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)

Neurotrophins have been suggested to act as liaison molecules between activity-dependent synaptic plasticity and the establishment of patterns of synaptic connectivity during postnatal developmental in different brain areas, including the visual cortex. In particular, recent studies have shown that Trk B ligands are involved in the formation of the ocular dominance columns during postnatal development. Here, we examined the contribution of endogenous Trk B activation to the regulation of different forms of synaptic plasticity including long-term potentiation (LTP), long-term depression (LTD) and LTP after LTD in the developing visual cortex. Rat cortical slices were incubated with a soluble form of Trk B receptor (TrkB IgG) preventing Trk B activation by endogenous ligands. LTP expression was also studied at P23 (postnatal), when the expression of brain-derived neurotrophic factor (BDNF) reaches a peak and the LTP expression is normally downregulated. The present results demonstrate that Trk B activation is required for the long-term maintenance, > 30 min, of both LTP and LTP after LTD at P17. At P23, a higher concentration of TrkB IgG was necessary to impair LTP. In contrast, neither amplitude nor duration of LTD were affected by Trk B ligands blockade. Taken together, these results indicate that endogenous Trk B ligands are necessary for the expression of LTP but not LTD at a critical time during postnatal cortical development.
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PMID:Trk B signalling controls LTP but not LTD expression in the developing rat visual cortex. 1076 69

Antidepressant drugs as well as electroconvulsive stimuli can significantly influence brain concentrations of neurotrophic factors. However, it is not known whether the baseline brain concentrations of neurotrophic factors are altered in human subjects suffering from affective disorders or whether there are sex differences in concentrations of neurotrophins in human brain. In order to elucidate some of these questions, we measured by ELISA brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in an animal model of depression, the Flinders Sensitive Line (FSL) rats and their controls, the Flinders Resistant Line (FRL). Altered BDNF and NGF concentrations were found in frontal cortex, occipital cortex, and hypothalamus of depressed FSL compared to FRL control rats. Furthermore, different levels of these neurotrophins were also found in the male and female brain. Cumulatively these observations suggest that BDNF and NGF may play a role in depression and, hypothetically, different brain regional concentrations of BDNF and NGF in male and female animals may be relevant to gender differences in vulnerability to depression.
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PMID:Mapping the differences in the brain concentration of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in an animal model of depression. 1081 24

A prolonged period (48 h) of cortical spreading depression (CSD) induced resistance against severe focal cerebral ischemia (infarct tolerance), however, the mechanism behind this is unknown. The infarct tolerance was a transient phenomenon; the resistance increased linearly for the initial 12 days, peaking from 12 to 15 days after a preconditioning of CSD, and was decreased thereafter. This study examined the time course of brain-derived neurotrophic factor (BDNF), heat shock protein (hsp)27 and 70, and glial fibrillary acidic protein (GFAP) expressions after CSD in the brain. Immunohistochemical expression of BDNF, hsp27, hsp70, or GFAP following a prolonged period of CSD induced by KCl-infusion, or following NaCl-infusion was analyzed by regional densitometry for 24 days in the rat neocortex. In addition, BDNF protein was measured quantitatively by two-site ELISA assay in the neocortex (n=6 at each time point). The GFAP expression was elevated in astrocytes (compared to the normal level of immunodensity) during the period peaking on day 3-6 following the CSD. The hsp27 immunoreactivity was also elevated in astrocytes from day 1 to 12 peaking on day 1 and 6, but there was no expression of hsp70 during the period following CSD. The immunoreactivity for BDNF was elevated in neurons from day 0 to 18 peaking on day 1 and 6. The protein levels of BDNF in the neocortex were significantly elevated from day 0 to 12 peaking on days 0 and 6 (compared to the normal level) (P<0.05). Using a laser-scanning confocal imaging system, the BDNF-like immunoreactivity in neuronal nuclei was found to increase linearly peaking on day 12, which correlated well with the development of infarct tolerance. The intranuclear increase in BDNF-like protein might contribute to the induction of infarct tolerance in the brain.
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PMID:Infarct tolerance accompanied enhanced BDNF-like immunoreactivity in neuronal nuclei. 1098 48

