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)

The neuregulins (NRGs) are cell-cell signaling proteins that are ligands for receptor tyrosine kinases of the ErbB family. The neuregulin family of genes has four members: NRG1, NRG2, NRG3, and NRG4. Relatively little is known about the biological functions of the NRG2, 3, and 4 proteins, and they are considered in this review only briefly. The NRG1 proteins play essential roles in the nervous system, heart, and breast. There is also evidence for involvement of NRG signaling in the development and function of several other organ systems, and in human disease, including the pathogenesis of schizophrenia and breast cancer. There are many NRG1 isoforms, raising the question "Why so many neuregulins?" Study of mice with targeted mutations ("knockout mice") has demonstrated that isoforms differing in their N-terminal region or in their epidermal growth factor (EGF)-like domain differ in their in vivo functions. These differences in function might arise because of differences in expression pattern or might reflect differences in intrinsic biological characteristics. While differences in expression pattern certainly contribute to the observed differences in in vivo functions, there are also marked differences in intrinsic characteristics that may tailor isoforms for specific signaling requirements, a theme that will be emphasized in this review.
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PMID:Neuregulins: functions, forms, and signaling strategies. 1264 63

Abnormal development of the brain is implicated in the etiology and/or pathology of various psychiatric diseases, including schizophrenia. Current evidence indicates that neurotrophic factors can strongly influence neuronal phenotypic differentiation and subsequent neuronal function in synaptic plasticity. Among various neurotrophic factors, the expression of brain-derived neurotrophic factor(BDNF) and epidermal growth factor (EGF) is impaired in the brain as well as in the periphery of patients with schizophrenia. Based on this result, a novel animal model for schizophrenia has been established by perturbing the neurotrophic signaling during development. This review summarizes the latest progress of these studies.
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PMID:[Contribution of neurotrophic factors and cytokines to schizophrenia]. 1270 Nov 84

Some recent data suggest that epidermal growth factor (EGF) protein levels are altered in the brain of schizophrenic patients. In addition, a novel polymorphism of the EGF gene is associated with enhanced production of EGF in vitro. We conducted a retrospective study to explore the impact of EGF polymorphism on factors associated with schizophrenia. The sample consisted of 94 patients with schizophrenia who had either responded to treatment with conventional neuroleptics or who were considered non-responders. The control sample consisted of 98 blood donors. In our sample, the G allele was associated with schizophrenia in male patients (OR = 3.594 (95% CI 1.347-9.591), p = 0.008). The G allele was also associated with a later age at onset in male patients with schizophrenia. However, no association was found between treatment response and EGF polymorphism.
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PMID:Association of EGF polymorphism with schizophrenia in Finnish men. 1512 77

The study population comprised 94 Finnish patients with DSM-IV diagnosis of schizophrenia. The patients were placed into two subgroups according to medication response to conventional neuroleptics. The aim of the study was to examine the frequency of tumor necrosis factor -308 (G > A) polymorphism in these patients and their 98 control subjects who were age- and gender-matched blood donors. Associations between TNFalpha -308 polymorphism alone and between the interaction of TNFalpha and epidermal growth factor gene polymorphisms, and medication response and age at onset of schizophrenia were also studied. The frequencies of TNFalpha A-allele were 11.7 % in patients and 12.8% in controls. The difference was not significant (p = 0.75). TNFalpha -308 polymorphism was not associated with medication response. However, patients with EGF AA and TNFalpha AG/AA genotype had a lower age at onset of schizophrenia compared with the rest of the patients not having this combination (20.0 years, 3.3 vs. 30.2 years, 10.1 mean + SD; p < 0.001). The results support earlier findings according to which TNFalpha polymorphism is not associated with the incidence of schizophrenia. On the other hand, the role of cytokines in schizophrenia may involve genetic interactions predisposing early onset of illness.
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PMID:Interaction of tumor necrosis alpha - G308A and epidermal growth factor gene polymorphisms in early-onset schizophrenia. 1561 91

