Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebrospinal fluid (CSF) cyclic GMP may derive from central cholinergic neurotransmission. Measurement of CSF cyclic GMP may allow evaluation of possible implications of the dopaminergic hyperactivity in schizophrenia proposed by the dopamine hypothesis. The CSF cyclic GMP levels in 27 drug-free schizophrenic patients was measured and compared to that in 9 psychiatrically-healthy individuals. The mean CSF cyclic GMP level of the schizophrenic patients was 23 per cent lower than that of the control group, but this difference did not attain statistical significance. In addition the CSF cyclic GMP levels in a group of 10 schizophrenic patients were compared before and after 2 months of neuroleptic treatment. The mean level of cyclic GMP rose 50 per cent after treatment with phenothiazines (P less than 0.05). These results could indicate some tendency for decreased activity of central cholinergic neurons in schizophrenia as well as a restored dopaminergic-cholinergic balance after neuroleptic treatment.
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PMID:Cyclic GMP in the CSF of patients with schizophrenia before and after neuroleptic treatment. 1 48

The experiment adopted radioimmunoassay to assay CSF, platelets cAMP cGMP levels of a group of Schizophrenia patients, and made a correlation analysis between the cAMP, cGMP and the evaluated factor scores of BPRS and SCL-90. The results showed: (1)CSF cAMP level of Schizophrenics was significantly higher than normal controls; (2)There was a significantly positive correlation between CSF cAMP and BPRS factor 1, a significantly negative correlation between platelets cAMP and BPRS factor 3, a significantly positive correlation between CSF cAMP and SCL-90 factor 5,8. The paper discussed the similarities and differences between the results of this experiment and the former studies.
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PMID:[Assaying the SCF platelets cyclic nucleotides of schizophrenics and analyzing its correlation with pathopschological factors]. 217 85

A yin-yang hypothesis is presented linking noradrenergic activity, thromboxane, melatonin, left hemisphere functioning, and cyclic AMP on the one hand, and dopamine, beta-endorphin, calcium, right hemisphere functioning, and cyclic GMP on the other. It is further suggested that there is a yoking of NA, TXA2, serotonin and melatonin in the left hemisphere, and a similar yoking of DA, BE, calcium and cGMP in the right. Evidence is presented to support the hypothesis that each element (NA, TXA2, etc.) on one side can modulate or balance a corresponding element (DA, BE, etc.) on the other. It is suggested that thromboxane is the key element in noradrenergic overactivity and that not taking this into consideration has confounded much prior research. This theory takes into account information processing models as well as pharmacological data and neurochemical theory on coupling of adenylate cyclase to its hormone receptors. Inhibiting noradrenergic overactivity can be obtained by inhibiting thromboxane and concomitantly activating opiate receptors. This protocol may have clinical utility in treating a wide range of disorders such as: anxiety, depression, schizophrenia, sleeplessness, withdrawal states, enuresis, Gilles de la Tourette syndrome, Parkinsonism, Alzheimers, dementia, anorexia, infant ruminations, essential tremor, spasticity of spinal cord injury, diarrhoea, ulcerative colitis, extrapyramidal symptoms, akathisia, neuroleptic malignant syndrome, attention deficit disorder, hyperhidrosis, and possibly AIDS.
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PMID:Inhibiting noradrenergic overactivity by inhibition of thromboxane and concomitant activation of opiate receptors via dietary means. 254 22

We demonstrated the presence of circulating Abs from schizophrenic patients able to interact with cerebral frontal cortex-activating muscarinic acetylcholine receptors (mAChR). Sera and purified IgG from 21 paranoid schizophrenic and 25 age-matched normal subjects were studied by indirect immunofluorescence, flow cytometry, immunoblotting, dot blot, ELISA, and radioligand competition assays. Rat cerebral frontal cortex membranes and/or a synthetic peptide, with an amino acid sequence identical with that of human M(1) mAChR, were used as Ags. By indirect immunofluorescence and flow cytometry procedures, we proved that serum-purified IgG fraction from schizophrenic patients reacted to neural cell surfaces from rat cerebral frontal cortex. The same Abs were able to inhibit the binding of the specific M(1) mAChR radioligand [(3)H]pirenzepine. Immunoblotting experiments showed that IgG from schizophrenic patients revealed a band with a molecular mass coincident to that labeled by an anti-M(1) mAChR Ab. Using synthetic peptide for dot blot and ELISA, we demonstrated that these Abs reacted against the second extracellular loop of human cerebral M(1) mAChR. Also, the corresponding affinity-purified antipeptide Ab displayed an agonistic-like activity associated to specific receptor activation, increasing cyclic GMP production and inositol phosphate accumulation, and protein kinase C translocation. This paper gave support to the participation of an autoimmune process in schizophrenia.
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PMID:Antibodies against cerebral M1 cholinergic muscarinic receptor from schizophrenic patients: molecular interaction. 1190 33

