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 X-ray repair cross-complementation group 1 (XRCC1) protein plays an important role in base excision repair. A high level of XRCC1 mRNA and/or protein has been found in rat and baboon brains. An exon 10 variant at codon 399 of XRCC1 leads to an Arg to Gln amino acid change. The 399Gln allele is associated with an increased risk of several types of cancers, increased DNA adducts and chromosomal changes; therefore, it appears that the 399Gln allele may alter the role of the XRCC1 protein in DNA repair. The present case-control study was performed on 303 (223 males, 80 females) in-patients with chronic schizophrenia and 303 healthy blood donors matched to the patients by age (+/-5 years) and gender. The XRCC1 genotypes were determined using a PCR-based method. Heterozygosity (OR=1.48, 95% CI: 1.05-2.09) and homozygosity (OR=2.00, 95% CI: 1.17-3.42) for the Gln399 allele increased the risk of schizophrenia. There was a significant linear trend in risk associated with zero, one, and two 399Gln alleles. The present finding indicates that XRCC1 is a candidate gene for susceptibility to schizophrenia.
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PMID:Genetic polymorphism in the DNA repair gene XRCC1 and susceptibility to schizophrenia. 1796 13

Agmatine, a decarboxylation product of arginine, is thought to be an important neuromodulator in the mammalian brain. It is proposed to exert neuroprotective, anxiolytic and antidepressant effects. The receptor-binding profile of agmatine is complex and includes interaction with alpha(2)-adrenergic and imidazoline I(1) receptors. Furthermore, agmatine is an NMDA-receptor antagonist and inhibits nitric oxide synthase. Prepulse inhibition (PPI) of the acoustic startle response is used as a measure of the pre-attentive information processing. PPI is lowered in schizophrenia and this impairment can be mimicked in experimental animals using the psychotomimetic drug phencyclidine (PCP). The aim of the present study was to investigate the effects of agmatine per se on the PPI response and the effects of agmatine pre-treatment on a PCP-induced disruption of PPI. Agmatine administration (10, 20 and 40 mg/kg) did not change the PPI response or the acoustic startle response. However, pre-treatment with agmatine 20 mg/kg, but not agmatine 40 mg/kg, significantly attenuated a PCP (5 mg/kg)-induced disruption of the PPI response. These results emphasize the potential role of agmatine as a neuromodulator and potential target for novel treatments for brain disorders.
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PMID:Agmatine attenuates the disruptive effects of phencyclidine on prepulse inhibition. 1857 47

There is evidence that brain lateralization underlying hemispheric specialization can be observed also at biochemical level. However, hemispheric differences in nitric oxide mediator system have not yet been evaluated. The hippocampus and planum temporale are highly asymmetrical regions but the degree of their laterality is altered in demented or psychotic people. In the study, l-glutamate/l-arginine/l-citrulline concentrations, nitric oxide synthase activities/expressions and nitrites/nitrates levels were estimated in autoptic hippocampi. Right/left laterality in endothelial synthase activity and in nitrites/nitrates was observed in controls. Lateral changes were estimated in patients with Alzheimer disease (a marked increase in activities of constitutive synthases and in expression of inducible enzyme in the left side) and schizophrenia (an increase in activities of all enzymes especially in the right side). Significant shifts from positive to negative correlations were found between laterality of some components of nitric oxide pathway and of planum temporale volumetry under pathological conditions. The hippocampal nitric oxide system appears to be globally right/left lateralized, especially via actions of highly asymmetrical endothelial synthase. The results suggest a specific involvement of all synthases in the development of selected diseases and show that lateral analyses are of sufficient sensitivity to reveal subtle links. The volumetric asymmetry of the planum temporale as a marker of handedness is not probably simply linked to brain laterality at biochemical level but reflects alterations due to pathological processes.
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PMID:Lateralization of hippocampal nitric oxide mediator system in people with Alzheimer disease, multi-infarct dementia and schizophrenia. 1864 32

Tardive dyskinesia (TD) has been considered as a major clinical issue in the treatment of schizophrenia. Various animal studies have indicated the role of oxidative stress and nitric oxide pathway in haloperidol-induced TD. The present study investigated the effect of NO donors (molsidomine and l-arginine) in haloperidol-induced TD in rats. Chronic administration of haloperidol (1 mg/kg i.p. for 21 days) significantly increased vacuous chewing movements (VCMs), tongue protrusions, and facial jerking in rats which was dose dependently inhibited by NO donors. Besides, haloperidol also increased striatal superoxide anion levels and decreased striatal NO and citrulline levels which were prevented by molsidomine and l-arginine. On chronic administration of haloperidol, there was a decrease in the striatal levels of dopamine, which was again reversed by treatment with NO donors. The findings of the present study suggested for the involvement of NO in the development of neuroleptic-induced TD and indicated the potential of NO donors as a possible therapeutic option. Furthermore, a sub-study on a possible schizophrenic phenotype, i.e. a possible clinical worsening in the animals receiving NO donors and neuroleptics will substantiate the clinical utility of the study.
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PMID:Co-administration of nitric oxide (NO) donors prevents haloperidol-induced orofacial dyskinesia, oxidative damage and change in striatal dopamine levels. 1878 60

