Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been demonstrated that the neuronal plasticity and resilience could participate in the pathophysiology of neurodegenerative diseases such as Alzheimer and others like depression and schizophrenia. Recently, it has been proposed a new intracellular pathway, known as Wnt pathway, which could be related to the induction of the plastic changes mentioned above. The glycogen synthase kinase-3beta (GSK-3beta), one of the main enzymes of the Wnt signaling, has been associated to Alzheimer;s and schizophrenia diseases etiology. Furthermore, the mood stabilizing agents;s action mechanism, like lithium and valproic acid, implies the inhibition of this protein. The issue of this work is to describe the proteins that are recruited when this pathway is activated and the GSK-3beta role in the pathologies mentioned.
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PMID:[The relationship between the Wnt signaling and the psychiatric diseases]. 1684 74

Converging evidence suggests that the regulation of glycogen synthase kinase 3 (GSK-3) might be important in schizophrenia. Atypical and typical antipsychotic drugs alter GSK-3 activity, as do drugs that induce psychosis. GSK-3 regulatory pathways are altered in schizophrenia, and many of the genes associated with schizophrenia directly or indirectly regulate GSK-3 activity. We propose a variant on the neurodevelopment and dopamine hypotheses of schizophrenia, whereby (i) an early dysfunction in GSK-3 regulation has neurodevelopmental consequences that predispose to disease and (ii) dysfunction in GSK-3 regulation in the adult brain alters dopamine signalling events, causing psychotic symptoms and cognitive dysfunction. If, as we suggest, GSK-3 regulation is crucial to schizophrenia, the Wnt and insulin signalling pathways become targets for therapy.
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PMID:Schizophrenia as a GSK-3 dysregulation disorder. 1732 75

Protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3) and members of the Wnt signal transduction pathway were recently found to be altered in schizophrenia and targeted by antipsychotic drugs. In the current study, selected Wnt signalling proteins were investigated to determine if they are altered by the antipsychotics clozapine or haloperidol in the rat prefrontal cortex. Pheochromocytoma (PC12) and neuroblastoma (SH-SY5Y) cells were also used to elucidate how antipsychotics generated the pattern of changes observed in vivo. Western blotting (WB) revealed that treatment with haloperidol or clozapine caused an up-regulation of Wnt-5a, dishevelled-3, Axin, total and phosphorylated GSK-3 and beta-catenin protein levels. Treatment of PC12 and SH-SY5Y cells with a variety of pharmacological agents as well as the over-expression of several Wnt related proteins failed to mimic the pattern observed in vivo following antipsychotic treatment. However, the over-expression of dishevelled-3 nearly perfectly duplicated the changes observed in vivo. Immunoprecipitations (IP) conducted using protein isolated from the rat prefrontal cortex indicated that dishevelled-3 is associated with the D2 dopamine receptor thereby suggesting that antipsychotics may act on dishevelled-3 via D2 dopamine receptors to initiate a cascade of downstream changes involving Axin, GSK-3 and beta-catenin that may help to alleviate psychosis in schizophrenic patients.
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PMID:Activation of the canonical Wnt pathway by the antipsychotics haloperidol and clozapine involves dishevelled-3. 1747 3

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) can induce positive and negative symptoms of schizophrenia in humans and related effects in rodents. PCP treatment of developing rats induces apoptotic neurodegeneration and behavioral deficits later in life that mimic some symptoms of schizophrenia. The precise mechanism of PCP-induced neural degeneration is unknown. This study used selective antagonists, siRNA, and Western analysis to investigate the role of the Akt-glycogen synthase kinase-3beta (GSK-3beta) pathway in PCP-induced neuronal apoptosis in both neuronal culture and postnatal day 7 rats. PCP administration in vivo and in vitro reduced the phosphorylation of Akt Ser427 and GSK-3beta Ser9, decreasing Akt activity and increasing GSK-3beta activity. The alteration of Akt-GSK-3beta signaling parallels the temporal profile of caspase-3 activation by PCP. Reducing GSK-3beta activity by application of selective inhibitors or depletion of GSK-3beta by siRNA attenuates caspase-3 activity and blocks PCP-induced neurotoxicity. Moreover, increasing synaptic strength by either activation of L-type calcium channels with BAY K8644 or potentiation of synaptic NMDA receptors with either a low concentration of NMDA or bicuculline plus 4-aminopyridine completely blocks PCP-induced cell death by increasing Akt phosphorylation. These neuroprotective effects are associated with activation of phosphoinositide-3-kinase-Akt signaling, and to a lesser extent, the MAPK signaling pathway. Overall, these data suggest that PCP-induced hypofunction of synaptic NMDA receptors impairs the Akt-GSK-3beta cascade, which is necessary for neuronal survival during development, and that interference with this cascade by PCP or natural factors may contribute to neural pathologies, perhaps including schizophrenia.
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PMID:The role of Akt-GSK-3beta signaling and synaptic strength in phencyclidine-induced neurodegeneration. 1763 6

