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)

Previous studies addressing the role of the transcription factor cAMP response element-binding protein (CREB) in mammalian long-term synaptic plasticity and memory by gene targeting were compromised by incomplete deletion of the CREB isoforms. Therefore, we generated conditional knock-out strains with a marked reduction or complete deletion of all CREB isoforms in the hippocampus. In these strains, no deficits could be detected in lasting forms of hippocampal long-term potentiation (LTP) and long-term depression (LTD). When tested for hippocampus-dependent learning, mutants showed normal context-dependent fear conditioning. Water maze learning was impaired during the early stages, but many mutants showed satisfactory scores in probe trials thought to measure hippocampus-dependent spatial memory. However, conditioned taste aversion learning, a putatively hippocampus-independent memory test, was markedly impaired. Our data indicate that in the adult mouse brain, loss of CREB neither prevents learning nor substantially affects performance in some hippocampus-dependent tasks. Furthermore, it spares LTP and LTD in paradigms that are sensitive enough to detect deficits in other mutants. This implies either a species-specific or regionally restricted role of CREB in the brain and/or a compensatory upregulation of the cAMP response element modulator (CREM) and other as yet unidentified transcription factors.
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PMID:Does cAMP response element-binding protein have a pivotal role in hippocampal synaptic plasticity and hippocampus-dependent memory? 1286 15

The present study examined the activities of adenylyl cyclase (AC) and rolipram-sensitive phosphodiesterase (PDE4) on brain regions in learned helplessness rat in order to clarify the cyclic AMP (cAMP) regulation system in the depressive state. Rats exposed to inescapable footshocks once a day for 3 days exhibited a significant increase in escape failure on Day 1 (the day after the last inescapable shock day) and Day 7. The plasma corticosterone level in rats subjected to inescapable shocks was significantly higher than that of nonstressed control rats on Days 1 and 7. The PDE4 activity of the frontal cortex was significantly lower than that of nonstressed control rats on Day 1. However, on Day 7, the PDE4 and [3H]-rolipram binding activities were significantly increased in the frontal cortex and hippocampus of learned helplessness rats compared with those of nonstressed control rats. Forskolin-stimulated AC activity was significantly decreased in the frontal cortex, hippocampus and striatum of learned helplessness rats on Day 1, but not on Day 7. Thus, a decrease in both AC and PDE4 activities was noted in the acute depressive state. In contrast, increase of PDE4 activity was noted in the delayed depressive phase, although no change of AC activity was observed. Gel shift assays also showed the decrease of cAMP-response element (CRE)-binding activity relating to cAMP activity in the frontal cortex and hippocampus of learned helplessness rats on Days 1 and 7. These findings indicated a delayed increase in PDE4 activity leading to hypofunction of the cAMP-dependent signal transduction system in the frontal cortex and hippocampus of learned helplessness rats, suggesting that up-regulation of the cAMP-degradation system by PDE4 may play a pivotal role in pathological states of chronic depression.
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PMID:Different regulation of adenylyl cyclase and rolipram-sensitive phosphodiesterase activity on the frontal cortex and hippocampus in learned helplessness rats. 1457 86

Corn steep water (CSW) and other byproducts derived from fermentations and sugar productions are presently forming the base of compositions for de-icing and anti-icing materials. Since the de-icing and anti-icing values are in part a colligative property, increase in the molar concentration of ionic species has been frequently necessary to decrease further the freezing point of this byproducts stream. In the present study this has been achieved by the generation of biodegradable organic acid salts in situ, without the use of chloride or other inorganic salts, by the alkaline degradation of reducing sugars added to corn steep water, which alone is not an efficient de-icer. Reducing sugars, such as glucose, react with alkali metal hydroxides to produce principally hydroxy carboxylic acids that react with the alkali metal hydroxide to form a mixture of organic acid salts. The ionic strength of the resulting solution is increased since each sugar molecule produces nearly two acid molecules upon degradation. The ionic strength necessary to achieve the desired freezing point depression is determined by the amount and concentration of the alkali metal hydroxide used, with the necessary counter anions being derived from the degradation of the reducing sugar. The amount of the sugar used is that required to result in a near to neutral final solution. The well-known anti-corrosive property of CSW is used in the de-icer preparations, either by conducting the alkaline degradation of the sugar in this medium, or by using water for the degradation of the sugar followed by dilution of the resulting solution with CSW to adjust the viscosity of the final solution to meet the requirements for spraying. The monovalent metal hydroxides are more efficient in producing de-icer solutions than the divalent metal hydroxides.
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PMID:De-icers derived from corn steep water. 1457 49