Nitric oxide (NO) is associated with dopamine (DA) release. Previously, we demonstrated that rats treated with a non-selective nitric oxide synthase inhibitor, N-omega-nitro-L-arginine (L-NNA) at postnatal days 4-6 (PD4-6) show increased locomotion and disrupt neuronal cytoarchitecture after puberty (PD60). Here, we investigate whether the modulation of NO production in rats at PD4-6 causes long term changes of NO system, its impact on DA innervation, and schizophrenia-like behaviors. NO levels were measured in seven brain areas at PD35, PD60, PD90, and PD120. Autoradiographic studies explored the effect of l-NNA on the expression of D1 and D2 receptors in the caudate-putamen (CPu) and nucleus accumbens (NAcc) at PD60. Locomotor activity was assessed at PD60 using the non-selective DA agonists, amphetamine and apomorphine, and the selective DA receptor agonist [D2, quinpirole; D3, 7-hydroxy-N,N-di-n-propylaminotetralin ((+/-)-7-OH-DPAT)]. L-NNA treatment produced decreases in NO levels in the frontal cortex, striatum, brainstem and cerebellum, while in the occipital cortex changes were observed at PD120. Hippocampus and temporoparietal cortex showed differential levels of NO. Receptor autoradiography revealed increases in D1 receptor levels in the NAcc (shell), while decreases in D2 receptor binding were observed in the CPu and NAcc (core). Amphetamine and quinpirole treatments resulted in increases in locomotion. In contrast, treatment with 7-OH-DPAT produced hypolocomotion at low doses, while increased locomotion was seen at the highest dose. These results show that modulation of NO levels early postnatally (PD4-6) produces long term alteration in NO levels, with possible consequences on DA transmission, and related behaviors relevant to schizophrenia.
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PMID:Neonatal administration of N-omega-nitro-L-arginine induces permanent decrease in NO levels and hyperresponsiveness to locomotor activity by D-amphetamine in postpubertal rats. 1879 Jul 2

Ionotropic AMPA and NMDA glutamate receptors are ligand-gated ion channels that mediate fast synaptic transmission in the brain and play a crucial role in learning and memory. Dysfunction of these receptors is believed to be associated with a number of neuropsychiatric disorders, including schizophrenia. As direct activation of these ionotropic receptors can lead to excitoxicity, allosteric modulation of these receptors could minimize side-effects to achieve better therapeutic efficacy. Our review here focuses on the allosteric modulation of the NMDA receptor. Endogenous glycine and D-serine both act as co-agonists on the strychnine-insensitive GlyB site on the NMDA receptor, and along with glutamate, co-activate the NMDA receptor. Forebrain synaptic glycine and d-serine levels are regulated by the Glycine Transporter-1 (GlyT1) and the arginine-serine-cysteine transporter-1 (Asc-1), respectively; in addition to D-serine metabolism by D-Amino Acid Oxidase (DAAO). Together, these processes prevent the GlyB site from being saturated by the high extracellular levels of brain glycine, and perhaps d-serine, in vivo. Blockade of NMDA receptors by phencyclidine induces schizophrenia-like symptoms with the associated cognitive deficits. It was proposed that: a) blockade of GlyT1 mediated reuptake of glycine, or b) inhibition of D-amino Acid Oxidase, or Asc-1 will elevate brain glycine, and D-serine to upregulate NMDA receptor functions via glycine and D-serine co-agonistic allosteric modulation of the GlyB sites on the NMDA receptor. These approaches may provide novel treatments to schizophrenia, provided that some of the known adverse effects associated with existing GlyT1 agents can be safely and adequately dealt with.
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PMID:Allosteric modulation of NMDA receptor via elevation of brain glycine and D-serine: the therapeutic potentials for schizophrenia. 1880 36

Disrupted-in-Schizophrenia 1 (DISC1) and its molecular cascade have been implicated in the pathophysiology of major psychoses. Previously, we identified pericentrin 2 (PCNT2) and DISC1-binding zinc finger protein (DBZ) as binding partners of DISC1; further, we observed elevated expression of PCNT2 in the postmortem brains and in the lymphocytes of bipolar disorder patients, compared to controls. Here, we examined the association of PCNT2 with schizophrenia in a case-control study of Japanese cohorts. We also examined the association of DBZ with schizophrenia and with bipolar disorder, and compared the mRNA levels of DBZ in the postmortem brains of schizophrenia, bipolar and control samples. DNA from 180 schizophrenia patients 201 controls were used for the association study of PCNT2 and DBZ with schizophrenia. Association of DBZ with bipolar disorder was examined in DNA from 238 bipolar patients and 240 age- and gender-matched controls. We observed significant allelic and genotypic associations of the PCNT2 SNPs, rs2249057, rs2268524, and rs2073380 (Ser/Arg) with schizophrenia; the association of rs2249057 (P = 0.002) withstand multiple testing correction. Several two SNP- and three SNP-haplotypes showed significant associations; the associations of haplotypes involving rs2249057 withstand multiple testing correction. No associations were observed for DBZ with schizophrenia or with bipolar disorder; further, there was no significant difference between the DBZ mRNA levels of control, schizophrenia and bipolar postmortem brains. We suggest a possible role of PCNT2 in the pathogenesis of schizophrenia. Abnormalities of PCNT2, the centrosomal protein essential for microtubule organization, may be suggested to lead to neurodevelopmental abnormalities.
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PMID:Association studies and gene expression analyses of the DISC1-interacting molecules, pericentrin 2 (PCNT2) and DISC1-binding zinc finger protein (DBZ), with schizophrenia and with bipolar disorder. 1919 Dec 56

