of cellular proteins determined from protein carbonyl content. An activation of the nuclear poly-(ADP-ribose) polymerase (EC 2.4.2.30) and an increase in the mono-ADP-ribosylation of glucose-regulated protein and desmin were observed in the cardiac tissue from ddC-treated animals. A decrease in the quantity of heat shock protein (HSP)70s was also detected, while the level of HSP25 and HSP60 remained unchanged. Surprisingly, ddC treatment induced a skeletal muscle-specific decrease in the quantity of three proteins, one of which was identified by N-terminal sequencing as myoglobin, and another by tandem mass spectrometer sequencing as triosephosphate isomerase (EC 5.3.1.1). These data show that the short term cardiotoxicity of ddC is partially based on ROS-mediated signalling through poly- and mono-ADP-ribosylation reactions and depression of HSP70 levels, whose processes represent a new mtDNA independent mechanism for ddC-induced cell damage.
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PMID:Molecular mechanism of the short-term cardiotoxicity caused by 2',3'-dideoxycytidine (ddC): modulation of reactive oxygen species levels and ADP-ribosylation reactions. 1059 Nov 46

Recent studies have identified the potential for an important role for serotonin (5-HT) receptors in the developmental plasticity of the kitten visual cortex. 5-HT(2C) receptors are transiently expressed in a patchy fashion in the visual cortex of kittens between 30-80 days of age complementary to patches demarcated by cytochrome oxidase staining. 5-HT, operating via 5-HT(2C) receptors, increases cortical synaptic plasticity as assessed both in brain slices and in vivo. Herein, we report that bath application of 5-HT substantially increases the probability of long-term potentiation within 5-HT(2C) receptor-rich zones of cortex, but this effect is not observed in the 5-HT(2C) receptor-poor zones. Instead, in these zones, 5-HT application increases the probability of long-term depression. These location-specific effects of 5-HT may promote the formation of compartment-specific cortical responses.
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PMID:Columnar distribution of serotonin-dependent plasticity within kitten striate cortex. 1067 43

Measurements of oxidative metabolic capacity following the ablation of rat sensorimotor cortex and the administration of amphetamine were examined to determine their effects on the metabolic dysfunction that follows brain injury. Twenty-four hours after surgery, rats sustaining either sham operations or unilateral cortical ablation were administered a single injection of D-amphetamine (2 mg/kg; i.p.) or saline and then sacrificed 24 h later. Brain tissue was processed for cytochrome oxidase histochemistry, and 12 bilateral cerebral areas were measured, using optical density as an index of the relative amounts of the enzyme. Compared with that of the control groups, cytochrome oxidase in the injured animals was significantly reduced throughout the cerebral cortex and in 5 of 11 subcortical structures. This injury-induced depression of oxidative capacity was most pronounced in regions of the hemisphere ipsilateral to the ablation. Animals given D-amphetamine had less depression of oxidative capacity, which was most pronounced bilaterally in the cerebral cortex, red nucleus, and superior colliculus; and in the nucleus accumbens, caudateputamen, and globus pallidus ipsilateral to the ablation. The ability of D-amphetamine to alleviate depressed cerebral oxidative metabolism following cortical injury may be one mechanism by which drugs increasing noradrenaline release accelerate functional recovery in both animals and humans.
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PMID:Alleviation of brain injury-induced cerebral metabolic depression by amphetamine: a cytochrome oxidase histochemistry study. 1070 18

The validity of congenital helplessness as a genetic rat model for human depression was investigated in cortical regions of the rat brain thought to be analogous to those showing abnormalities in human neuroimaging studies. Cortex metabolism was analyzed using quantitative cytochrome oxidase histochemistry. Congenital helpless rats showed changes in frontal and cingulate regions comparable to those that have demonstrated metabolic differences in human depression. Significant metabolic decreases were found in dorsal frontal, medial orbital, and anterior cingulate, whereas a significant increase was found in infraradiata (subgenual) cingulate. The direction of these changes were the same as those seen in human studies. These findings support the validity of congenital helplessness as a model for human depression.
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PMID:Congenital helpless rats as a genetic model for cortex metabolism in depression. 1111 93