A disruption of corticostriatal signaling is believed to underlie the psychotic symptoms of schizophrenia and also contribute to many of the cognitive deficits associated with this disorder. Phosphodiesterase (PDE)10A is a dual substrate PDE highly expressed in striatal medium spiny neurons. Biochemical and behavioral studies indicate that the inhibition of PDE10A enhances striatal output by increasing activity in the cGMP and cAMP signaling pathways. PDE10A inhibitors reduce exploratory activity and antagonize the stimulant response to both amphetamine and N-methyl-d-aspartate antagonists such as phencyclidine. Consistent with their potential as antipsychotic agents, PDE10A inhibitors are potent antagonists of conditioned avoidance responding. The presence of PDE10A in both striatal output pathways may reduce the incidence and severity of dopamine D2 receptor antagonist-like side effects, including extrapyramidal symptoms. In addition, by enhancing corticostriatal signaling, PDE10A inhibitors have the potential to improve some of the cognitive symptoms of schizophrenia.
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PMID:Phosphodiesterase 10A inhibitors: a novel approach to the treatment of the symptoms of schizophrenia. 1726 85

The prefrontal cortex (PFC) is believed to play an important role in the cognitive impairments observed in schizophrenia and has also been shown to be involved in the modulation of prepulse inhibition (PPI), a measure of preattentive information processing that is impaired in schizophrenic individuals. Phencyclidine (PCP), a noncompetitive inhibitor of the NMDA receptor, exerts psychotomimetic effects in humans, disrupts PPI, and causes hypofrontality in rodents and monkeys. We have previously demonstrated that interfering with the production of nitric oxide (NO) can prevent a wide range of PCP-induced behavioral deficits, including PPI disruption. In the present study, the role of NO signaling for the behavioral and biochemical effects of PCP was further investigated. Dialysate from the medial PFC of mice receiving systemic treatment with PCP and/or the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 40 mg/kg), was analyzed for cGMP content. Furthermore, a specific inhibitor of NO-sensitive soluble guanylyl cyclase (sGC), 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ, 0.01-1 mM), was administered into the medial PFC of mice in combination with systemic injections of PCP, followed by PPI and locomotor activity testing. PCP (5 mg/kg) caused an increase in prefrontal cGMP that could be attenuated by pretreatment with the NO synthase inhibitor, L-NAME. Moreover, bilateral microinjection of the sGC inhibitor, ODQ, into the medial PFC of mice attenuated the disruption of PPI, but not the hyperlocomotion, caused by PCP. The present study shows that NO/sGC/cGMP signaling pathway in the medial PFC is involved in specific behavioral effects of PCP that may have relevance for the disabling cognitive dysfunction found in patients with schizophrenia.
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PMID:Nitric oxide signaling in the medial prefrontal cortex is involved in the biochemical and behavioral effects of phencyclidine. 1789 15

We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.
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PMID:Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia. 1828 14