The brain cAMP regulating system and its downstream elements play a pivotal role in the therapeutic effects of antidepressants. We previously reported the increase in activities of phosphodiesterase 4, a major phosphodiesterase isozyme hydrolyzing cAMP, in the frontal cortex and hippocampus of learned helplessness rats, an animal model for depression. The present study was undertaken to examine the combination of effects of rolipram, a phosphodiesterase 4 inhibitor, with imipramine, a typical tricyclic antidepressant, on depressive behavior in learned helplessness rats. Concurrently, cAMP-response element (CRE)-binding activity and brain-derived neurotrophic factor (BDNF) levels related to the therapeutic effects of antidepressants were determined. Repeated administration of imipramine (1.25-10 mg/kg, i.p.) or rolipram (1.25 mg/kg, i.p.) reduced the number of escape failures in learned helplessness rats. Imipramine could not completely ameliorate the escape behavior to a level similar to that of non-stressed rats even at 10 mg/kg. However, repeated coadministration of rolipram with imipramine (1.25 and 2.5 mg/kg, respectively) almost completely eliminated the escape failures in learned helplessness rats. The reduction of CRE-binding activities and BDNF levels in the frontal cortex or hippocampus in learned helplessness rats were ameliorated by treatment with imipramine or rolipram alone. CRE-binding activities and/or BDNF levels of the frontal cortex and hippocampus were significantly increased by treatment with a combination of rolipram and imipramine compared to those in imipramine-treated rats. These results indicated that coadministration of phosphodiesterase type 4 inhibitors with antidepressants may be more effective for depression therapy and suggest that elevation of the cAMP signal transduction pathway is involved in the antidepressive effects.
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PMID:Effects of rolipram, a phosphodiesterase 4 inhibitor, in combination with imipramine on depressive behavior, CRE-binding activity and BDNF level in learned helplessness rats. 1536 87

Increasing evidences indicate the concurrence and interrelationship of depression and cognitive impairments. The present study was undertaken to investigate the effects of two depressive animal models, learned helplessness (LH) and chronic mild stress (CMS), on the cognitive functions of mice in the Morris water maze task. Our results demonstrated that both LH and CMS significantly decreased the cognitive performance of stressed mice in the water maze task. The escaping latency to the platform was prolonged and the probe test percentage in the platform quadrant was reduced. These two models also increased the plasma corticosterone concentration and decreased the brain derived neurotrophic factor (BDNF) and cAMP-response element-biding protein (CREB) messenger ribonucleic acid (mRNA) levels in hippocampus, which might cause the spatial cognition deficits. Repeated treatment with antidepressant drugs, imipramine (Imi) and fluoxetine (Flu), significantly reduced the plasma corticosterone concentration and enhanced the BDNF and CREB levels. Furthermore, antidepressant treated animals showed an ameliorated cognitive performance compared with the vehicle treated stressed animals. These data suggest that both LH and CMS impair the spatial cognitive function and repeated treatment with antidepressant drugs decreases the prevalence of cognitive impairments induced by these two animal models. Those might in part be attributed to the reduced plasma corticosterone and enhanced hippocampal BDNF and CREB expressions. This study provided a better understanding of molecular mechanisms underlying interactions of depression and cognitive impairments, although animal models used in this study can mimic only some aspects of depression or cognition of human.
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PMID:Impairment of the spatial learning and memory induced by learned helplessness and chronic mild stress. 1651 25

Sugar beet and sugar cane molasses have been shown to be suitable starting materials for producing de-icer preparations. The sucrose in the molasses is hydrolyzed to glucose and fructose by invertase. The reducing sugars are then degraded by NaOH, the alkali being neutralized by the sugar acids produced, resulting in an increase of the ionic strength and consequently depression of the freezing point of the resulting solution. For the preparation of de-icers, the desired freezing point depression to a temperature of less than about -20 degrees C can be achieved by adjusting the amount and concentration of the alkali metal hydroxide used. The resulting products are biodegradable and eliminate the corrosive effects associated with the use of conventional chloride salts. Degradation of invert sugar by NaOH has been achieved without an external heat source. The reaction products showed the same freezing point depression as seen in the degradation products from pure glucose.
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PMID:Alkaline degradation of invert sugar from molasses. 1722 51

In order to probe the nature and validity of olfactory bulbectomized (OB) rats as a model of depression, we reevaluated their behavioural and neurochemical deficits in relation to the symptoms and neurochemical abnormalities of depression using our protocols, which distinguish anhedonia-resembling behaviour in sexual behavioural test, the hippocampus (Hip)-dependent long-term memory and anxiety-resembling behaviour specially. Besides exploratory hyperactivity in response to a novel environmental stress resembling the psychomotor agitation, OB rats showed a decrease of libido, and a deficit of long-term explicit memory, resembling loss of interest and cognitive deficits in depressive patients, respectively. OB rats also exhibited the anxiety symptom-resembling behaviour in social interaction and plus-maze tests. In the OB rats, we found degenerated neurons in the piriform cortex, decreased protein expression of NMDA receptor subunit 1 (NR1), but not NR2A or NR2B, in the prefrontal cortex (PFC), Hip and amygdala (Amg), and decreased phosphorylation of cAMP-response element-binding protein (CREB) in the PFC and Hip, but not Amg. The behavioural and neurochemical abnormalities in OB rats, except for the performance in the plus-maze task and neuronal degeneration, were significantly attenuated by repeated treatment with desipramine (10 mg/kg), a typical antidepressant. The present study indicated that OB rats may be a model of depression with comorbid anxiety, characterized by agitation, sexual and cognitive dysfunction, neuronal degeneration, decreased protein expression of NR1, and decreased phosphorylation of CREB.
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PMID:Behavioural and neurochemical features of olfactory bulbectomized rats resembling depression with comorbid anxiety. 1726 34

