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)

It has recently been reported that Parkinson's disease (PD) is preceded and accompanied by daytime sleep attacks, nocturnal insomnia, REM sleep behaviour disorder, hallucinations and depression, symptoms which are frequently as troublesome as the motor symptoms of PD. All these symptoms are present in narcolepsy, which is linked to a selective loss of hypocretin (Hcrt) neurons. In this study, the Hcrt system was examined to determine if Hcrt cells are damaged in PD. The hypothalamus of 11 PD (mean age 79 +/- 4) and 5 normal (mean age 77 +/- 3) brains was examined. Sections were immunostained for Hcrt-1, melanin concentrating hormone (MCH) and alpha synuclein and glial fibrillary acidic protein (GFAP). The substantia nigra of 10 PD brains and 7 normal brains were used for a study of neuromelanin pigmented cell loss. The severity of PD was assessed using the Hoehn and Yahr scale and the level of neuropathology was assessed using the Braak staging criteria. Cell number, distribution and size were determined with stereologic techniques on a one in eight series. We found an increasing loss of hypocretin cells with disease progression. Similarly, there was an increased loss of MCH cells with disease severity. Hcrt and MCH cells were lost throughout the anterior to posterior extent of their hypothalamic distributions. The percentage loss of Hcrt cells was minimal in stage I (23%) and was maximal in stage V (62%). Similarly, the percentage loss of MCH cells was lowest in stage I (12%) and was highest in stage V (74%). There was a significant increase (P = 0.0006, t = 4.25, df = 15) in the size of neuromelanin containing cells in PD patients, but no difference in the size of surviving Hcrt (P = 0.18, t = 1.39, df = 14) and MCH (P = 0.28, t = 1.39, df = 14) cells relative to controls. In summary, we found that PD is characterized by a massive loss of Hcrt neurons. Thus, the loss of Hcrt cells may be a cause of the narcolepsy-like symptoms of PD and may be ameliorated by treatments aimed at reversing the Hcrt deficit. We also saw a substantial loss of hypothalamic MCH neurons. The losses of Hcrt and MCH neurons are significantly correlated with the clinical stage of PD, not disease duration, whereas the loss of neuromelanin cells is significantly correlated only with disease duration. The significant correlations that we found between the loss of Hcrt and MCH neurons and the clinical stage of PD, in contrast to the lack of a relationship of similar strength between loss of neuromelanin containing cells and the clinical symptoms of PD, suggests a previously unappreciated relationship between hypothalamic dysfunction and the time course of the overall clinical picture of PD.
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PMID:Hypocretin (orexin) cell loss in Parkinson's disease. 1789 5

Recent research has changed the perception of glia from being no more than silent supportive cells of neurons to being dynamic partners participating in brain metabolism and communication between neurons. This discovery of new glial functions coincides with growing evidence of the involvement of glia in the neuropathology of mood disorders. Unanticipated reductions in the density and number of glial cells are reported in fronto-limbic brain regions in major depression and bipolar illness. Moreover, age-dependent decreases in the density of glial fibrillary acidic protein (GFAP) - immunoreactive astrocytes and levels of GFAP protein are observed in the prefrontal cortex of younger depressed subjects. Since astrocytes participate in the uptake, metabolism and recycling of glutamate, we hypothesize that an astrocytic deficit may account for the alterations in glutamate/GABA neurotransmission in depression. Reductions in the density and ultrastructure of oligodendrocytes are also detected in the prefrontal cortex and amygdala in depression. Pathological changes in oligodendrocytes may be relevant to the disruption of white matter tracts in mood disorders reported by diffusion tensor imaging. Factors such as stress, excess of glucocorticoids, altered gene expression of neurotrophic factors and glial transporters, and changes in extracellular levels of neurotransmitters released by neurons may modify glial cell number and affect the neurophysiology of depression. Therefore, we will explore the role of these events in the possible alteration of glial number and activity, and the capacity of glia as a promising new target for therapeutic medications. Finally, we will consider the temporal relationship between glial and neuronal cell pathology in depression.
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PMID:Gliogenesis and glial pathology in depression. 1751 18

