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)

Panamesine (PAN) is a nearly specific sigma ligand. Recently, we showed that PAN in doses up to 90 mg/day improved psychometric variables in patients with an acute episode of schizophrenia. No side effects connected to the extrapyramidal motoric system occurred; there was even an absence of daytime sedation. We investigated the effects of PAN on plasma cytokine and soluble cytokine receptor levels and blood cell counts during 4 weeks in ten patients out of the previous study sample. Under PAN treatment, tumor necrosis factor (TNF)-alpha, soluble TNF receptors p55 and p75, and soluble interleukin-2 receptor levels were not increased and neither were monocyte and lymphocyte counts affected. This absence of immunomodulation is in contrast to clozapine, but similar to haloperidol treatment. In a second study, a single dose of PAN (30 mg) or placebo was administered at 2200 hours to ten young male controls in order to investigate changes in the sleep EEG under the substance. Sleep efficiency index increased, whereas time spent awake decreased. No significant changes in rapid eye movement (REM) sleep or non-REM parameters occurred. The sleep-EEG investigation showed sleep-consolidating effects of the drug, comparable to those of classical neuroleptics. Our results support the hypothesis that the sigma ligand PAN, which has antipsychotic properties, shares biological aspects with haloperidol.
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PMID:Characterization of the sigma ligand panamesine, a potential antipsychotic, by immune response in patients with schizophrenia and by sleep-EEG changes in normal controls. 995 72

Neuroanatomical studies of schizophrenia suggest that progressive neuropathological changes (such as neuronal atrophy and/or cell death) occur over the lifetime course of the disease. Early intervention with atypical neuroleptics has been shown to prevent progression of at least some symptoms, although the mechanisms by which neuroleptics may do this remain unknown. In this study, PC12 cells were used to determine the effects of the new atypical antipsychotic olanzapine on the gene expression of superoxide dismutase (SOD1) and the low affinity nerve growth factor receptor (p75). The results show that olanzapine increases SOD1 at concentrations of 10 and 100 microM after 48 hr of incubation in PC12 cultures. The treatment decreases p75 gene expression at concentrations 100 microM after 48 hr of incubation. Since both the upregulation of SOD1 mRNA and the antisense blockade of p75 mRNA have been associated with reduced cell death, our results suggest that olanzapine has neuroprotective potential and thus may be useful in preventing further neurodegeneration accompanying schizophrenia.
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PMID:Differential effects of olanzapine on the gene expression of superoxide dismutase and the low affinity nerve growth factor receptor. 1021 77

It has been hypothesized that the immune system plays a pathogenetic role in psychiatric disorders, in particular in major depression and schizophrenia. This hypothesis is supported by a number of reports on altered circulating levels and in vitro production of cytokines in these disorders. However, the respective evidence is not consistent. This may be in part due to an incomplete control for numerous confounding influences in earlier studies. We investigated the plasma levels of cytokines and soluble cytokine receptors in psychiatric patients (N = 361) upon hospital admission and compared the results to those obtained in healthy controls (N = 64). By multiple regression analysis we found that circulating levels of interleukin-1 receptor antagonist (IL-1Ra), soluble IL-2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors (sTNF-R p55, sTNF-R p75) and IL-6 were significantly affected by age, the body mass index (BMI), gender, smoking habits, ongoing or recent infectious diseases, or prior medication. Cytokine or cytokine receptor levels were significantly increased in patients treated with clozapine (sIL-2R, sTNF-R p75), lithium (TNF-alpha, sTNF-R p75, IL-6) or benzodiazepines (TNF-alpha, sTNF-R p75). Taking all these confounding factors into account, we found no evidence for disease-related alterations in the levels of IL-1Ra, sIL-2R, sTNF-R p75 and IL-6, whereas levels of TNF-alpha and sTNF-R p55 in major depression and sTNF-R p55 in schizophrenia were slightly decreased compared to healthy controls. We conclude that, if confounding factors are carefully taken into account, plasma levels of the above mentioned cytokines and cytokine receptors yield little, if any, evidence for immunopathology in schizophrenia or major depression.
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PMID:Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. 1050 9

