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)

We investigated the effects of a schizophrenomimetic drug, phencyclidine (PCP), on substance P (SP) contents in the discrete rat brain areas using an enzyme-immunoassay for SP. The acute intraperitoneal (i.p.) administration of PCP (10 mg/kg), which is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) type glutamate receptor and a dopamine uptake inhibitor, reduced the concentration of the peptide in the prefrontal cortex, limbic forebrain, striatum, and substantia nigra, but not in the ventral tegmental area, at 60 or 120 min postinjection. A selective noncompetitive NMDA antagonist, dizocilpine hydrogen maleate ((+)-MK-801) (1 mg/kg, i.p.), also caused a decrease in the SP content in the prefrontal cortex and limbic forebrain but failed to alter the content in the other areas studied 30 min thereafter. Dopamine agonists, methamphetamine (4.8 mg/kg, i.p.) and apomorphine (4.4 mg/kg, i.p.), diminished the SP contents in the striatum and substantia nigra 60 min after their injection without effects in the prefrontal cortex, limbic forebrain, and ventral tegmental area. Furthermore, pretreatment with haloperidol (1 mg/kg, i.p.), a D2 preferable dopamine receptor antagonist and a typical antipsychotic, blocked the ability of PCP to decrease the SP concentrations in the substantia nigra but not in the prefrontal cortex. PCP, therefore, might diminish the SP levels by NMDA receptor-mediated and dopamine-independent mechanisms in the prefrontal cortex and limbic forebrain, but by NMDA receptor-independent and dopamine-dependent mechanisms in the striatum and substantia nigra. The haloperidol-insensitive reduction of the frontal SP could be involved in certain neuroleptic-resistant symptoms of PCP-treated animals, PCP psychosis, or schizophrenia.
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PMID:Differential effects of haloperidol on phencyclidine-induced reduction in substance P contents in rat brain regions. 1065 39

Numerous studies have shown alterations of some structures and/or cerebral functions in patients with schizophrenia. However, the nature of the neurobiological process which could be at the origin of schizophrenic symptoms is still unknown. Magnetic resonance spectroscopy (MRS) is a unique technique which allows us to estimate the concentrations of endogenous substances which contain natural paramagnetic nuclei such as phosphorus (31P) and hydrogen (proton or 1H). The non invasive character of this technique, the absence of side effects, and the possibility of repetitive evaluations allowing for longitudinal studies, make possible MRS studies on the in vivo cerebral metabolism in schizophrenia. The prefrontal cortex, the hippocampus and the basal ganglia have all been implicated in the pathophysiology of schizophrenia. Therefore these brain regions have been frequently studied using MRS. Both proton and phosphorus spectroscopy have been used to study schizophrenia. Compounds that are detectable by 1H-MRS include N-acetyl aspartate (NAA), choline (Cho), creatine (Cr) and myo-inositol (ml). A deficit in NAA has been consistently shown in both the frontal and temporal lobes suggesting neuronal loss in these areas. Compounds detectable by 31P-MRS include phosphomonoesters (PMEs) and phosphodiesters (PDEs), which largely represent metabolites generated by lipid turnover. 31P-MRS can also detect certain energy-containing phosphorus metabolites such as phosphocreatine (PCr) and nucleotide triphosphates. Decreased levels of PMEs and increased levels of PDEs have been consistently described in the prefrontal lobes suggesting an alteration of phospholipid metabolism. The purpose of this review is to summarize the research on schizophrenia using MRS, to show the utility of this technique in understanding schizophrenia.
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PMID:[Magnetic resonance spectroscopy in schizophrenia]. 1087 59

