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)

Growing consistent evidence indicates that hypofunction of N-methyl-D-aspartate (NMDA) transmission plays a pivotal role in the neuropathophysiology of schizophrenia. Hence, drugs which modulate NMDA neurotransmission are promising approaches to the treatment of schizophrenia. The aim of this article is to review clinical trials with novel compounds acting on the NMDA receptor (NMDA-R). This review also includes a discussion and translation of neuroscience into schizophrenia therapeutics. Although the precise mechanism of action of minocycline in the brain remains unclear, there is evidence that it blocks the neurotoxicity of NMDA antagonists and may exert a differential effect on NMDA signaling pathways. We, therefore, hypothesize that the effects of minocycline on the brain may be partially modulated by the NMDA-R or related mechanisms. Thus, we have included a review of minocycline neuroscience. The search was performed in the PubMed, Web of Science, SciELO, and Lilacs databases. The results of glycine and D-cycloserine trials were conflicting regarding effectiveness on the negative and cognitive symptoms of schizophrenia. D-serine and D-alanine showed a potential effect on negative symptoms and on cognitive deficits. Sarcosine data indicated a considerable improvement as adjunctive therapy. Finally, minocycline add-on treatment appears to be effective on a broad range of psychopathology in patients with schizophrenia. The differential modulation of NMDA-R neurosystems, in particular synaptic versus extrasynaptic NMDA-R activation and specific subtypes of NMDA-R, may be the key mediators of neurogenesis and neuroprotection. Thus, psychotropics modulating NMDA-R neurotransmission may represent future monotherapy or add-on treatment strategies in the treatment of schizophrenia.
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PMID:Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update. 1985

Recent evidence indicates that enhancing N-methyl-D-aspartate (NMDA) neurotransmission with the treatment of NMDA/glycine site agonists, such as D-serine, or a glycine transporter-1 (GlyT-1) antagonist, N-methylglycine (sarcosine), can improve symptoms of schizophrenia. To compare these two novel approaches, 60 patients with chronic schizophrenia were enrolled into a 6-wk double-blind, placebo-controlled trial of add-on treatments at the reported effective dosages (2 g/d). Clinical assessments were conducted every other week. Treatment group x treatment duration interaction analysis by multiple linear regression showed that sarcosine was superior to placebo at all four outcome measures of Positive and Negative Syndrome Scale (PANSS) total (p=0.005), Scale for the Assessment of Negative Symptoms (SANS) (p=0.021), Quality of Life (QOL) (p=0.025), and Global Assessment of Functioning (GAF) (p=0.042). However, d-serine did not differ significantly from placebo in any measure. Sarcosine treatment was better than d-serine in effect sizes for all outcome measures. Sarcosine also surpassed placebo in most of the measures of five PANSS factors and five SANS subscales. All treatments were well tolerated. These findings suggest that the GlyT-1 inhibitor is more efficacious than the NMDA/glycine site agonist in treatment for schizophrenia, including life quality and global function, at the dosages tested.
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PMID:A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia. 1988 19

Although hypofunction of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission is proposed to play an important role in the pathophysiology of schizophrenia, results of the clinical trials of small molecules that enhance the NMDA function are inconsistent. A meta-analysis of all the double-blind, placebo-controlled studies in patients with schizophrenia was performed to examine their efficacy on different symptom domains, the dose-response, the effects of concomitant antipsychotics, and their side effects. About eight hundred subjects from 26 studies were included in current meta-analysis. Overall, the NMDA-enhancing molecules are effective in most schizophrenic symptom domains with the effect size (ES) of total psychopathology of 0.40 (p<1 x 10(-4)). The ES of clinical efficacy of the symptom domains were in the order of depressive (0.40, p=3 x 10(-4)), negative (0.38, p<1 x 10(-4)), cognitive (0.28, p=2 x 10(-3)), positive symptom (0.26, p=0.0006), and general psychopathology (0.26, p=0.006). Glycine, D-serine, and sarcosine treatments significantly improved multiple symptom domains, whereas D-cycloserine did not improve any symptom domain. Moderator analysis revealed that glycine, D-serine and sarcosine are better than D-cycloserine in improving the overall psychopathology. Patients receiving risperidone or olanzapine, but not clozapine, improved. No significant side effect or safety concern was noted. In addition to testing more lead compounds, long-term trials are required to determine their functional improvement capacity. Other drug targets that may enhance NMDA neurotransmission more than the molecules tested so far need to be explored.
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PMID:Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis. 1990 29