We measured the activities of Na(+)K(+) ATPase and of enzymes of the glycolytic pathway, Krebs cycle, and the respiratory chain in cerebral cortex of mice exposed to chronic hypoxia for three weeks and compared their values with those of sea level controls. There were no differences in Na(+)K(+) ATPase activity or in the activity of glycolytic enzymes. In the Krebs cycle, a 66% increase of succinate dehydrogenase activity was found due to a lower Km. In contrast, respiratory chain cytochrome oxidase activity was reduced by 12% in mice exposed to hypoxia. This suggested that the metabolic demand would be satisfied despite the respiratory chain depression (cytochrome oxidase), probably due to anaerobic energy production within the mitochondria (succinate dehydrogenase).
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PMID:Energetic metabolism in mouse cerebral cortex during chronic hypoxia. 1125 25

Apoptosis of HL-60 cells induced by actinomycin D, H7, or daunorubicin was shown to involve the activation of caspase-3-like protease, 2 h after the addition of these drugs, based on microassay of enzyme activity by high-performance liquid chromatography. Catalase and a spin trap, N-t-butyl-alpha-phenylnitrone, which effectively inhibited the apoptosis induced by these drugs, also inhibited the activation of caspase-3-like protease. These results suggest that hydrogen peroxide and the hydroxyl radical are common mediators of caspase-3 activation caused by these chemicals, with apparently different functional mechanisms. Based on mitochondrial activity determined by oxygen consumption, complexes I, II, and IV were inhibited by actinomycin D. H7 inhibited complexes I and IV, 1 and 1.5 h respectively, after the addition of the drug to HL-60 cells. Daunorubicin inhibited complex IV, 1.5 h after the addition of the drug to HL-60 cells. Inhibition of complex IV by actinomycin D, H7, and daunorubicin were almost fully restored by the addition of cytochrome c. The release to the cytosol of cytochrome c by these drugs was also demonstrated by Western blot analysis. Addition of catalase inhibited the depression of complex IV activity induced by actinomycin D and H7. These observations indicate a direct relationship between hydrogen peroxide and the release of cytochrome c during apoptosis caused by actinomycin D, H7, and daunorubicin.
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PMID:Hydrogen peroxide and hydroxyl radical involvement in the activation of caspase-3 in chemically induced apoptosis of HL-60 cells. 1131 94

The congenitally helpless rat, selectively bred to model behavioral features of depression, has shown metabolic activity patterns in frontal and cingulate cortex similar to those detected in human imaging studies of depression and sadness. This study extends the same metabolic mapping technique (quantitative cytochrome oxidase histochemistry) to the hypothalamus, where activity levels were assessed in six nuclei: paraventricular nucleus, medial preoptic area, lateral hypothalamic area, supraoptic nucleus, suprachiasmatic nucleus, and ventromedial nucleus. Helpless rats were compared with a strain of non-helpless rats selectively bred for stress resistance. Only the paraventricular nucleus showed a significant group difference, with helpless rats showing elevated metabolism and non-helpless rats showing reduced metabolism relative to normal rats. Thus, paraventricular nucleus activity may be associated with genetic susceptibility to helpless behavior.
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PMID:Hypermetabolism of paraventricular hypothalamus in the congenitally helpless rat. 1158 64