Long-term bilateral common carotid occlusion (BCCAO) in rats induces brain hypoperfusion and structural injury, and could have relevance as a model of vascular dementia in which cortical metabolism is reduced. The present study was designed to assess whether phosphate-related energy compounds and blood supplies are markedly affected by KCI-induced cortical spreading depression (CSD), which leads to metabolic and cerebral blood flow changes in rats with chronic BCCAO, by means of near-infrared spectroscopy and phosphorus magnetic resonance spectroscopy. Male Wistar rats were divided into 4 groups: BCCAO for 1 week (n = 6) and 4 weeks (n = 15), and sham operation for 1 week (n = 7) and 4 weeks (n = 7). The phosphocreatine (Pcr) index (PCr/PCr+Pi) and intracellular pH (pHi) were measured pre-CSD, just after KCl application, and at 20 and 40 minutes after CSD. Brains were evaluated by histology with hematoxylin and eosin and immunohistochemical reaction for glial fibrillary acidic protein (GFAP). Rapid signal changes of oxy-, deoxy-, and total hemoglobin were observed in all KCl-applied brains. The PCr index and pHi values in BCCAO were not different than those in control rats. The percentage of vacuolated area in the optic tract and percentage values of GFAP-positive area in the frontoparietal cortex were significantly increased in BCCAO. The generation of CSD was seen in regions of cortical gliosis induced by BCCAO, and severe energy exhaustion did not occur during or after CSD. Our results may suggest that the functional interaction of neurons and glia is sustained even in brain tissue where the metabolic state of neurons is impaired and astrocytes are proliferated.
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PMID:Phosphate-related energy compounds are not exhausted in chronically hypoperfused rat brain cortex after cortical spreading depression. 1790 87

We aimed to test the feasibility of detecting gliosis in living brains when the blood-brain barrier (BBB) is disrupted. We designed a novel magnetic resonance (MR) probe that contains superparamagnetic iron oxide nanoparticles (SPION, a T2 susceptibility contrast agent) linked to a short DNA sequence complementary to the cerebral mRNA of glial fibrillary acidic protein (GFAP) found in glia and astrocytes. As a control, we also used a sequence complementary to the mRNA of beta-actin. Our objectives are to demonstrate that this new probe, SPION-gfap, could be delivered to the brain when administered by eyedrop solution to the conjunctival sac. We induced BBB leakage by puncture wound, global cerebral ischemia, and cortical spreading depression in C57BL6 mice; 1 day after probe delivery we acquired T2* MR images and R2* (R2* = 1/T2*) maps using a transcription MRI technique in live mice. We found that the SPION-gfap probe reported foci with elevated signal in subtraction R2* maps and that these foci matched areas identified as having extensive glial network (gliosis) in postmortem immunohistochemistry. Similarly, animals administered the control probe exhibited foci of R2* elevation that matched beta-actin-expressing endothelia in the vascular wall. We conclude that our modular MR probe, delivered in an eyedrop solution, effectively reports gliosis associated with acute neurological disorders in living animals. As BBB leakage is often observed in acute neurological disorders, this study also served to validate noninvasive delivery of MR probes to the brains of live animals after acute neurological disorders.
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PMID:Noninvasive delivery of gene targeting probes to live brains for transcription MRI. 1802 47

A growing body of evidence from human postmortem and animal studies suggests that deficits in glial cell (particularly astrocytes) density and function, in limbic regions of the brain contribute to the etiology of depressive disorders. Despite the widespread use of Wistar-Kyoto (WKY) rat strain as a model of depression and stress susceptibility, there is a paucity of data examining whether alterations in brain astrocytic population are present in the model. In the present study, we investigated the expression of the astrocytic markers glial fibrillary acidic protein (GFAP) in various brain regions in WKY rats in comparison to Sprague-Dawley rats. A significant deficit in GFAP-immunoreactive cells was found in the prefrontal cortex region (infralimbic, prelimbic and anterior cingulate cortex), in the basolateral amygdala as well as in the hippocampus (CA3 and dentate gyrus) in WKY rat brain. No statistical difference was found in the other brain regions analyzed (insular cortex, somatosensory cortex, CA1 and callosal white matter). No difference was found in the total density of astrocytes (assessed by s-100beta immunoreactivity), neurons (determined by NeuN expression) or in the total number of cells in the regions of interest. A slight increase in the intensity of s-100beta immunoreactivity was observed. The lower expression of GFAP in WKY rats was further confirmed by Western-blot analysis. These results suggest that specific astrocytic deficits in GFAP expression in corticolimbic circuits may be a general correlate of depressive-like behavior in animal models in addition to human major depression. Moreover, they suggest that glial physiology may become a therapeutic target in depression and other stress-related conditions.
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PMID:Region specific decrease in glial fibrillary acidic protein immunoreactivity in the brain of a rat model of depression. 1900 Jul 45

