UMLS:C0036341 - FACTA Search

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology as well as treatment outcome of schizophrenia. Rodent studies indicate that several antipsychotic drugs have time-dependent (and differential) effects on BDNF levels in the brain. Earlier studies from our laboratory have indicated that long-term treatment with haloperidol (HAL) decreases BDNF, reduced GSH and anti-apoptotic marker, Bcl-xl protein levels and increases the expression of pro-apoptotic proteins in rat frontal cortex. Furthermore, findings from human as well as rodent studies suggest that treatment of schizophrenia must involve the neuroprotective strategies to improve the neuropathology and thereby clinical outcome. In the present study, we investigated the potential of cystamine (CYS), an anti-oxidant and anti-apoptotic compound, to prevent HAL-induced reduction in BDNF, GSH, and Bcl-xl protein levels in mice and the signaling mechanism(s) involved in the beneficial effects of CYS. The results indicated that CYS as well as cysteamine (the FDA-approved precursor of CYS) increased BDNF protein levels in mouse frontal cortex 7 days after treatment. CYS co-treatment prevented chronic HAL treatment-induced reduction in BDNF, GSH, and Bcl-xl protein levels. CYS treatment enhanced TrkB-tyrosine phosphorylation and activated Akt and extracellular signal-regulated kinase (ERK)1/2, downstream molecules of TrkB signaling. In addition, in vitro experiments with mouse cortical neurons showed that CYS prevented the HAL-induced reduction in neuronal cell viability and BDNF protein levels, and increase in apoptosis. BDNF-neutralizing antibody as well as K252a, a selective inhibitor of neurotrophin signaling blocked the CYS-mediated neuroprotection. Moreover, CYS-mediated neuroprotection is also blocked by LY294002, a phosphatidylinositol 3-kinase inhibitor or PD98059, a mitogen-activated protein kinase kinase (MEK) inhibitor. Thus, CYS protects cortical neurons through a mechanism involving TrkB receptor activation, and a signaling pathway involving phosphatidylinositol 3-kinase and MAPK. The findings from the present study may be helpful for the development of novel neuroprotective strategies to improve the treatment outcome of schizophrenia.
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PMID:Cystamine prevents haloperidol-induced decrease of BDNF/TrkB signaling in mouse frontal cortex. 1878 74

Gene expression changes in neuropsychiatric and neurodegenerative disorders, and gene responses to therapeutic drugs, provide new ways to identify central nervous system (CNS) targets for drug discovery. This review summarizes gene and pathway targets replicated in expression profiling of human postmortem brain, animal models, and cell culture studies. Analysis of isolated human neurons implicates targets for Alzheimer's disease and the cognitive decline associated with normal aging and mild cognitive impairment. In addition to tau, amyloid-beta precursor protein, and amyloid-beta peptides (Abeta), these targets include all three high-affinity neurotrophin receptors and the fibroblast growth factor (FGF) system, synapse markers, glutamate receptors (GluRs) and transporters, and dopamine (DA) receptors, particularly the D2 subtype. Gene-based candidates for Parkinson's disease (PD) include the ubiquitin-proteosome system, scavengers of reactive oxygen species, brain-derived neurotrophic factor (BDNF), its receptor, TrkB, and downstream target early growth response 1, Nurr-1, and signaling through protein kinase C and RAS pathways. Increasing variability and decreases in brain mRNA production from middle age to old age suggest that cognitive impairments during normal aging may be addressed by drugs that restore antioxidant, DNA repair, and synaptic functions including those of DA to levels of younger adults. Studies in schizophrenia identify robust decreases in genes for GABA function, including glutamic acid decarboxylase, HINT1, glutamate transport and GluRs, BDNF and TrkB, numerous 14-3-3 protein family members, and decreases in genes for CNS synaptic and metabolic functions, particularly glycolysis and ATP generation. Many of these metabolic genes are increased by insulin and muscarinic agonism, both of which are therapeutic in psychosis. Differential genomic signals are relatively sparse in bipolar disorder, but include deficiencies in the expression of 14-3-3 protein members, implicating these chaperone proteins and the neurotransmitter pathways they support as possible drug targets. Brains from persons with major depressive disorder reveal decreased expression for genes in glutamate transport and metabolism, neurotrophic signaling (eg, FGF, BDNF and VGF), and MAP kinase pathways. Increases in these pathways in the brains of animals exposed to electroconvulsive shock and antidepressant treatments identify neurotrophic and angiogenic growth factors and second messenger stimulation as therapeutic approaches for the treatment of depression.
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PMID:Target identification for CNS diseases by transcriptional profiling. 1892 5