The cachexia-anorexia syndrome occurs in chronic pathophysiologic processes including cancer, infection with human immunodeficiency virus, bacterial and parasitic diseases, inflammatory bowel disease, liver disease, obstructive pulmonary disease, cardiovascular disease, and rheumatoid arthritis. Cachexia makes an organism susceptible to secondary pathologies and can result in death. Cachexia-anorexia may result from pain, depression or anxiety, hypogeusia and hyposmia, taste and food aversions, chronic nausea, vomiting, early satiety, malfunction of the gastrointestinal system (delayed digestion, malabsorption, gastric stasis and associated delayed emptying, and/or atrophic changes of the mucosa), metabolic shifts, cytokine action, production of substances by tumor cells, and/or iatrogenic causes such as chemotherapy and radiotherapy. The cachexia-anorexia syndrome also involves metabolic and immune changes (mediated by either the pathophysiologic process, i.e., tumor, or host-derived chemical factors, e.g., peptides, neurotransmitters, cytokines, and lipid-mobilizing factors) and is associated with hypertriacylglycerolemia, lipolysis, and acceleration of protein turnover. These changes result in the loss of fat mass and body protein. Increased resting energy expenditure in weight-losing cachectic patients can occur despite the reduced dietary intake, indicating a systemic dysregulation of host metabolism. During cachexia, the organism is maintained in a constant negative energy balance. This can rarely be explained by the actual energy and substrate demands by tumors in patients with cancer. Overall, the cachectic profile is significantly different than that observed during starvation. Cachexia may result not only from anorexia and a decreased caloric intake but also from malabsorption and losses from the body (ulcers, hemorrhage, effusions). In any case, the major deficit of a cachectic organism is a negative energy balance. Cytokines are proposed to participate in the development and/or progression of cachexia-anorexia; interleukin-1, interleukin-6 (and its subfamily members such as ciliary neurotrophic factor and leukemia inhibitory factor), interferon-gamma, tumor necrosis factor-alpha, and brain-derived neurotrophic factor have been associated with various cachectic conditions. Controversy has focused on the requirement of increased cytokine concentrations in the circulation or other body fluids (e.g., cerebrospinal fluid) to demonstrate cytokine involvement in cachexia-anorexia. Cytokines, however, also act in paracrine, autocrine, and intracrine manners, activities that cannot be detected in the circulation. In fact, paracrine interactions represent a predominant cytokine mode of action within organs, including the brain. Data show that cytokines may be involved in cachectic-anorectic processes by being produced and by acting locally in specific brain regions. Brain synthesis of cytokines has been shown in peripheral models of cancer, peripheral inflammation, and during peripheral cytokine administration; these data support a role for brain cytokines as mediators of neurologic and neuropsychiatric manifestations of disease and in the brain-to-peripheral communication (e.g., through the autonomic nervous system). Brain mechanisms that merit significant attention in the cachexia-anorexia syndrome are those that result from interactions among cytokines, peptides/neuropeptides, and neurotransmitters. These interactions could result in additive, synergistic, or antagonistic activities and can involve modifications of transducing molecules and intracellular mediators. Thus, the data show that the cachexia-anorexia syndrome is multifactorial, and understanding the interactions between peripheral and brain mechanisms is pivotal to characterizing the underlying integrative pathophysiology of this disorder.
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PMID:Central nervous system mechanisms contributing to the cachexia-anorexia syndrome. 1105 8

Brain-derived neurotrophic factor, the most abundant of the neurotrophins in the brain, enhances the growth and maintenance of several neuronal systems, serves as a neurotransmitter modulator, and participates in use-dependent plasticity mechanisms such as long-term potentiation and learning. In recent years, evidence has been gathering that brain-derived neurotrophic factor may have an important role in the neuropathology and treatment of depression. It has recently been reported that chronic (at least two weeks) antidepressant treatment leads to an up-regulation of brain-derived neurotrophic factor messenger RNA levels in the hippocampus, an important brain area for behavioral regulation, as well as learning and memory. Our laboratory has previously shown that general physical exercise very rapidly increases brain-derived neurotrophic factor messenger RNA in this brain area. In this report, we have tested the hypothesis that the combination of these two interventions, general physical activity and antidepressant treatment, leads to increased levels of specific promoter-derived transcripts of brain-derived neurotrophic factor messenger RNA in a manner that appears to be both additive and accelerated. Our results suggest that these two very different interventions may possibly converge at the cellular level. The induction of brain-derived neurotrophic factor expression by activity/pharmacological treatment combinations could represent an important intervention for further study, to potentially improve depression treatment and management.
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PMID:Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. 1107 54