Hepatitis C virus (HCV) infection often is associated with cognitive dysfunction and depression. HCV sequences and replicative forms were detected in autopsy brain tissue and cerebrospinal fluid from infected patients, suggesting direct neuroinvasion. However, the phenotype of cells harboring HCV in brain remains unclear. We studied autopsy brain tissue from 12 HCV-infected patients, 6 of whom were coinfected with human immunodeficiency virus. Cryostat sections of frontal cortex and subcortical white matter were stained with monoclonal antibodies specific for microglia/macrophages (CD68), oligodendrocytes (2',3'-cyclic nucleotide 3'-phosphodiesterase), astrocytes (glial fibrillary acidic protein [GFAP]), and neurons (neuronal-specific nuclear protein); separated by laser capture microscopy (LCM); and tested for the presence of positive- and negative-strand HCV RNA. Sections also were stained with antibodies to viral nonstructural protein 3 (NS3), separated by LCM, and phenotyped by real-time PCR. Finally, sections were double stained with antibodies specific for the cell phenotype and HCV NS3. HCV RNA was detected in CD68-positive cells in eight patients, and negative-strand HCV RNA, which is a viral replicative form, was found in three of these patients. HCV RNA also was found in astrocytes from three patients, but negative-strand RNA was not detected in these cells. In double immunostaining, 83 to 95% of cells positive for HCV NS3 also were CD68 positive, while 4 to 29% were GFAP positive. NS3-positive cells were negative for neuron and oligodendrocyte phenotypic markers. In conclusion, HCV infects brain microglia/macrophages and, to a lesser extent, astrocytes. Our findings could explain the biological basis of neurocognitive abnormalities in HCV infection.
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PMID:Hepatitis C virus neuroinvasion: identification of infected cells. 1901 68

We have previously reported that dietary tryptophan (TRP) restriction in a rat crucial postnatal developmental stage induces depression-like behavior and alters dendritic spine density in CA1 pyramidal neurons and granule cells of the hippocampus. Due to astrocyte involvement in critical brain mechanisms, it seems worth to investigate possible adaptive changes in the glial population with TRP restriction. Experimental rats were fed with low TRP diet (20% of TRP level of the laboratory rat chow) from postnatal days 30-60. Antibody against glial fibrillary acidic protein (GFAP), a principal intermediate filament in astrocytes, was used to evaluate cytoskeletal hypertrophy and glial proliferation. Our results showed an increase in size and branching of GFAP-immunoreactive (IR) cells in the dorsal hippocampus and amygdala, characteristics of an astrocytic activation. No significant differences were found regarding the number of GFAP-IR cells in both regions. These results indicate that dietary TRP restriction can induce astrocytic activation, hence, provide further evidences supporting the hypothesis that serotonin may also modulate glial morphology.
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PMID:Dietary tryptophan restriction in rats triggers astrocyte cytoskeletal hypertrophy in hippocampus and amygdala. 1909 41