(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (4, LY354740), a highly selective and orally active group II metabotropic glutamate receptor (mGluR) agonist, has increased interest in the study of group II mGluRs. Our interest focused on a conformationally constrained form of compound 4, because it appeared that the rigid form resulted in not only selectivity for group II mGluR but was orally active. Therefore, we introduced a fluorine atom to compound 4, based on the molecular size (close resemblance to hydrogen atom) and electronegativity (effects on the electron distribution in the molecule) of this atom and carbon-fluorine bond energy. Compound (+)-7 (MGS0008), the best compound among 3-fluoro derivatives 7-10, retained the agonist activity of compound 4 for mGluR2 and mGluR3 ((+)-7: EC(50) = 29.4 +/- 3.3 nM and 45.4 +/- 8.4 nM for mGluR2 and mGluR3, respectively; 4: EC(50) = 18.3 +/- 1.6 nM and 62.8 +/- 12 nM for mGluR2 and mGluR3, respectively) and increased the oral activity of compound 4 ((+)-7: ED(50) = 5.1 mg/kg and 0.26 mg/kg for phencyclidine (PCP)-induced hyperactivity and PCP-induced head-weaving behavior, respectively; 4: ED(50) = >100 mg/kg and 3.0 mg/kg for PCP-induced hyperactivity and PCP-induced head-weaving behavior, respectively). In addition, a compound [(3)H]-(+)-7 binding study using mGluR2 or 3 expressed in CHO cells was successful ((+)-7: K(i) = 47.7 +/- 17 nM and 65.9 +/- 7.1 nM for mGluR2 and mGluR3, respectively; 4: K(i) = 23.4 +/- 7.1 nM and 53.5 +/- 13 nM for mGluR2 and mGluR3, respectively). On the basis of a successful result of compound 7, we focused on the introduction of a fluorine atom on the C6 position of compound 4. (1R,2S,5R, 6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid ((-)-11) exhibited a high degree of agonist activity for group II mGluRs equal to that of compound 4 or 7 ((-)-11: K(i) = 16.6 +/- 5.6 and 80.9 +/- 31 nM for mGluR2 and mGluR3, respectively). Our interest shifted to modification on CH(2) at C4 position of compound 11, since replacement of the CH(2) group with either an oxygen atom or sulfur atom yielded compound 5 or 6, resulting in increased agonist activity. We selected a carbonyl group instead of CH(2) at the C4 position of compound 11. The carbonyl group might slightly change the relative conformation of three functional groups, the amino group and two carboxylic acids, which have important roles in mediating the interaction between group II mGluRs and their ligand, compared with the CH(2) group of 4, oxygen atom of 5, and sulfur atom of 6. (1R,2S,5S,6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1. 0]hexane-2,6-dicarboxylic acid monohydrate ((+)-14, MGS0028) exhibited a remarkably high degree of agonist activity for mGluR2 (K(i) = 0.570 +/- 0.10 nM) and mGluR3 (K(i) = 2.07 +/- 0.40 nM) expressed in CHO cells but not mGluR4, 6, 7, 1a, or 5 expressed in CHO cells (K(i) = >100 000 nM). Furthermore, compound (+)-14 strongly inhibited phencyclidine (PCP)-induced head-weaving behavior (ED(50) = 0.090 microg/kg) and hyperactivity (ED(50) = 0.30 mg/kg) in rats. Thus, (+)-7 and (+)-14 are potent, selective, and orally active group II mGluR agonists and might be useful not only for exploring the functions of mGluRs but in the treatment of schizophrenia.
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PMID:Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists. 1112 99

This review covers certain novel aspects of catecholamine signaling in neurons that involve redox systems and synaptic plasticity. The redox hypothesis suggests that one important factor in neurocomputation is the formation of new synapses and the removal of old ones (synaptic plasticity), which is modulated in part by the redox balance at the synapse between reactive oxygen species (ROS) (such as hydrogen peroxide and the nitric oxide radical) and neuroprotective antioxidants (such as ascorbate, glutathione, and catecholamines). Catecholamines, in particular dopamine, which signals positive reinforcement, may play a key role in this activity. Dopamine has powerful antioxidant properties by several separate mechanisms-direct ROS scavenging, activation of the synthesis of antioxidant proteins, and possibly via dismuting complexes with iron inside endosomes or in catecholaminergic synaptic vesicles. This may contribute to synaptic growth and reinforcement-directed learning. On the other hand, catecholamines are easily oxidized to toxic quinones on the neuromelanin pathway. This might contribute under certain circumstances to synaptic deletion. Evidence is presented that abnormalities in this system may contribute to the pathogenesis of Parkinson's disease and schizophrenia.
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PMID:Redox aspects of signaling by catecholamines and their metabolites. 1122 69