Neboglamine is a functional modulator of the glycine site on the N-methyl-d-aspartate (NMDA) receptor. Dysfunction of this receptor has been associated with negative and cognitive symptoms in schizophrenia. Thus, we tested the hypothesis that neboglamine behaves as a potential antipsychotic. We compared the effects of neboglamine, D-serine, clozapine, and haloperidol on the expression of Fos-like immunoreactivity (FLI), a marker of neuronal activation, in rat forebrain. We also studied the effects of these agents on phencyclidine (PCP)-induced behaviour in rats, a model predictive of potential antipsychotic activity. Neboglamine, like haloperidol and clozapine, significantly increased the number of FLI-positive cells in the prefrontal cortex, nucleus accumbens, and lateral septal nucleus (3.2-, 4.8-, and 4.5-fold over control, respectively). Haloperidol dramatically increased FLI (390-fold over control) in the dorsolateral striatum, a brain region in which neboglamine and clozapine had no effect. The pattern of FLI induced by neboglamine closely matched that of d-serine, an endogenous agonist at the glycine site of NMDA receptors. Consistent with this finding, neboglamine restored NMDA-mediated neurotransmitter release in frontal cortex punches exposed to the NMDA antagonist PCP. In the behavioural model, all test compounds significantly inhibited PCP-induced hyperlocomotion. Unlike haloperidol and clozapine, neither neboglamine nor D-serine affected the basal levels of locomotor activity. Moreover, oral neboglamine dose-dependently inhibited both the hyperlocomotion and the frequency of rearing behaviour induced by PCP. These results, while confirming that the NMDA glycine site is a feasible target for activating the frontostriatal system, support the clinical evaluation of neboglamine as a treatment for schizophrenia.
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PMID:Antipsychotic-like effects of the N-methyl-D-aspartate receptor modulator neboglamine: an immunohistochemical and behavioural study in the rat. 2004 56

D-serine is an endogenous N-methyl-D-aspartate (NMDA) receptor coagonist. It is synthesized from L-serine by serine racemase (SRR), but many aspects of its metabolism remain unclear, especially in the forebrain, which lacks active D-amino acid oxidase (DAO), the major D-serine degradative enzyme. Candidate mechanisms include SRR operating in alpha,beta-eliminase mode (converting D-serine to pyruvate) and regulation by serine transport, in which the alanine-serine-cysteine transporter ASCT2 is implicated. Here we report studies in C6 glioma cells, which "simulate" the forebrain, in that the cells express SRR and ASCT2 but lack DAO activity. We measured D-serine, ASCT2, SRR, and DAO expression and DAO activity in two situations: after incubation of cells for 48 hr with serine isomers and after increased or decreased SRR expression by transfection and RNA interference, respectively. Incubation with serine enantiomers decreased [(3)H]D-serine uptake and ASCT2 mRNA and increased SRR immunoreactivity but did not alter DAO immunoreactivity, and DAO activity remained undetectable. SRR overexpression increased D-serine and pyruvate and decreased [(3)H]D-serine uptake and ASCT2 mRNA but did not affect DAO. SRR knockdown did not alter any of the parameters. Our data suggest that D-serine transport mediated by ASCT2 contributes prominently to D-serine homeostasis when DAO activity is absent. The factors regulating D-serine are important for understanding normal NMDA receptor function and because D-serine, along with DAO and SRR, is implicated in the pathogenesis and treatment of schizophrenia.
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PMID:D-Serine metabolism in C6 glioma cells: Involvement of alanine-serine-cysteine transporter (ASCT2) and serine racemase (SRR) but not D-amino acid oxidase (DAO). 2009 74

Currently prescribed antipsychotics attenuate the positive symptoms of schizophrenia but fail or only mildly improve negative symptoms. The present study aimed to establish an animal model of negative symptoms by examining the effects of the NMDA receptor antagonist MK-801 on sucrose preference. We sought to validate the model by examining the effects of clozapine and D-serine, for which there are positive clinical data regarding their effects on negative symptoms, and haloperidol which is clinically ineffective. We extended our analysis by examining CDPPB, an mGlu5 receptor positive allosteric modulator. Acute MK-801 produced effects indicative of a shift in the hedonic experience of sucrose not confounded by disruptions in motor abilities or taste as revealed by: 1) a decrease in sucrose intake at low concentrations (0.8% or 1.2%), but no effect on water, 2) an increase in consumption for higher (7%) sucrose concentrations, reflecting a shift to the right in the concentration-consumption curve, and 3) no effect on quinine intake. Sub-chronic clozapine and acute d-serine attenuated the MK-801-induced deficit in 1.2% sucrose consumption, whereas sub-chronic haloperidol (0.02 mg/kg) did not. Finally, acute treatment with CDPPB also attenuated this deficit. These data suggest that this model may be useful for identifying novel agents that improve negative symptoms, and that compounds which enhance NMDA receptor function, such as mGlu5 receptor PAMs, may have clinical utility in this regard.
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PMID:MK-801 produces a deficit in sucrose preference that is reversed by clozapine, D-serine, and the metabotropic glutamate 5 receptor positive allosteric modulator CDPPB: relevance to negative symptoms associated with schizophrenia? 2012 52