Vitamin D, a multipurpose steroid hormone vital to health, has been increasingly implicated in the pathology of cognition and mental illness. Hypovitaminosis D is prevalent among older adults, and several studies suggest an association between hypovitaminosis D and basic and executive cognitive functions, depression, bipolar disorder, and schizophrenia. Vitamin D activates receptors on neurons in regions implicated in the regulation of behavior, stimulates neurotrophin release, and protects the brain by buffering antioxidant and anti-inflammatory defenses against vascular injury and improving metabolic and cardiovascular function. Although additional studies are needed to examine the impact of supplementation on cognition and mood disorders, given the known health benefits of vitamin D, we recommend greater supplementation in older adults.
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PMID:Some new food for thought: the role of vitamin D in the mental health of older adults. 1918 3

Altered neurodevelopment and plasticity are implicated in schizophrenia pathology. Based on the important role of neurotrophic factors in brain development and plasticity as well as their extensive expression in hippocampal areas, we hypothesized that a variation in the neurotrophin receptor 3 gene (NTRK-3) is associated to hippocampal function and schizophrenia. Thirty-three tagging NTRK-3 single nucleotide polymorphisms (SNPs) were genotyped in 839 schizophrenia patients and 1473 healthy controls. SNPs that were significantly associated with schizophrenia were evaluated in subgroups of the sample with neuropsychological test battery (n=104 patients and 175 controls) and functional magnetic resonance imaging tests of hippocampal function (n=36 controls). rs999905 was nominally significantly associated with schizophrenia and the haplotype block that included markers rs999905 and rs4887348 remained significant after permutation tests. These gene variants are also related to in vivo brain function in healthy control subjects, shown by a significant association with hippocampal activation during an encoding task. The present results, although not robust, suggest that the NTRK-3 gene influences hippocampal function and may modify the risk for schizophrenia.
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PMID:Evidence for a possible association of neurotrophin receptor (NTRK-3) gene polymorphisms with hippocampal function and schizophrenia. 1934 62

Recent evidence suggests that brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) enhance the survival of ventral mesencephalic dopaminergic neurons. In this study, cellular distributions of mRNAs for the nerve growth factor (NGF) family of neurotrophins (NGF, BDNF, and NT-3) and the catecholamine biosynthetic enzyme tyrosine hydroxylase (TH) were evaluated in the ventral mesencephalon of adult rat to determine if the neurotrophins are synthesized in regions of the responsive dopaminergic cells. Messenger RNAs were localized by in situ hybridization of (35)S-labeled cRNA probes and emulsion autoradiography. Neurotrophin-3 cRNA labeled neurons in the ventral tegmental area, medial substantia nigra pars compacta, and retrorubral field. The distributions of NT-3 mRNA-containing and TH mRNA-containing neurons corresponded very well in these areas. Hybridization of the BDNF cRNA labeled scattered cells in corresponding fields of TH mRNA-containing neurons in both the ventral tegmental area and the medial substantia nigra pars compacta but, in contrast to NT-3 cRNA, labeled fewer cells in these areas. Somata containing BDNF mRNA were also present in surrounding regions, including the interfascicular and interpeduncular nuclei, the supramammillary region, the periaqueductal grey matter, and fields dorsal to the lateral substantia nigra. Hybridization of NGF cRNA was not observed in the ventral mesencephalon. These results demonstrate that mRNAs for NT-3 and BDNF are expressed by neurons in both the substantia nigra and ventral tegmental area of adult rat and suggest that trophic support for the dopaminergic neurons in these areas may arise from local synthesis. Moreover, these results raise the possibility that perturbations in local neurotrophin synthesis might contribute to dopamine-related disorders including Parkinson's disease and schizophrenia.
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PMID:Brain-derived neurotrophic factor and neurotrophin-3 mRNAs are expressed in ventral midbrain regions containing dopaminergic neurons. 1991 46

The p75 neurotrophin receptor (p75NTR) was originally identified as a low-affinity receptor for neurotrophins. Recent studies have revealed that p75NTR can promote cell death or survival and modulate neurite outgrowth depending on the operative ligands and co-receptors. Up-regulation and ligand activation of p75NTR have been shown to be involved in neuronal cell death in cultured cells and animal models of neurodegenerative diseases. The levels of proneurotrophins, which bind to p75NTR to promote neuronal death, have been found to be increased in postmortem brains of patients with Alzheimer's disease. Furthermore, there is some evidence for the involvement of this molecule in psychiatric diseases, such as depression and schizophrenia. Mice lacking p75NTR have been shown to have several alterations in central nervous system and cognitive function. Notably, recent progress in genome-based drug discovery has enabled the identification of peptides and non-peptide small molecules targeting p75NTR, which may be potentially beneficial in the treatment of neuropsychiatric diseases. In this review, we focus on recent findings on p75NTR as a therapeutic target for neuropsychiatric diseases.
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PMID:p75NTR as a therapeutic target for neuropsychiatric diseases. 2002 47