A recent report demonstrated that serum levels of epidermal growth factor (EGF) were significantly decreased in patients with schizophrenia, suggesting that impaired EGF signaling might be associated with the pathophysiology of schizophrenia. Our goal in the present study was to determine whether serum levels of EGF are altered in patients with schizophrenia. We found that serum levels of EGF in drug-naive (n = 15) or medicated patients (n = 25) with schizophrenia did not differ from those of age- and sex-matched normal controls (n = 40). However, we found a significant correlation between serum EGF levels and BPRS scores in the combined groups of patients. Therefore, our results do not support the claim that EGF plays a role in the pathogenesis of schizophrenia, but they suggest that EGF may serve as a state marker, that is, as an index of symptom-linked deficits.
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PMID:No changes in serum epidermal growth factor levels in patients with schizophrenia. 1599 91

Epidemiologic studies demonstrate significant environmental impact of maternal viral infection and obstetric complications on the risk of schizophrenia and indicate their detrimental influences on brain development in this disorder. Based on these findings, animal models for schizophrenia have been established using double stranded RNA, bacterial lipopolysaccharides, hippocampal lesion, or prenatal/perinatal ischemia. Key molecules regulating such immune/inflammatory reactions are cytokines, which are also involved in brain development, regulating dopaminergic and GABAergic differentiation, and synaptic maturation. Specific members of the cytokine family, such as interleukin-1, epidermal growth factor, and neuregulin-1, are induced after infection and brain injury; therefore, certain cytokines are postulated to have a central role in the neurodevelopmental defects of schizophrenia. Recently, to test this hypothesis, a variety of cytokines were administered to rodent pups. Cytokines administered in the periphery penetrated the immature blood-brain barrier and perturbed phenotypic neural development. Among the many cytokines examined, epidermal growth factor (or potentially other ErbB1 ligands) and interleukin-1 specifically induced the most severe and persistent behavioral and cognitive abnormalities, most of which were ameliorated by antipsychotics. These animal experiments illustrate that, during early development, these cytokine activities in the periphery perturbs normal brain development and impairs later psychobehavioral and/or cognitive traits. The neurodevelopmental and behavioral consequences of prenatal/perinatal cytokine activity are compared with those of other schizophrenia models and cytokine interactions with genes are also discussed in this review.
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PMID:Recent progress in animal modeling of immune inflammatory processes in schizophrenia: implication of specific cytokines. 1683 94

Neuregulin 1 (NRG1) is essential for the development and function of multiple organ systems, and its dysregulation has been linked to diseases such as cancer and schizophrenia. Recently, altered expression of a novel isoform (type IV) in the brain has been associated with schizophrenia-related genetic variants, especially rs6994992 (SNP8NRG243177). Here we have isolated and characterized full-length NRG1 type IV cDNAs from the adult and fetal human brain and identified novel splice variants of NRG1. Full-length type IV spans 1.8 kb and encodes a putative protein of 590 amino acids with a predicted molecular mass of approximately 66 kDa. The transcript consists of 11 exons with an Ig-like domain, an epidermal growth factor-like (EGF) domain, a beta-stalk, a transmembrane domain, and a cytoplasmic "a-tail," placing it in the beta1a NRG1 subclass. NRG1 type IV was not detected in any tissues except brain and a putative type IV NRG1 protein of 66 kDa was similarly brain-specific. Type IV transcripts are more abundantly expressed in the fetal brain, where, in addition to the full-length structure, two novel type IV variants were identified. In vitro luciferase-reporter assays demonstrate that the 5' promoter region upstream of type IV is functional, with differential activity associated with genetic variation at rs6994992, and that promoter competition may impact on type IV expression. Our data suggest that type IV is a unique brain-specific NRG1 that is differentially expressed and processed during early development, is translated, and its expression regulated by a schizophrenia risk-associated functional promoter or single nucleotide polymorphism (SNP).
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PMID:Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia. 1756 85