Previous research has shown that cAMP response element (CRE) binding protein (CREB) in the nucleus accumbens gates behavioral responses to emotional stimuli. For example, overexpression of CREB decreases anxiety, sucrose preference, and sensitivity to drugs of abuse and increases depression-like behavior, whereas blocking CREB via overexpression of inducible cAMP early repressor (ICER) or other dominant-negative inhibitors of CRE-mediated transcription has the opposite effects. However, CREB and ICER are but two members of a larger family of leucine zipper-containing transcription factors composed of multiple products of the creb, crem (cAMP response element modulator), and atf (activating transcription factor) genes. We demonstrate here that ATF2, ATF3, and ATF4 are each robustly induced in the nucleus accumbens and dorsal striatum by restraint stress or by amphetamine administration. In contrast, little induction is seen for ATF1 or CREM. Using viral-mediated gene transfer, we show that ATF2 overexpression in nucleus accumbens produces increases in emotional reactivity and antidepressant-like responses, a behavioral phenotype similar to that caused by dominant-negative antagonists of CREB. In contrast, ATF3 or ATF4 overexpression in nucleus accumbens decreases emotional reactivity and increases depression-like behavior, consistent with the behavioral phenotype induced by CREB. Because amphetamine and stress induce ATF2, ATF3, and ATF4 in nucleus accumbens, and overexpression of these transcription factors in this brain region in turn alters behavioral responsiveness to amphetamine and stress, our findings support novel roles for these ATF family members in regulating emotional behavior.
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PMID:Induction of activating transcription factors (ATFs) ATF2, ATF3, and ATF4 in the nucleus accumbens and their regulation of emotional behavior. 1830 37

Hyperactivity of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN) of the hypothalamus is a prominent feature in depression and may be important in the etiology of this disease. The activity of the CRF neurons in the stress response is modulated by a number of factors that stimulate or inhibit CRF expression, including (1) corticosteroid receptors and their chaperones, heat shock proteins 70 and 90, (2) sex hormone receptors, (3) CRF receptors 1 (CRFR1) and 2, (4) cytokines interleukin 1-beta and tumor necrosis factor-alpha, (5) neuropeptides and receptors, vasopressin (AVP), AVP receptor 1a (AVPR1A) and oxytocin and (6) transcription factor cAMP-response element-binding protein. We hypothesized that, in depression, the transcript levels of those genes that are involved in the activation of the hypothalamo-pituitary-adrenal (HPA) axis are upregulated, whereas the transcript levels of the genes involved in the inhibition of the HPA axis are downregulated. We performed laser microdissection and real-time PCR in the PVN and as a control in the supraoptic nucleus. Snap-frozen post-mortem hypothalami of seven depressed and seven matched controls were used. We found significantly increased CRF mRNA levels in the PVN of the depressed patients. This was accompanied by a significantly increased expression of four genes that are involved in the activation of CRF neurons, that is, CRFR1, estrogen receptor-alpha, AVPR1A and mineralocorticoid receptor, while the expression of the androgen receptor mRNA involved in the inhibition of CRF neurons was decreased significantly. These findings raise the possibility that a disturbed balance in the production of receptors may contribute to the activation of the HPA axis in depression.
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PMID:Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances. 1860 75

G protein-activated K+ channel 2 (GIRK2) and cAMP-response element binding protein (CREB1) are involved in synaptic plasticity and their genes have been implicated depression and memory processing. Excessive rumination is a core cognitive feature of depression which is also present in remission. High scores on the Ruminative Response Scale (RRS) questionnaire are predictive of relapse and recurrence. Since rumination involves memory, we tested the hypothesis that variation in the genes encoding GIRK2 (KCNJ6) and CREB1 mechanisms would influence RRS scores. GIRK2 and CREB1 polymorphisms were studied in two independent samples (n=651 and n=1174) from the general population. Strongly significant interaction between the TT genotype of rs2070995 (located in KCNJ6) and the GG genotype of rs2253206 (located in CREB1) on RRS were found in both samples. These results were validated in an independent third sample (n=565; individuals with personality disorders) showing significant main effect of the variants mentioned as well as significant interaction on a categorical diagnosis of Cluster C personality disorder (obsessional-compulsive, avoidant and dependent) in which rumination is a prominent feature. Our results suggest that genetic epistasis in post-receptor signaling pathways in memory systems may have relevance for depression and its treatment.
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PMID:Epistatic interaction of CREB1 and KCNJ6 on rumination and negative emotionality. 2094 50


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