Agmatine is a guanidine-amine formed by the enzymatic decarboxylation of arginine. Agmatine has been proposed to be a neuromodulator and its downstream derivatives, the polyamines, have been suggested to be responsible for sensory gating deficits seen in schizophrenia. In this study, male Wistar rats underwent treatments with agmatine, vehicle or other agents known to alter sensory gating in an experimental paradigm of prepulse inhibition (PPI) of the acoustic startle response. Apomorphine (1 mg/kg s.c.), a nonselective dopamine agonist known to disrupt PPI responses, was injected as the positive reference. Neither apomorphine nor agmatine (40-160 mg/kg i.p.) induced effects on the intensity of startle reflex without a prepulse. However, apomorphine or agmatine (160 mg/kg i.p.) disrupted the PPI of acoustic startle reflex. Furthermore, when given 30 min prior, agmatine acted additively with apomorphine's effect on PPI. In an attempt to gain more insight, haloperidol (1 and 2 mg/kg i.p.), clozapine (2.5-7.5 mg/kg i.p.) or quetiapine (2.5 and 7.5 mg/kg i.p.) was also injected prior to agmatine (160 mg/kg i.p.). Haloperidol (1 mg/kg) and clozapine (2.5 and 5 mg/kg) were able to prevent the PPI-disrupting effects of apomorphine. However, none of these antipsychotics prevent the PPI-disrupting effects of agmatine. These results suggest that agmatine disrupts the PPI of acoustic startle reflex of rats in a fundamentally different manner than apomorphine does. It may also have a critical role in the pathogenesis of sensorimotor gating-related dysfunctions.
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PMID:Agmatine disrupts prepulse inhibition of acoustic startle reflex in rats. 1928 21

Peptidylarginine deiminases (PADIs), five isoforms of which have been identified, catalyze the conversion of arginine residues to citrulline residues in proteins. Recent studies have revealed that abnormal activation of PADI2, the gene for which is expressed throughout the nervous system, is likely to be related to the pathogenesis of neuropsychiatric diseases with neurodegenerative processes, such as Alzheimer's disease and multiple sclerosis. Such a progressive neurodegenerative process could be involved in the etiology and/or course of schizophrenia, and PADI2 may be a candidate gene for schizophrenia. To assess whether PADI2 has a role in vulnerability to schizophrenia, we conducted a two-stage case-control association study in Japanese individuals. In a screening population of 534 patients and 559 control individuals, we examined eight single-nucleotide polymorphisms (SNPs) including four haplotype tag SNPs and four coding SNPs in PADI2. There was a potential association of a synonymous SNP in exon 7 with schizophrenia. However, we could not replicate this association in a confirmatory population of 2126 patients and 2228 control individuals. The results of this study suggest that PADI2 does not contribute to genetic susceptibility to schizophrenia.
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PMID:A two-stage case-control association study of PADI2 with schizophrenia. 1947 18

Schizophrenia is a serious mental disorder with a challenging rational pharmacotherapy. Neurochemical transmission in the dopaminergic system, especially via D2 receptors, and related changes in postsynaptic signal transduction are very important in both the formation of schizophrenia and current pharmacotherapeutic treatment with antipsychotic drugs. Blocking the serotonergic 5-HT2A and 5-HT2C receptors is growing growing importance with regard to the action mechanisms of new generation antipsychotic medications. Recent preclinical and clinical data show that dysfunction of central neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurophin-3 (NT-3) might contribute to impaired brain development and neuroplasticity, leading to schizophrenia. In addition, some recent studies suggest that there is an important relationship between alcohol and substance addiction, and schizophrenia. There is also some preclinical data indicating that the central nitrergic system and agmatine(3/4)a biologically active agent produced after decarboxylation of arginine(3/4)might be interesting and important targets for understanding the etiopathogenesis of schizophrenia and for development of new drugs. Selective dopamine D3 receptor antagonists, specific agonists for metabotropic and NMDA receptors of the glutamatergic system, and nicotinic alpha-7 receptor agonists were reported in preclinical and a limited number of clinical studies as potential new targets for schizophrenia treatment. In this review, new advances in the pharmacotherapy of schizophrenia and possible new targets are discussed in the light of the current literature.
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PMID:[New pharmacological approaches to the treatment of schizophrenia]. 1950 68


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