The dopamine hypothesis of schizophrenia postulates hyperactivity of dopaminergic neurotransmission in the mesolimbic system. However, the possible underlying causes for this dopaminergic overfunction are not well understood. Therefore, the main aim of this study was to examine the effect of central cholinergic denervation on dopamine-mediated functions. We also examined the effect of neonatal cholinergic denervation upon adult brain function. The immunotoxin 192 IgG-saporin causes severe lesions of the basal forebrain cholinergic system when infused into the lateral ventricles by targeting neurons expressing the p75 neurotrophin receptor. The toxin may also damage p75-expressing Purkinje neurons in the cerebellum. We have compared the behavioral effects of intracerebroventricular injections of 192 IgG-saporin to adult rats with that of injections to neonate rats. As expected, adult treated rats displayed an almost complete cholinergic denervation of forebrain corticohippocampal areas concomitant with a marked impairment in the Morris water maze. When tested as adults, neonatally treated animals had a less complete cholinergic denervation and showed lesser impairments in water maze behaviors. Interestingly, adult treated rats showed increased spontaneous horizontal activity and a remarkable increase in locomotor response to d-amphetamine as evidenced by increased horizontal and vertical activity. There were no marked changes of spontaneous or drug-induced locomotor activity in adult rats treated with 192 IgG-saporin as neonates. These results suggest that cholinergic denervation of the forebrain causes a marked enhancement of behavioral responses related to dopaminergic activity, probably mainly mediated presynaptically. However, it cannot be fully excluded that damage to noncholinergic systems, e.g., Purkinje cells, might contribute to the effects. The striking overreaction to dopaminergic stimuli, presumably caused by the cholinergic deficit, is discussed in relation to the suggested role of cholinergic malfunctioning in schizophrenia.
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PMID:Facilitation of dopamine-mediated locomotor activity in adult rats following cholinergic denervation. 1186 38

Atypical antipsychotic drugs are widely used in the treatment of schizophrenia, and clinical evidence has shown that early and prolonged intervention with these drugs will improve the long-term outcome. It is still unclear, however, whether the atypical antipsychotic drugs are also neuroprotective. To clarify this matter, we used PC12 cell cultures and the MTT assay for cell viability to determine whether various concentrations of the atypical antipsychotics clozapine, quetiapine, and risperidone are neuroprotective after serum withdrawal. In addition, to explore the drugs' actions, Northern blot was used to examine the gene expression of SOD1 (Cu/Zn superoxide dismutase) and p75NTR (p75 neurotrophin receptor). The results demonstrated that 1) the antipsychotic drugs can protect PC12 cells from death after serum withdrawal; cell viability in these drug treatment groups is significantly different from that in the groups without serum in the medium (P < 0.01); and 2) these drugs up-regulated the SOD1 gene expression to more than 120% (P < 0.05) and also down-regulated p75NTR mRNA levels to less than 65% of their respective control values (P < 0.05). These findings suggest that the atypical antipsychotics clozapine, quetiapine, and risperidone may exert a neuroprotective function through the modulation of SOD1 and p75NTR expression.
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PMID:Protective effects of atypical antipsychotic drugs on PC12 cells after serum withdrawal. 1211 9