Selective inhibitors of the glycine transporter 1 (GlyT1) have been implicated in central nervous system disorders related to hypoglutamatergic function such as schizophrenia. The selective GlyT1 inhibitors ALX5407 (NFPS) and LY2365109 {[2-(4-benzo[1,3]dioxol-5-yl-2-tert-butylphenoxy)ethyl]-methylamino}-acetic acid increased cerebrospinal fluid levels of glycine and potentiated NMDA-induced increases in dialysate levels of neurotransmitters in the prefrontal cortex (PFC) and the striatum. However, higher doses produced both stimulatory and inhibitory effects on motor performance and impaired respiration, suggesting significant involvement of cerebellar and brain stem areas. A dual probe microdialysis study showed that ALX5407 transiently elevated extracellular levels of glycine in the PFC with more sustained increases in the cerebellum. In support of these findings, immuno-staining with pan-GlyT1 and GlyT1a antibodies showed a higher abundance of immunoreactivity in the brain stem/cerebellum as compared to the frontal cortical/hippocampal brain areas in four different species studied, including the mouse, rat, monkey and human. In addition, the inhibitory effects of ALX5407 on cerebellar levels of cGMP in the mouse could be reversed by the glycine A receptor antagonist strychnine but not the glycine B receptor antagonist L-701324. We propose that the adverse events seen with higher doses of ALX5407 and LY2365109 are the result of high GlyT1 inhibitory activity in caudal areas of the brain with sustained elevations of extracellular glycine. High levels of glycine in these brain areas may result in activation of strychnine-sensitive glycine A receptors that are inhibitory on both motor activity and critical brain stem functions such as respiration.
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PMID:Neurochemical and behavioral profiling of the selective GlyT1 inhibitors ALX5407 and LY2365109 indicate a preferential action in caudal vs. cortical brain areas. 1860 30

Recent studies have suggested that currently available antipsychotic medications, while useful in treating some aspects of schizophrenia, still possess considerable limitations. Improving the treatment of negative symptoms and cognitive dysfunction, and decreasing adverse effects remain significant challenges. Many new drug strategies have been proposed in recent years and increasing evidence suggests that members of the phosphodiesterase (PDE) gene family may play a role in the aetiology or treatment of schizophrenia. PDEs are key enzymes responsible for the degradation of the second messengers cAMP (3',5'-cyclic adenosine monophosphate) and cGMP (3',5'-cyclic guanosine monophosphate). Mammalian PDEs are composed of 21 genes and are categorized into 11 families based on sequence homology, enzymatic properties and sensitivity to pharmacological inhibitors. Representatives from most families have been identified in the brain by the presence of protein or RNA, and numerous studies suggest that PDEs play an important role in the regulation of intracellular signalling downstream of receptor activation in neurons. Insights into the multiple brain processes to which PDEs contribute are emerging from the phenotype of genetically engineered mice that lack activity of specific PDEs (knockout mice), as well as from in vitro and in vivo studies with PDE inhibitors.This article provides a brief overview of recent studies implicating PDE inhibition, focusing on PDE4 and PDE10, as targets for treating the positive, negative or cognitive symptoms associated with schizophrenia.
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PMID:The role of phosphodiesterases in schizophrenia : therapeutic implications. 1899 37

The second messenger cyclic guanosine 3',5'-monophosphate (cGMP) plays a crucial role in the control of cardiovascular and gastrointestinal homeostastis, but its effects on neuronal functions are less established. This review summarizes recent biochemical and functional data on the role of the cGMP signalling pathway in the mammalian brain, with a focus on the regulation of synaptic plasticity, learning, and other complex behaviours. Expression profiling, along with pharmacological and genetic manipulations, indicates important functions of nitric oxide (NO)-sensitive soluble guanylyl cyclases (sGCs), cGMP-dependent protein kinases (cGKs), and cGMP-regulated phosphodiesterases (PDEs) as generators, effectors, and modulators of cGMP signals in the brain, respectively. In addition, neuronal cGMP signalling can be transmitted through cyclic nucleotide-gated (CNG) or hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels. The canonical NO/sGC/cGMP/cGK pathway modulates long-term changes of synaptic activity in the hippocampus, amygdala, cerebellum, and other brain regions, and contributes to distinct forms of learning and memory, such as fear conditioning, motor adaptation, and object recognition. Behavioural studies indicate that cGMP signalling is also involved in anxiety, addiction, and the pathogenesis of depression and schizophrenia. At the molecular level, different cGK isoforms appear to mediate effects of cGMP on presynaptic transmitter release and postsynaptic functions. The cGKs have been suggested to modulate cytoskeletal organization, vesicle and AMPA receptor trafficking, and gene expression via phosphorylation of various substrates including VASP, RhoA, RGS2, hSERT, GluR1, G-substrate, and DARPP-32. These and other components of the cGMP signalling cascade may be attractive new targets for the treatment of cognitive impairment, drug abuse, and psychiatric disorders.
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PMID:cGMP signalling in the mammalian brain: role in synaptic plasticity and behaviour. 1908 45


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