The aim of this study was to explore the role of endogenous neurotrophins for inhibitory synaptic transmission in the dentate gyrus of adult mice. Heterozygous knockout (+/-) mice or neurotrophin scavenging proteins were used to reduce the levels of endogenous brain-derived neurotrophic factor and neurotrophin-3. Patch-clamp recordings from dentate granule cells in brain slices showed that the frequency, but not the kinetics or amplitude, of miniature inhibitory postsynaptic currents was modulated in brain-derived neurotrophic factor +/- compared to wild-type (+/+) mice. Furthermore, paired-pulse depression of evoked inhibitory synaptic responses was increased in brain-derived neurotrophic factor +/- mice. Similar results were obtained in brain slices from brain-derived neurotrophic factor +/+ mice incubated with tyrosine receptor kinase B-immunoglobulin G, which scavenges endogenous brain-derived neurotrophic factor. The increased inhibitory synaptic activity in brain-derived neurotrophic factor +/- mice was accompanied by decreased excitability of the granule cells. No differences in the frequency, amplitude or kinetics of miniature inhibitory postsynaptic currents were seen between neurotrophin-3 +/- and +/+ mice. From these results we suggest that endogenous brain-derived neurotrophic factor, but not neurotrophin-3, has acute modulatory effects on synaptic inhibition onto dentate granule cells. The site of action seems to be located presynaptically, i.e. brain-derived neurotrophic factor regulates the properties of inhibitory interneurons, leading to increased excitability of dentate granule cells. We propose that through this mechanism, brain-derived neurotrophic factor can change the gating/filtering properties of the dentate gyrus for incoming information from the entorhinal cortex to hippocampus. This will have consequences for the recruitment of hippocampal neural circuitries both under physiological and pathological conditions, such as epileptogenesis.
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PMID:Increased synaptic inhibition in dentate gyrus of mice with reduced levels of endogenous brain-derived neurotrophic factor. 1111 2

As a testable heuristic, the concept of stress response and adaptation is highly appealing, and the support for the concept is strong. This explanatory model of depression may account for hitherto apparently discordant facts--contradictory symptoms, antidepressant drugs that act on differing systems, facilitation of antidepressant response by augmentation, and response to psychotherapy and pharmacotherapy. This article has focused narrowly on specific cellular elements of the stress-adaptational mechanisms, including the AC-PKA and PLC-PKC transductional cascades, together with specific response elements, such as the HPA axis, BDNF, and NMDA receptors; however, other important mechanisms, including specific receptor subtypes (e.g., 5-HT1A and NE alpha 2), transmitter systems (e.g., acetylcholine and depamine), and hormones (e.g., thyroid and growth hormones and prolactin), which may be important, have not been discussed. As the complex interactions of these systems gradually yield to investigation, not only will new treatments be developed, but better matching of treatment to patient may become an achievable goal.
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PMID:Cellular mechanisms in the vulnerability to depression and response to antidepressants. 1114 43