Proton magnetic resonance spectroscopy ((1)H-MRS) is a noninvasive technique that can quantify biochemical compounds in the brain. (1)H-MRS has been used to investigate neural structures implicated in the pathology of schizophrenia. The majority of research has revealed reduced N-acetylaspartate (NAA), an index of neuronal integrity, in frontal and temporal regions of medicated and chronically ill patients with schizophrenia. This review summarizes basic principles of (1)H-MRS, studies of frontal, temporal, subcortical, and cerebellar regions in schizophrenia. Technical and study design limitations are also discussed.
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PMID:Proton magnetic resonance spectroscopy (H-MRS) studies of schizophrenia. 1129 12

Brain metabolic abnormalities and aberrant dopamine (DA) metabolism have been reported in patients with schizophrenia. The authors hypothesized that mitochondria is a primary target of damage by increased free radical generation secondary to increased DA metabolism by monoamine oxidase (MAO). Epstein-Barr virus (EBV)-transformed human B-lymphocytes cell lines derived from patients with schizophrenia and normal controls were incubated in the absence or presence of DA, hydrogen peroxide (H2O2), or rotenone (Rot). The cells were then stained with rhodamine 123 (Rh 123) and analyzed for uptake using flow cytometry. Compared with untreated cells, DA significantly decreased Rh 123 uptake by the mitochondria. This effect was similar to the control cells treated with H2O2 or Rot. Nevertheless, there were no differences in Rh 123 uptake between the cells of schizophrenic patients and normal controls. This study shows that DA can impair the mitochondria membrane potential but that mechanism may not be evident in schizophrenia.
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PMID:Dopamine effect on the mitochondria potential in B lymphocytes of schizophrenic patients and normal controls. 1185 5

Proton magnetic resonance spectra (MRS) were acquired from 1.5 x 1.5 x 1.5-cm voxels in the left and right mesial temporal lobes of 20 schizophrenic patients and 20 non-psychiatric comparison subjects. Choline (Cho) to creatine (and phosphocreatine) (Cr(PCr)) ratios were estimated as were the percent gray matter, white matter and CSF contributing to the voxel. The Cho/Cr(PCr) metabolite ratio was significantly lower in the left temporal lobe than in the right temporal lobe for both the schizophrenia subjects and control group. This difference was greater in the schizophrenia subjects. Left temporal lobe gray matter voxel content was significantly higher and white matter content was significantly lower than in the right temporal lobe for both the schizophrenia subjects and control group. This difference was the same for the schizophrenia subjects and control group. Left voxel gray matter and white matter content correlated with Cho/Cr(PCr) metabolite ratios for the schizophrenic subjects but not for the control subjects. No such correlations were noted on the right side. No significant difference was found between Cho/Cr(PCr) in the left temporal lobe or in the right temporal lobe of the schizophrenia subjects vs. the control group.
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PMID:Mesial temporal lobe Cho to Cr(PCr) ratio asymmetry in chronic schizophrenics. 1216 74

DMP 406 is a clozapine analogue developed by Dupont-Pharma for the treatment of schizophrenia. Unfortunately it caused agranulocytosis in dogs during preclinical studies. Clozapine also causes agranulocytosis and this is believed to be due to a reactive nitrenium ion metabolite produced by neutrophils. We studied the oxidation of DMP 406 by activated neutrophils and found that the major reactive species that is produced is not a nitrenium ion but rather an imine. This metabolite is similar to the reactive metabolite that has been proposed to be responsible for mianserin-induced agranulocytosis. Therefore we also studied the oxidation of mianserin by activated neutrophils and found that, although the major species is an iminium ion, it also bears a lactam moiety in the piperazine ring resulting from further oxidation. We usually find that HOCl is a good model system for the production of reactive metabolites of drugs that are formed by activated neutrophils, but in the case of both DMP 406 and mianserin, the products produced were significantly different than those formed by activated neutrophils. In contrast, the combination of horseradish peroxidase and hydrogen peroxide (HRP/H(2)O(2)) formed a very similar pattern of products, and this system was used to produce sufficient quantities of metabolites to allow for identification. The reactive metabolites of both DMP 406 and mianserin reacted with a range of nucleophiles, but in many cases the reaction was reversible. The best nucleophile for trapping these reactive metabolites was cyanide. It has been demonstrated that the products of clozapine oxidation by HRP/H(2)O(2), presumably the nitrenium ion, induced apoptosis in neutrophils at therapeutic concentrations of clozapine. It has been suggested that this process is involved in the mechanism of clozapine-induced agranulocytosis. We tested DMP 406 and mianserin in this system to see if the ability of a reactive metabolite of a drug to cause apoptosis could predict the ability of that drug to cause agranulocytosis. We used clozapine as a positive control and we also tested olanzapine, a drug that forms a reactive metabolite similar to that of clozapine but is given at a lower dose and does not cause agranulocytosis. We found that DMP 406 did not increase apoptosis at concentrations below 50 microM, and although mianserin did increase apoptosis at 10 microM this is above the therapeutic concentration. Olanzapine caused an increase in apoptosis at the same concentration as clozapine (1 microM), but because its therapeutic concentration is lower, this concentration was above the pharmacological range. There was no increase in apoptosis with any drug in the absence of HRP/H(2)O(2). These results indicate that this assay is unable to reliably predict the ability of different types of drugs to cause agranulocytosis. This is not a surprising result given that different drugs may induce agranulocytosis by different mechanisms.
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PMID:Predicting drug-induced agranulocytosis: characterizing neutrophil-generated metabolites of a model compound, DMP 406, and assessing the relevance of an in vitro apoptosis assay for identifying drugs that may cause agranulocytosis. 1239 62