Clozapine is a potent atypical neuroleptic or antipsychotic agent used to relieve symptoms of early-diagnosed schizophrenia. Aside from well-described dopamine and serotonin receptor blockade effects, clozapine may also be neuroprotective through its modulation of the p75 neurotrophin receptor (p75(NTR)) and superoxide dismutase 1 (SOD1) expression. The death-signalling activities of both p75(NTR) and mutant SOD1 are implicated in motor neuron degeneration in humans and transgenic mice with amyotrophic lateral sclerosis (ALS). We therefore investigated the effects of clozapine in cell culture and mouse models of ALS. Clozapine dose-dependently inhibited full-length and cleaved p75(NTR) but not SOD1 protein expression in the motor neuron-like (NSC-34) cell line. Furthermore, low concentrations of clozapine protected NSC-34 cells from paraquat-mediated superoxide toxicity, nerve growth factor (NGF)-induced death signalling, and serum deprivation, whereas high concentrations potentiated death. Systemic thrice-weekly administration of low and high-dose clozapine to mutant superoxide dismutase 1 (SOD1(G93A)) mice produced differential effects on disease onset and survival. Low-dose treatment was associated with delayed locomotor impairment and death, compared to high-dose clozapine, which accelerated paralysis and mortality (P < 0.05). Increased death was not attributable to toxicity, as clozapine-induced agranulocytosis was not detected from blood analysis. High-dose clozapine, however, produced extrapyramidal symptoms in mice manifest by hindlimb rigidity, despite reducing spinal cord p75(NTR) levels overall. These results suggest that although clozapine may exert p75(NTR)-mediated neuroprotective activity in vitro, its profound antagonistic effects on dopaminergic and serotonergic systems in vivo at high doses may exacerbate the phenotype of transgenic ALS mice.
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PMID:Opposing effects of low and high-dose clozapine on survival of transgenic amyotrophic lateral sclerosis mice. 1459 5

There is growing evidence that 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is active in the brain but until recently there was a lack of evidence about its role during brain development. Guided by certain features of the epidemiology of schizophrenia, our group has explored the role of 1,25(OH)(2)D(3) in brain development using whole animal models and in vitro culture studies. The expression of the vitamin D receptor (VDR) in the embryonic rat brain rises steadily between embryonic day 15-23, and 1,25(OH)(2)D(3) induces the expression of nerve growth factor and stimulates neurite outgrowth in embryonic hippocampal explant cultures. In the neonatal rat, low prenatal vitamin D(3) in utero leads to increased brain size, altered brain shape, enlarged ventricles, reduced expression of nerve growth factors, reduced expression of the low affinity p75 receptor and increased cellular proliferation. In summary, there is growing evidence that low prenatal levels of 1,25(OH)(2)D(3) can influence critical components of orderly brain development. It remains to be seen if these processes are of clinical relevance in humans, but in light of the high rates of hypovitaminosis D in pregnant women and neonates, this area warrants further scrutiny.
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PMID:Vitamin D3-implications for brain development. 1522 38

A decrease in the number of nicotinic-acetylcholine receptors (nAChRs) in the brain is thought to contribute to the cognitive dysfunction associated with diseases as diverse as Alzheimer's disease and schizophrenia. Interestingly, nicotine and similar compounds have been shown to enhance memory function and increase the expression of nAChRs and therefore, could have a therapeutic role in the aforementioned diseases. Nicotine has also been shown to exert positive effects on certain neurotrophins such as nerve growth factor (NGF), and therefore could play a role beyond mere symptomatic therapy. However, to date, comprehensive studies of nicotine's effects on the expression of specific acetylcholine (ACh) receptor subtypes, key cholinergic proteins (that are regulated by NGF) such as choline acetyltransferase (ChAT) and the vesicular ACh transporter (VAChT) are lacking. Studies to further investigate the effects of nicotine on NGF especially its high- and low-affinity receptors are also needed. In the present study, male Wistar rats exposed a relatively low dosage of nicotine (0.35 mg/kg every 12 h) for 14 days demonstrated improved memory performance (assessed in two separate water maze testing methods) when compared with controls. Autoradiographic experiments indicated that nicotine increased [3H]-epibatidine, [125I]-alpha-bungarotoxin and [3H]-AFDX384, but not [3H]-pirenzepine binding sites in several learning- and memory-related brain areas. The expression of ChAT, VAChT, as well as tropomyosin-receptor kinase A (TrkA) NGF receptors and phospho-TrK receptors was increased by nicotine in the hippocampus. No changes were observed in the levels of the NGF peptide or low affinity p75 neurotrophin receptors (p75NTR), however. These results suggest that repeated exposure to nicotine results in positive effects on central cholinergic markers and memory function, which may be mediated via effects on high-affinity NGF receptors.
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PMID:Repeated nicotine exposure in rats: effects on memory function, cholinergic markers and nerve growth factor. 1565 96