Recent experimental studies in rodents suggest that treatment with inhibitors of phosphodiesterase type 5 (PDE5) (tadalafil, sildenafil, zaprinast) not only increases cerebral blood flow but also improves functional recovery after stroke. Here, we investigated in a mouse model of stroke the effects of vardenafil on survival, functional outcome and lesion size after experimental stroke. Mice were subjected to experimental stroke by occlusion of the middle cerebral artery (MCAO) for 45 min. A group of mice received vardenafil (twice 10 mg/kg body weight per day orally over 14 days) starting 3 h after MCAO. Control animals received the vehicle only. Survival, body weight, and behavior were monitored over 4 weeks and brain lesions were measured by T2-weighted MRI, hematoxylin/eosin -- as well as GFAP-staining of cryostat sections, subsequently. The mortality in MCAO-operated animals amounted to 45% until day 10 after stroke and no significant difference in survival between the vardenafil- and vehicle-treatment groups was observed. Compared to sham-operated animals, MCAO-operated mice from both treatment groups demonstrated a significant weight loss until day 5 and regained their body weight by day 14 after ischemia. There was no significant difference between the vardenafil and vehicle-treated MCAO groups. In behavioral studies (sucrose consumption and pole test), analyzing sensorimotor functions as well as a parameter of depression-like symptoms, we observed no significant effect of vardenafil treatment on functional recovery in our model of stroke. Although we observed a trend towards less hemispherical atrophy in the vardenafil compared to the vehicle-treated group four weeks after MCAO our data do not suggest a functionally relevant CNS-tissue protective or regenerative effect in murine stroke.
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PMID:Effects of the PDE5-inhibitor vardenafil in a mouse stroke model. 1936 9

The physiological link between neuropathic pain and depression remains unknown despite a high comorbidity between these two disorders. A mouse model of spared nerve injury (SNI) was used to test the hypothesis that nerve injury precipitates depression through the induction of inflammation in the brain, and that prior exposure to stress exacerbates the behavioral and neuroinflammatory consequences of nerve injury. As compared with sham surgery, SNI induced mechanical allodynia, and significantly increased depressive-like behavior. Moreover, SNI animals displayed increased interleukin-1beta (IL-1beta) gene expression within the frontal cortex and concurrent increases in the expression of glial fibrillary acidic protein (GFAP) within the periaqueductal grey (PAG). Additionally, exposure to chronic restraint stress for 2 weeks before SNI exacerbated mechanical allodynia and depressive-like behavior, and resulted in an increase in IL-1beta gene expression in the frontal cortex and brain-derived neurotrophic factor (BDNF) gene expression in PAG. Treatment with metyrapone (MET), a corticosteroid synthesis inhibitor, before stress eliminated deleterious effects of chronic stress on SNI. Finally, this study showed that interference with IL-1beta signaling, through administration of IL-1 receptor antagonist (IL-1ra), ameliorated the effects of neuropathic pain on depressive-like behavior. Taken together, these data suggest that peripheral nerve injury leads to increased cytokine expression in the brain, which in turn, contributes to the development of depressive-like behavior. Furthermore, stress can facilitate the development of depressive-like behavior after nerve injury by promoting IL-1beta expression.
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PMID:Stress and IL-1beta contribute to the development of depressive-like behavior following peripheral nerve injury. 1977 12

Ferulic acid (4-hydroxy-3-methoxycinnamic acid; FA) is a plant constituent and is contained in several medicinal plants for clinical use. In this paper, we investigated the effects of FA on the proliferation of neural stem/progenitor cells (NSC/NPCs) in vitro and in vivo. FA significantly increased the proliferation of NSC/NPCs cultured from the telencephalon of embryonic day-14 rats, and increased the number and size of secondary formed neurospheres. An in vitro differentiation assay showed that FA did not affect the percentage of either neuron-specific class III beta-tubulin (Tuj-1)-positive cells or glial fibrillary acidic protein (GFAP)-positive cells in the total cell population. Oral administration of FA increased the number of newly generated cells in the dentate gyrus (DG) of the hippocampus of corticosterone (CORT)-treated mice, indicating that FA enhances the proliferation of adult NSC/NPCs in vivo. We also found that oral administration of FA increased cAMP response element binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) mRNA level in the hippocampus of CORT-treated mice, and ameliorated the stress-induced depression-like behavior of mice. These novel pharmacological effects of FA may be useful for the treatment of mood disorders such as depression.
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PMID:Ferulic acid induces neural progenitor cell proliferation in vitro and in vivo. 1983 39


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