Traumatic brain injury (TBI) is documented to have detrimental effects on CNS metabolism, including alterations in glucose utilization and the depression of mitochondrial oxidative phosphorylation. Studies on mitochondrial metabolism have also provided evidence for reduced activity of the cytochrome oxidase complex of the electron transport chain (complex IV) after TBI and an immediate (lhr) reduction in mitochondrial state 3 respiratory rate, which can persist for up to 14 days postinjury. Using differential display methods to screen for differences in gene expression, we have found that cytochrome c oxidase II (COII), a mitochondrial encoded subunit of complex IV, is upregulated following TBI. Since COII carries a binding site for cytochrome c in the respiratory chain, and since it is required for the passage of chain electrons to molecular oxygen, driving the production of ATP, we hypothesized that metabolic dysfunction resulting from TBI alters COII gene expression directly, perhaps influencing the synaptic plasticity that occurs during postinjury recovery processes. To test this hypothesis, we documented COII mRNA expression and complex IV (cytochrome c oxidase) functional activity at 7 days postinjury, focusing on the long-term postinjury period most closely associated with synaptic reorganization. Both central fluid percussion TBI and combined TBI and bilateral entorhinal cortical lesion were examined. At 7 days survival, differential display, RT-PCR, and Northern blot analysis of hippocampal RNA from both TBI and combined insult models showed a significant induction of COII mRNA. This long-term elevation in COII gene expression was supported by increases in COII immunobinding. By contrast, cytochrome oxidase histochemical activity within tissue sections from injured brains suggested a reduction of complex IV activity within the TBI cases, but not within animals subjected to the combined insult. These differences in cytochrome c oxidase activity were supported by in vitro assay of complex IV using cerebral cortical and hippocampal tissues. Our present results support the hypothesis that COII is selectively vulnerable to TBI and that COII differences may indicate the degree of metabolic dysfunction induced by different pathologies. Taken together, such data will better define the role of metabolic function in long-term recovery after TBI.
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PMID:Traumatic brain injury-induced changes in gene expression and functional activity of mitochondrial cytochrome C oxidase. 1168 99

Following a subarachnoid hemorrhage (SAH), adult rats exhibit dynamic regional changes in cerebral glucose metabolism characterized by an increase in metabolic rates and a subsequent upregulation of cytochrome oxidase (CO). We evaluated both local cerebral metabolic rates for glucose (ICMRglc: (mol/100 g/min) and CO in 23 brain regions of interest (ROI). Sham animals underwent anesthesia and superficial surgery; saline-controls received an injection of 0.9% saline into the cisterna magna; and SAH rats received an injection of autologous blood into the cisterna magna. This blood, measured by albumin labeled with radioactive carbon 14, distributed throughout the brain but predominated ventrally. After experimental animals were sacrificed at day 0 (3 h), 1, 3, and 7 days postinjection, ROI were analyzed using [14C]2-deoxy-D-glucose autoradiography and CO histochemistry. ICMRglc in SAH rats increased in many regions (ranging from 0.7% to 32.2% above sham levels). Cytochrome oxidase also increased from 1% to 9% above sham levels, peaking on day 3. Conversely, saline-controls exhibited prolonged depression of ICMRglc (ranging from 11% to 35% below sham levels) and CO (ranging from 4% to 11% below sham levels) from day 0 through day 7. All saline-control ROI for all time points showed this metabolic depression, and between 91% and 95% of saline-control ROI presented lower CO levels as compared to sham. Overall, ICMRglc and CO levels were greater in SAH than in saline-control ROI. However, when considering the influence of subarachnoid blood on metabolic changes in SAH animals, both CO and 2DG levels did not correlate well with the amount of 14C-albumin binding. While previous studies have measured both metabolic rates of glucose and CO soon after SAH, this is the first to simultaneously conduct these measurements in the same SAH rat model.
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PMID:Subarachnoid hemorrhage induces dynamic changes in regional cerebral metabolism in rats. 1199 Mar 51

Congenitally helpless rats have been selectively bred to display an immediate helpless response to stress in order to model hereditary brain differences that contribute to depression vulnerability. Differences in regional brain metabolism between congenitally helpless and non-helpless rats were investigated using quantitative cytochrome oxidase histochemistry. The results indicated that congenitally helpless rats had 64-71% elevated metabolism in the habenula and a 25% elevation in the related interpeduncular nucleus. In contrast, helpless rats had 28% reduced metabolism in the ventral tegmental area (VTA) and 14-16% reductions in the basal ganglia and basolateral and central amygdala. The opposite metabolic changes in the habenula and ventral tegmental area may be especially important for determining the congenitally helpless rat's global pattern of brain activity, which resembles the metabolic activity pattern produced by dopamine antagonism.
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PMID:Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior. 1256 Jan 33


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