Consistent with the hypothesis that neuroinflammatory processes contribute to the neuropathology of schizophrenia, the protein levels of epidermal growth factor (EGF) and its receptor ErbB1 are abnormal in patients with schizophrenia. To evaluate neuropathological significance of this abnormality, we established an animal model for behavioral deficits by administering EGF into the striatum and evaluated the effects of cyclooxygenase-2 (Cox-2) inhibitor celecoxib. Intracranial infusion of EGF into the striatum of adult male rats activated ErbB1 and induced neurobehavioral impairments observed in several schizophrenia models. Unilateral EGF infusion to the striatum lowered prepulse inhibition (PPI) in a dose-dependent manner and impaired latent learning of active shock avoidance without affecting basal learning ability. Bilateral EGF infusion similarly affected PPI. In contrast, EGF infusion to the nucleus accumbens did not induce a behavioral deficit. Intrastriatal EGF infusion also increased Cox-2 expression, elevated tyrosine hydroxylase activity, and upregulated the levels of dopamine and its metabolites. Subchronic administration of celecoxib (10 mg/kg, p.o.) ameliorated the abnormalities in PPI and latent learning as well as normalized dopamine metabolism. We conclude that this EGF-triggered neuroinflammatory process is mediated in part by Cox-2 activity and perturbs dopamine metabolism to generate neurobehavioral abnormalities.
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PMID:A cyclooxygenase-2 inhibitor ameliorates behavioral impairments induced by striatal administration of epidermal growth factor. 1788 18

Neurotrophic factors (NFs) play a pivotal role in the development of the central nervous system. They are thus also suspected of being involved in the etiology of schizophrenia. Previous studies reported a decreased level of serum brain-derived neurotrophic factor (BDNF) in schizophrenia, whereas the association of epidermal growth factor (EGF) with this illness remains controversial. Using a two-site enzyme immunoassay, we conducted the simultaneous measurement of serum BDNF and EGF levels in a group of patients with chronic schizophrenia (N=74) and a group of normal controls matched in age, body mass index, smoking habit and sex (N=87). We found that, compared to normal controls, patients with chronic schizophrenia exhibited lower serum levels of both BDNF and EGF across all ages examined (21-59 years). The serum levels of BDNF and EGF were negatively correlated in the controls (r=-0.387, P=0.0002) but not in the patients. Clinical parameters such as duration of illness and psychiatric rating scale also showed no robust correlations with the NF levels. Collectively, these results suggest that pervasive, abnormal signaling of NFs underlies the pathophysiology of chronic schizophrenia.
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PMID:Low serum levels of brain-derived neurotrophic factor and epidermal growth factor in patients with chronic schizophrenia. 1828 32

Abnormality in cytokine signaling is implicated in the neuropathology of schizophrenia. Previously, we established an animal model for schizophrenia by administering epidermal growth factor (EGF) to neonatal rats. Here we investigated effects of the anthraquinone derivatives emodin (3-methyl-1,6,8-trihydroxyanthraquinone) and sennoside (bis-[D: -glucopyranosyl-oxy]-tetrahydro-4,4'-dihydroxy-dioxo[bianthracene]-2,2'-dicarboxylic acid) on behaviors of this model and EGF signaling. Subchronic oral administration of emodin (50 mg/kg) suppressed acoustic startle responses and abolished prepulse inhibition (PPI) deficits in this rodent model. ANCOVA revealed that emodin had distinct effects on PPI and startle responses. In contrast, sennoside (50 mg/kg) had no effects. Emodin attenuated weight gain initially during treatment but had no apparent effect on weight gain and locomotor activity thereafter. Application of emodin to neocortical cultures attenuated the phosphorylation of ErbB1 and ErbB2. We conclude that emodin can both attenuate EGF receptor signaling and ameliorate behavioral deficits. Therefore, emodin might be a novel class of a pro-drug for anti-psychotic medication.
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PMID:The anthraquinone derivative Emodin ameliorates neurobehavioral deficits of a rodent model for schizophrenia. 1830 53


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