First and second generation antipsychotics (FGAs and SGAs) ameliorate psychotic symptoms of schizophrenia, however, their chronic effects on information processing and memory function (i.e. key determinants of long term functional outcome) are largely unknown. In this rodent study the effects of different time periods (ranging from 2 weeks to 6 months) of oral treatment with the FGA, haloperidol (2.0 mg/kg/day), or the SGA, risperidone (2.5 mg/kg/day) on a water maze repeated acquisition procedure, the levels of nerve growth factor receptors, and two important cholinergic proteins, the vesicular acetylcholine transporter and the high affinity choline transporter were evaluated. The effects of the antipsychotics on a spontaneous novel object recognition procedure were also assessed during days 8-14 and 31-38 of treatment. Haloperidol (but not risperidone) was associated with impairments in water maze hidden platform trial performance at each of the time periods evaluated up to 45 days, but not when tested during days 83-90. In contrast, risperidone did not impair water maze task performance at the early time periods and it was actually associated with improved performance during the 83-90 day period. Both antipsychotics, however, were associated with significant water maze impairments during the 174-180 day period. Further, haloperidol was associated with decrements in short delay performance in the spontaneous novel object recognition task during both the 8-14 and 31-38 day periods of treatment, while risperidone was associated with short delay impairment during the 31-38 day time period. Both antipsychotics were also associated with time dependent alterations in the vesicular acetylcholine transporter, the high affinity choline transporter, as well as tyrosine kinase A, and p75 neurotrophin receptors in specific brain regions. These data from rats support the notion that while risperidone may hold some advantages over haloperidol, both antipsychotics can produce time-dependent alterations in neurotrophin receptors and cholinergic proteins as well as impairments in the performance of tasks designed to assess spatial learning and episodic memory.
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PMID:Oral haloperidol or risperidone treatment in rats: temporal effects on nerve growth factor receptors, cholinergic neurons, and memory performance. 1743 84

The primary therapeutic agents used for schizophrenia, antipsychotic drugs, ameliorate psychotic symptoms; however, their chronic effects on cognition (or the physiologic processes of the brain that support cognition) are largely unknown. The purpose of this rodent study was to extend our previous work on this subject by investigating persistent effects (i.e. during a 14 day drug-free washout period) of chronic treatment (i.e. ranging from 45 days to 6 months) with a representative first and second generation antipsychotic. Drug effects on learning and memory and important neurobiological substrates of memory, the neurotrophin, nerve growth factor (NGF) and its receptors, and certain components of the basal forebrain cholinergic system were investigated. Behavioral effects of oral haloperidol (2.0 mg/kg/day), or risperidone (2.5 mg/kg/day) were assessed in an open field, a water maze task, and a radial arm maze procedure and neurochemical effects in brain tissue were subsequently measured by enzyme-linked immunosorbent assays (ELISAs). The results indicated that both antipsychotics produced time-dependent and protracted deficits in the performance of a water maze procedure when compared with vehicle-treated controls, while neither drug was associated with significant alterations in radial arm maze performance. Interestingly, haloperidol, but not risperidone, was detectible in the rodent brain in appreciable levels for up to 2 weeks after drug discontinuation. Both antipsychotics were also associated with reduced levels of NGF protein in the basal forebrain and prefrontal cortex and significant (or nearly significant) decreases in phosphorylated tropomyosin-receptor kinase A (TrkA) protein and the vesicular acetylcholine transporter (depending on the brain region analyzed). Neither antipsychotic markedly affected TrkA or p75 neurotrophin receptor levels. These data in rats indicate that chronic treatment with either haloperidol or risperidone may be associated with protracted negative effects on cognitive function as well as important neurotrophin and neurotransmitter pathways that support cognition.
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PMID:Protracted effects of chronic oral haloperidol and risperidone on nerve growth factor, cholinergic neurons, and spatial reference learning in rats. 1794 37


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