There is growing evidence of neurotrophin alterations in neuropsychiatric illnesses such as schizophrenia and further, neurotransmitters known to be adversely affected in schizophrenia (e.g. dopamine) can activate neurotrophin signalling pathways via G protein-coupled receptors. However, it is unclear how the primary therapeutic agents used in schizophrenia affect neurotrophin signalling. This is important given that all currently prescribed antipsychotic drugs serve as ligands at dopamine receptors. In this study, chronic effects of representative conventional and second-generation antipsychotics on nerve growth factor (NGF) receptor levels were assessed in the rat. The results indicated no significant drug effects on TrkA levels in any brain region analysed; however, three of the five antipsychotics analysed significantly decreased phospho-TrkA (i.e. the activated form of the receptor) in the hippocampus. These data indicate that chronic antipsychotic treatment may result in deleterious effects on neurotrophin signalling in an important brain region for information processing and cognition.
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PMID:Chronic antipsychotic treatment: protracted decreases in phospho-TrkA levels in the rat hippocampus. 2005 2

The aim of this review is to highlight past and ongoing studies on neurotrophin (NT) role, in particular focusing on nerve growth factor (NGF), on behavioral response to stress, agonistic and emotional behavior, anxiety, and schizophrenia. One of the first evidences of NGF involvement in behavioral response to a social challenge was published in 1986. In male mice, agonistic encounters caused a massive NGF release into the bloodstream and in the hypothalamus. Subsequent studies revealed that this NGF release was not strictly linked to agonistic behavior, but to mice hierarchical status, with subordinates having higher NGF levels than dominants. This observation led to the hypothesis and later to the demonstration that NGF release is associated to anxiety-related behaviors. Later studies provided evidence for the involvement of NTs, including NGF, in the development of neuropsychiatric disorders. Interestingly, pharmacological treatment can reduce the effects of the maldevelopment and neuropathology due to NT imbalance during early periods of life crucial for development. Further understanding of the core pathophysiological mechanism for neurodegenerative and psychiatric disorders will eventually provide tools for amelioration of symptoms of those psychiatric disorders characterized by an NT imbalance.
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PMID:Stress, anxiety and schizophrenia and neurotrophic factors: the pioneer studies with nerve growth factor. 2006 9

Fusion of synaptic vesicles with the plasma membrane is mediated by the SNARE (soluble NSF attachment receptor) proteins and is regulated by synaptotagmin (syt). There are at least 17 syt isoforms that have the potential to act as modulators of membrane fusion events. Synaptotagmin IV (syt IV) is particularly interesting; it is an immediate early gene that is regulated by seizures and certain classes of drugs, and, in humans, syt IV maps to a region of chromosome 18 associated with schizophrenia and bipolar disease. Syt IV has recently been found to localize to dense core vesicles in hippocampal neurons, where it regulates neurotrophin release. Here we have examined the ultrastructure of cultured hippocampal neurons from wild-type and syt IV -/- mice using electron tomography. Perhaps surprisingly, we observed a potential synaptic vesicle transport defect in syt IV -/- neurons, with the accumulation of large numbers of small clear vesicles (putative axonal transport vesicles) near the trans-Golgi network. We also found an interaction between syt IV and KIF1A, a kinesin known to be involved in vesicle trafficking to the synapse. Finally, we found that syt IV -/- synapses exhibited reduced numbers of synaptic vesicles and a twofold reduction in the proportion of docked vesicles compared to wild-type. The proportion of docked vesicles in syt IV -/- boutons was further reduced, 5-fold, following depolarization.
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PMID:Loss of synaptotagmin IV results in a reduction in synaptic vesicles and a distortion of the Golgi structure in cultured hippocampal neurons. 2013 28

Nerve growth factor (NGF) plays a crucial role in central nervous system neuron plasticity. Low levels of serum NGF in schizophrenic patients suggest that the neurotrophin contributes to the pathogenesis of the disease. NGF is also thought to alter characteristics of event-related brain potential (ERP) components. The auditory-evoked P300 ERP component, considered an index of brain activity, has reduced amplitude in acute and chronic schizophrenia. This study evaluated the relationship among serum NGF levels, P300 characteristics, and Positive and Negative Symptom Scale (PANSS) scores in first episode, neuroleptic naive schizophrenic patients (N=30) and healthy controls (N=28). Serum NGF was measured by ELISA and P300 elicited using auditory oddball paradigm. Compared to control subjects, schizophrenic patients had significantly reduced serum NGF (p<0.001) and lower P300 amplitudes at Fz (p=0.003). Additionally, there was a positive correlation between serum NGF serum and P300 amplitude at Fz. No correlation was found between serum NGF or P300 characteristics and PANSS scores. These results suggest that the effects of NGF in schizophrenia are related not only to regulation of neurodevelopment, but also to the electrophysiological characteristics of nerve growth factor.
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PMID:Reduced NGF serum levels and abnormal P300 event-related potential in first episode schizophrenia. 2030 41

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