Par-4 has been suggested to mediate dopamine neurotransmission. Dopamine D2 receptor (DRD2) activation induces a signalling complex of AKT1, PP2A and beta-arrestin2 which dephosphorylates/inactivates AKT1 thereby activating GSK-3beta, transducing dopamine-dependent behaviour. DRD2 activation also results in down-regulation of PKA activity. Among other substrates PKA phosphorylates GSK-3beta. Prolonged DRD2 activation leads to its 'desensitization' which involves GRKs and beta-arrestins. beta-arrestin1 binds to phosphorylated receptors preventing further G-protein stimulation. This study examined whether Par-4, beta-arrestin1, AKT1 and GSK-3beta are involved in the pathophysiology of schizophrenia. Lymphocytes obtained from schizophrenia and bipolar patients and healthy controls recruited from the Beer-Sheva Mental Health Center were transformed by Epstein-Barr virus (EBV) into lymphocyte-derived cell lines (LDCL). Post-mortem brain samples were obtained from the Rebecca L. Cooper Brain Bank, Parkville, Australia. The study was approved by the IRB committees of Beer-Sheva, Israel and Parkville, Australia. Levels of the specific proteins were assayed by Western blotting. beta-arrestin1 protein levels were significantly ~2-fold increased in LDCL from schizophrenia patients while Par-4 protein levels were unaltered. A 63% significant decrease was found in frontal cortex phospho-Ser9-GSK-3beta protein levels in schizophrenia but not in those of AKT1, Par-4 or beta-arrestin1. Elevated beta-arrestin1 protein levels in LDCL and decreased phospho-Ser9-GSK-3beta protein levels in post-mortem frontal cortex of schizophrenia patients vs. control groups support the possible involvement of these proteins in the pathophysiology of schizophrenia. However, since we did not find differences in beta-arrestin1, AKT1 and Par-4 protein levels in post-mortem frontal cortex of schizophrenia patients and although GSK-3beta participates in other signalling cascades we can not rule out the possibility that the differences found reflect deviation in DRD2 signalling.
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PMID:Possible involvement of post-dopamine D2 receptor signalling components in the pathophysiology of schizophrenia. 1768 Oct 85

Phosphorylation is the most common post-translational modification of cellular proteins, essential for most physiological functions. Deregulation of phosphorylation has been invoked in disease mechanisms, and the case of Alzheimer's disease (AD) is no exception: both in the amyloid pathology and in the tauopathy are kinases deeply implicated. The glycogen synthase kinase-3 (GSK-3) isozymes participate in diverse cellular processes and important signalling pathways and have been implicitly linked to diverse medical problems, i.e. from diabetes and cancer to mood disorders and schizophrenia, and in the neurodegeneration of AD. Here, we review specific aspects of GSK-3 isozymes in the framework of recent data that we obtained in novel transgenic mouse models that robustly recapitulate the pathology and mechanistical problems of AD.
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PMID:Glycogen synthase kinase-3beta, or a link between amyloid and tau pathology? 1818 70

Glycogen synthase kinase-3 (GSK-3), an important component of the glycogen metabolism pathway, is highly expressed in the CNS. It has been implicated in major neurological disorders including Alzheimer's disease, schizophrenia and bipolar disorders. Despite its central role in these conditions it was not known until recently whether GSK-3 has neuronal-specific functions under normal conditions. However recent work has shown that GSK-3 is involved in the regulation of, and cross-talk between, two major forms of synaptic plasticity, N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and NMDAR-dependent long-term depression (LTD). The present article summarizes this recent work and discusses its potential relevance to the treatment of neurological disorders.
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PMID:The role of GSK-3 in synaptic plasticity. 1831 Nov 57