Neurotensin (NT) is a tridecapeptide that acts as a neuromodulator in the central nervous system mainly through two NT receptors: NTS1 and NTS2. The present study was done to determine the roles of NTS1 and NTS2 on amino acid release in striatum with the use of NTS1 or NTS2 knockout ((-/-)) mice given d-amphetamine. Both NTS1(-/-) and NTS2(-/-) mice had lower extracellular concentrations of D-serine in striatum than did wild type (WT) mice. NTS2(-/-) but not NTS1(-/-) mice also had significantly lower basal concentrations of glutamate in striatum as compared to that for WT mice. Systemic administration of d-amphetamine (4 mg/kg, ip) increased glutamate release by 500% in WT mice, as compared to 300% in NTS2(-/-) mice, and 250% in NTS1(-/-) mice. Additionally, d-amphetamine injection caused a 4-fold increase in GABA release in both WT and NTS2(-/-) mice, but only a 2-fold increase in NTS1(-/-) mice. Therefore, NTS1 and NTS2 modulate basal release of D-serine and glutamate, and also d-amphetamine-induced GABA and glutamate release in striatum. These results provide further support for the involvement of NT receptors in the pathogenesis of schizophrenia and provide a better understanding of the imbalance of amino acid systems through investigation of a DA-based animal model.
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PMID:Effect of amphetamine on extracellular concentrations of amino acids in striatum in neurotensin subtype 1 and 2 receptor null mice: a possible interaction between neurotensin receptors and amino acid systems for study of schizophrenia. 2019 96

In the past 20 years, an extra layer of information processing, in addition to that provided by neurons, has been proposed for the CNS. Neuronally evoked increases of the intracellular calcium concentration in astrocytes have been suggested to trigger exocytotic release of the 'gliotransmitters' glutamate, ATP and D-serine. These are proposed to modulate neuronal excitability and transmitter release, and to have a role in diseases as diverse as stroke, epilepsy, schizophrenia, Alzheimer's disease and HIV infection. However, there is intense controversy about whether astrocytes can exocytose transmitters in vivo. Resolving this issue would considerably advance our understanding of brain function.
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PMID:Do astrocytes really exocytose neurotransmitters? 2030 Jan 1

In human brain the flavoprotein D-amino acid oxidase (hDAAO) is responsible for the degradation of the neuromodulator D-serine, an important effector of NMDA-receptor mediated neurotransmission. Experimental evidence supports the concept that D-serine concentration increase by hDAAO inhibition may represent a valuable therapeutic approach to improve the symptoms in schizophrenia patients. This study investigated the effects on hDAAO conformation and stability of the substrate D-serine (or of the pseudo-substrate trifluoro-D-alanine), the FAD cofactor, and two inhibitors (benzoate, a classical substrate-competitive inhibitor and the drug chlorpromazine (CPZ), which competes with the cofactor). We demonstrated that all these compounds do not alter the interaction of hDAAO with its physiological partner pLG72. The ligands used affect the tertiary structure of hDAAO differently: benzoate or trifluoro-D-alanine binding increases the amount of the holoenzyme form in solution and stabilizes the flavoprotein, while CPZ binding favors a protein conformation resembling that of the apoprotein, which is more sensitive to degradation. Interestingly, the apoprotein form of hDAAO binds the substrate D-serine: this interaction increases FAD binding thus increasing the amount of active holoenzyme in solution. Benzoate and CPZ similarly modify the short-term cellular D-serine concentration but affect the cellular concentration of hDAAO differently. In conclusion, the different alteration of hDAAO conformation and stability by the ligands used represents a further parameter to take into consideration during the development of new drugs to cope schizophrenia.
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PMID:Effect of ligand binding on human D-amino acid oxidase: implications for the development of new drugs for schizophrenia treatment. 2052 34

D-amino acid oxidase (DAO) catalyzes oxidative deamination of D-amino acids. Since D-amino acids are considered to be rare in eukaryotes, physiological function of this enzyme has been enigmatic for a long time. Mutant mice lacking DAO were found, and their strain was established. The urine of the mutant mice contained large amounts of D-amino acids. D-Amino acids were also present in their organs and blood. The origin of these D-amino acids was pursued. The results indicate that one of the physiological functions of DAO is the metabolism of D-amino acids of internal and external origin. A large amount of D-serine is shown to exist in the brain of mammals. It binds to the coagonist-binding site of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors and enhances the neurotransmission. DAO metabolizes this D-serine and, therefore, modulates neurotransmission. Mutant mice displayed phenotypes resulting from the enhanced NMDA receptor function. Recent studies have shown that DAO is associated with schizophrenia. Mutant mice were resistant to the drugs which act on NMDA receptors and elicit schizophrenia-like symptoms. Recently, mutant rats lacking DAO have also been found. They were free from D-serine-induced nephrotoxicity, indicating involvement of DAO in this toxicity. The mutant mice and rats lacking DAO would be useful for the elucidation of the physiological functions of DAO and the etiology of neuronal diseases associated with DAO.
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PMID:Mutant mice and rats lacking D-amino acid oxidase. 2056 63


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