DMSO is an amphipathic molecule with a highly polar domain and two apolar methyl groups, making it soluble in both aqueous and organic media. It is one of the most common solvents for the in vivo administration of several water-insoluble substances. Despite being frequently used as a solvent in biological studies and as a vehicle for drug therapy, the side-effects of DMSO (undesirable for these purposes) are apparent from its utilization in the laboratory (both in vivo and in vitro) and in clinical settings. DMSO is a hydrogen-bound disrupter, cell-differentiating agent, hydroxyl radical scavenger, intercellular electrical uncoupler, intracellular low-density lipoprotein-derived cholesterol mobilizing agent, cryoprotectant, solubilizing agent used in sample preparation for electron microscopy, antidote to the extravasation of vesicant anticancer agents, and topical analgesic. Additionally, it is used in the treatment of brain edema, amyloidosis, interstitial cystitis, and schizophrenia. Several systemic side-effects from the use of DMSO have been reported, namely nausea, vomiting, diarrhea, hemolysis, rashes, renal failure, hypertension, bradycardia, heart block, pulmonary edema, cardiac arrest, and bronchospasm. Looking at the multitude of effects of DMSO brought to light by these studies, it is easily understood how many researchers working with DMSO (or studying one of its specific effects) might not be fully aware of the experiences of other groups who are working with it but in a different context.
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PMID:Multidisciplinary utilization of dimethyl sulfoxide: pharmacological, cellular, and molecular aspects. 1266 39

How glutamate regulates dopamine (DA) release in striatum has been a controversial issue. Here, we resolve this by showing that glutamate, acting at AMPA receptors, inhibits DA release by a nonclassic mechanism mediated by hydrogen peroxide (H(2)O(2)). Moreover, we show that GABA(A)-receptor activation opposes this process, thereby enhancing DA release. The influence of glutamate and GABA on DA release was assessed in striatal slices using carbon-fiber microelectrodes and fast-scan cyclic voltammetry. Modulation by both transmitters was prevented by H(2)O(2)-metabolizing enzymes. In addition, the influence of GABA(A)-receptor activation was lost when AMPA receptors were blocked with GYKI-52466. Together, these data show that modulation of DA release by glutamate and GABA depends on H(2)O(2) generated downstream from AMPA receptors. This is the first evidence that endogenous glutamate can lead to the generation of reactive oxygen species under physiological conditions. We also show that inhibition of DA release by H(2)O(2) is mediated by sulfonylurea-sensitive K(+) channels: tolbutamide blocked DA modulation by glutamate and by GABA. The absence of ionotropic glutamate or GABA receptors on DA terminals indicates that modulatory H(2)O(2) is generated in non-DA cells. Thus, in addition to its known excitatory actions in striatum, glutamate mediates inhibition by generating H(2)O(2) that must diffuse from postsynaptic sites to inhibit presynaptic DA release via K(+)-channel opening. These findings have significant implications not only for normal striatal function but also for understanding disease states that involve DA and oxidative stress, including disorders as diverse as Parkinson's disease and schizophrenia.
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PMID:Glutamate-dependent inhibition of dopamine release in striatum is mediated by a new diffusible messenger, H2O2. 1268 60


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