Antipsychotic agents are major drugs for human neuropsychiatric conditions including schizophrenia, mood disorders, Tourette syndrome, and Alzheimer's disease. These drugs are divided in two groups-first-generation/typical and second-generation/atypical-on the basis of their propensity to induce extrapyramidal motor side effects. Furthermore, second-generation antipsychotics have been reported to be superior in addressing cognitive deficits in schizophrenia. Understanding differences between the mechanism of action of first- and second-generation antipsychotic agents thus represents an interesting opportunity for the development of new compounds having better therapeutic action and less side effects. In this issue of Molecular Pharmacology, Fumagalli et al. (p. 1484) report that long-term treatment with the first-generation drug haloperidol interferes with the trafficking of both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate glutamate receptor complexes and associated molecules post-synaptic densities 95 and Ca(2+)calmodulin-dependent protein kinase in the rat frontal cortex. In contrast, the second-generation drug olanzapine did not affect glutamate receptor trafficking. The action of haloperidol on glutamate receptor trafficking in specific brain regions may contribute to the low efficacy of this drug on cognitive deficits and to the development of side effects. Overall, antipsychotics have been shown to act upon multiple signaling mechanisms (e.g., cAMP-protein kinase A, betaArrestin 2-Akt-GSK-3, and phospholipase C-inositol-protein kinase C pathways), mostly by blocking D2-class dopamine receptors (first generation) or D2-class dopamine and 5-HT(2) serotonin receptors (second generation). Identification of specific pathways by which haloperidol affects glutamate receptor trafficking may thus represent an important next step toward the development of better antipsychotic drugs.
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PMID:Messing up with traffic: different effects of antipsychotic agents on glutamate receptor complexes in vivo. 1825 Jan 47

Glycogen synthase kinase (GSK-3beta) has been implicated in the pathophysiology of mood disorders and schizophrenia. To examine its role in suicide, we determined GSK-3beta messenger RNA (mRNA) in human postmortem brain from suicide and normal control subjects using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) technique. We found that GSK-3beta mRNA was highly abundant in almost all of the 12 brain areas we studied. We also found a significant age effect on GSK-3beta and that GSK-3beta mRNA level were significantly higher in prefrontal cortex (PFC) and hippocampus of teenage normal controls compared with adult normal controls and was significantly decreased in PFC of teenage suicide but not adult suicide victims compared with respective normal control subjects. The decrease observed in the mRNA levels in teenage suicide but not in adult suicide victims may represent a neurodevelopmentally associated decrease and may be important in the pathophysiology of teenage suicide.
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PMID:GSK-3beta gene expression in human postmortem brain: regional distribution, effects of age and suicide. 1858 22

Recent studies have suggested that first and second generation antipsychotics (FGAs and SGAs) have different neuroprotective effects. However, the molecular mechanisms of SGAs are not fully understood, and investigations into changes in intracellular signaling related to their neuroprotective effects remain scarce. In the present study, we compared the SGA aripiprazole with the FGA haloperidol in SH-SY5Y human neuroblastoma cells via brain-derived neurotrophic factor (BDNF)-mediated signaling, notably BDNF, glycogen synthase kinase-3beta (GSK-3beta), and B cell lymphoma protein-2 (Bcl-2). We examined the effects of aripiprazole (five and 10 microM) and haloperidol (one and 10 microM) on BDNF gene promoter activity in SH-SY5Y cells transfected with a rat BDNF promoter fragment (-108 to +340) linked to the luciferase reporter gene. The changes in BDNF, p-GSK-3beta, and Bcl-2 levels were measured by Western blot analysis. The haloperidol was not associated with a significant difference in BDNF promoter activity. In contrast, aripiprazole was associated with increased BDNF promoter activity only with a dose of 10 microM (93%, p<0.01). Treatment with aripiprazole at 10 microM increased the levels of BDNF by 85%, compared with control levels (p<0.01), whereas haloperidol had no effect. Moreover, cells treated with aripirazole effectively increased the levels of GSK-3beta phosphorylation and Bcl-2 at doses of five and 10 microM (30% and 58% and 31% and 80%, respectively, p<0.05 or p<0.01). However, haloperidol had no effects on p-GSK-3 beta and Bcl-2 expression. This study showed that aripiprazole, but not haloperidol, appeared to offer neuroprotective effects on human neuronal cells. The actions of signaling systems associated with BDNF may represent key targets for both aripiprazole and haloperidol, but the latter may be associated with distinct effects. These differences might be related to the different therapeutic effects of FGAs and SGAs in patients with schizophrenia.
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PMID:Differential effects of aripiprazole and haloperidol on BDNF-mediated signal changes in SH-SY5Y cells. 1919 96


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