The mechanism of antidepressant action, at the cellular level, is not clearly understood. It has been reported that chronic antidepressant treatment leads to an up-regulation of brain-derived neurotrophic factor (BDNF) mRNA levels in the hippocampus, and that physical activity (voluntary running) enhances this effect. We wished to investigate whether BDNF expression brought about by these interventions may overcome deficits caused by acute stress, and might impact behavior in an animal model. In this report, we have tested the hypothesis that the combination of the antidepressant, tranylcypromine, and physical exercise could lead to decreased neurotrophin deficits and enhanced swimming time in animals that have been forced to swim in an inescapable water tank. Rats were either treated with tranylcypromine, engaged in voluntary running, or both for one week. After these treatments, the animals underwent a two-day forced swimming procedure. BDNF mRNA levels were significantly depressed in untreated animals subjected to forced swimming. Animals that either underwent prior activity or received antidepressant showed BDNF mRNA levels restored to baseline. Animals receiving the combined intervention showed an increase in hippocampal BDNF mRNA well above baseline. Swimming time during a five-minute test was significantly enhanced in animals receiving the combined intervention over untreated animals. Swimming time was not significantly enhanced over that of animals receiving antidepressant alone, however. Enhanced swimming time correlated with increased levels of BDNF mRNA in one hippocampal sub-region (CA4-hilus). These results suggest that the combination of exercise and antidepressant treatment may have significant neurochemical, and possibly behavioral, effects. In addition, these results support the possibility that the enhancement of BDNF expression may be an important element in the clinical response to antidepressant treatment. The induction of BDNF expression by activity/pharmacological treatment combinations could represent an important intervention for further study, to potentially improve depression treatment and management.
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PMID:Physical activity-antidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model. 1117 88

Recent evidence suggests hippocampal and possibly cortical atrophy is associated with major depression. Chronic electroconvulsive seizures (ECS) induce brain-derived neurotrophic factor (BDNF) expression and sprouting of the mossy fiber pathway in the hippocampus, effects that may be related to electroconvulsive therapy's (ECT) mechanism of action. The objective of this study was to investigate the role of NMDA (N-methyl-D-aspartate) receptor in mediating the ECS-induced mossy fiber sprouting and BDNF expression. Timm histochemistry and in situ hybridization methodologies were used to determine the effect of pretreatment with ketamine, an NMDA antagonist, on ECS-induced sprouting and BDNF expression. The results demonstrate the ability of ketamine pretreatment to attenuate ECS-induced sprouting in the dentate gyrus and BDNF expression in the medial prefrontal cortex and the dentate gyrus. In addition, we found a significant decrease in seizure duration with ketamine pretreatment. These data suggest that NMDA receptor activation contributes to both the regulation of neurotrophic factor expression and the morphological changes associated with seizure activity. However, other effects resulting from shortened seizure duration and seizure intensity cannot be excluded. These findings are of increasing interest, as they relate to the use of ECT in the treatment of depression, and the specific anesthetic agents that are used.
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PMID:ECS-Induced mossy fiber sprouting and BDNF expression are attenuated by ketamine pretreatment. 1128 11

Previous studies have demonstrated that cortical spreading depression (CSD) increases the expression of putative neuroprotective proteins. The objective of the present study was to elucidate the relationship between the number of episodes of CSD and steady-state levels of mRNAs encoding brain-derived neurotrophic factor (BDNF), heat-shock protein-72 (hsp72) and c-fos. Wistar rats were administered one, five, or twenty-five episodes of CSD evoked by application of 2 M KCl to the frontal cortex of one hemisphere. Animals were permitted to recover for 30 min, 2 h or 24 h prior to sacrifice. Total RNA was isolated from the parietal cortex of each hemisphere and analyzed using Northern blots. At 30 min recovery, levels of BDNF mRNA were not significantly elevated after 1 episode of CSD, but were increased 4-fold after five episodes of CSD and 11-fold after twenty-five episodes of CSD, relative to levels in the contralateral hemisphere. At 2 h recovery, BDNF mRNA levels increased 2-, 3- and 9-fold, respectively. At 24 h, BDNF mRNA had returned to control levels in all groups. Thus, CSD increased levels of BDNF mRNA in a dose-dependent fashion at the early recovery times. Hsp72 mRNA was below the level of detection after 1 and 5 episodes of CSD. However, after twenty-five episodes of CSD, hsp72 mRNA levels were increased in the ipsilateral hemisphere at 30 min and 2 h recovery. Unlike levels of BDNF and hsp72 mRNA, levels of c-fos mRNA were increased nearly to the same extent at 30 min and 2 h after one, five or twenty-five episodes of CSD before returning to control by 24 h recovery. These results demonstrate that CSD triggers a dose-dependent increase in the expression of genes encoding neuroprotective proteins, which may mediate tolerance to ischemia induced by CSD.
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PMID:Dose-dependent induction of mRNAs encoding brain-derived neurotrophic factor and heat-shock protein-72 after cortical spreading depression in the rat. 1129 36


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