cyclic-gmp and Schizophrenia

Schizophrenia is a progressive psychotic disorder with devastating effects on the broad aspects of human emotion, perception, thought, and psychosocial interactions. Although treatment with antipsychotic drugs, the mainstay in the treatment of schizophrenia, the large number of patients with schizophrenia respond poorly to the pharmacological and, the large number of patients with schizophrenia poorly respond to the pharmacological treatment. Although a variety of novel therapeutics have long been tested, to date, no drugs clinically efficacious for schizophrenia are available. The multiple lines of evidence strongly suggest that the modulation of cyclic guanosine monophosphate (cGMP) is a promising target in promoting the novel therapeutic strategies of schizophrenia beyond the "receptor-dependent" psychopharmacology. cGMP is modulated via regulating its synthesis by N-methyl-d-aspartate receptor (NMDAR) and nitric oxide (NO), which regulate guannylyl cyclase (GC), the enzyme producing cGMP. cGMP is also regulated by phosphodiesterase (PDE), the enzyme hydrolyzing cGMP. In this review, we critically evaluate the therapeutic potential of agents modulating cGMP activity by regulating cGMP synthesis including NMDAR enhancers, NO enhancers, NO inhibitors including minocycline with anti-inflammatory properties and PDE inhibitors in improving the negative, cognitive and positive symptoms of schizophrenia. We also discuss the possible mechanisms by which these agents produce therapeutic effects on schizophrenia including cGMP signaling pathways, oxidative stress, and neuroinflammation.

Topics: Animals; Antipsychotic Agents; Cyclic GMP; Humans; Schizophrenia

The distribution and functions of certain neurotransmitter substances seem to correlate with clinical, anatomical and physiological evidence about the mediation of normal and abnormal behaviors in man, though much remains to be learned. The biosynthetic and metabolic pathways, receptors and reuptake mechanisms, and relationships to cyclic nucleotides for several major neurotransmitters are characterized, as well as the specific actions of many behavior-modifying drugs employed clinically. Experimental systems, including nerve cells in culture, permit tests of molecular actions inferred from biochemical and neurophysiological analyses in intact brain. This selective review emphasizes advances in neurochemistry which provide a context for current and future research on neurological and psychiatric disorders encountered in clinical practice.

Topics: Affective Symptoms; Behavior; Biogenic Amines; Brain Chemistry; Cyclic AMP; Cyclic GMP; Deficiency Diseases; Humans; Neurochemistry; Neurons; Neurotransmitter Agents; Pain; Peptides; Prostaglandins; Proteins; Receptors, Drug; Schizophrenia; Substance P; Substance-Related Disorders; Synaptic Transmission

Here, we present the pharmacological characterisation of Lu AF64280, a novel, selective, brain penetrant phosphodiesterase (PDE) 2A inhibitor, in in vitro/in vivo assays indicative of PDE2A inhibition, and in vivo models/assays relevant to cognitive processing or antipsychotic-like activity. The in vitro selectivity of Lu AF64280 was determined against a panel of PDE enzymes and 3',5'-cyclic guanosine monophosphate (cGMP) levels in the hippocampus were determined using in vivo microdialysis. Lu AF64280 potently inhibited hPDE2A (Ki = 20 nM), 50-fold above moderate inhibition of both hPDE9A (Ki = 1,000 nM) and hPDE10A (Ki = 1,800 nM), and displayed a >250-fold selectivity over all other full-length human recombinant PDE family members (Ki above 5,000 nM). Lu AF64280 (20 mg/kg) significantly increased cGMP levels in the hippocampus (p < 0.01 versus vehicle-treated mice), attenuated sub-chronic phencyclidine-induced deficits in novel object exploration in rats (10 mg/kg, p < 0.001 versus vehicle-treated), blocked early postnatal phencyclidine-induced deficits in the intradimensional/extradimensional shift task in rats (1 and 10 mg/kg, p < 0.001 versus vehicle-treated) and attenuated spontaneous P20-N40 auditory gating deficits in DBA/2 mice (20 mg/kg, p < 0.05 versus vehicle-treated). In contrast, Lu AF64280 failed to attenuate phencyclidine-induced hyperactivity in mice, and was devoid of antipsychotic-like activity in the conditioned avoidance response paradigm in rats, at any dose tested. Lu AF64280 represents a novel tool compound for selective PDE2A inhibition that substantiates a critical role of this enzyme in cognitive processes under normal and pathological conditions.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Cognition Disorders; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Excitatory Amino Acid Antagonists; Heterocyclic Compounds, 4 or More Rings; Hippocampus; Humans; Hyperkinesis; Male; Mice; Mice, Inbred DBA; Phencyclidine; Phosphodiesterase Inhibitors; Rats; Recognition, Psychology; Recombinant Proteins; Schizophrenia; Schizophrenic Psychology; Sensory Gating

We describe the discovery of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of phosphodiesterase 10A by systematic optimization of a novel HTS lead. Lead compound THPP-1 exhibits nanomolar potencies, excellent pharmacokinetic properties, and a clean off-target profile. It displays in vivo target engagement as measured by increased rat striatal cGMP levels upon oral dosing. It shows dose-dependent efficacy in a key pharmacodynamic assay predictive of antipsychotic activity, the psychostimulant-induced rat hyperlocomotion assay. Further, THPP-1 displays significantly fewer preclinical adverse events in assays measuring prolactin secretion, catalepsy, and weight gain, in contrast to the typical and atypical antipsychotics haloperidol and olanzapine.

Topics: Administration, Oral; Animals; Cyclic GMP; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pyridines; Pyrimidines; Rats; Schizophrenia; Structure-Activity Relationship

Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability.

Topics: Animals; Antipsychotic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Avoidance Learning; Binding Sites; Blood-Brain Barrier; Corpus Striatum; Crystallography, X-Ray; Cyclic GMP; Databases, Factual; Drug Design; Humans; In Vitro Techniques; Mice; Mice, Knockout; Microsomes, Liver; Models, Molecular; Permeability; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Protein Conformation; Schizophrenia; Structure-Activity Relationship

Topics: Antipsychotic Agents; Cyclic GMP; Humans; Nitric Oxide; Receptors, N-Methyl-D-Aspartate; Schizophrenia

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.

Topics: Animals; Behavior, Animal; Brain; Cyclic AMP; Cyclic GMP; Dopamine; Male; Mice; Mice, Inbred C57BL; Motor Activity; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pyrazoles; Quinolines; Rats; Rats, Inbred F344; Recombinant Proteins; Reflex, Startle; Schizophrenia

D-amino acid oxidase (DAO) degrades D-serine, a co-agonist at the NMDA receptor (NMDAR). Hypofunction of the NMDAR has been suggested to contribute to the pathophysiology of schizophrenia. Intriguingly, DAO has been recently identified as a risk factor for schizophrenia through genetic association studies. A naturally occurring mouse strain (ddY/DAO-) has been identified which lacks DAO activity. We have characterized this strain both behaviorally and biochemically to evaluate DAO as a target for schizophrenia. We have confirmed that this strain lacks DAO activity and shown for the first time it has increased occupancy of the NMDAR glycine site due to elevated extracellular D-serine levels and has enhanced NMDAR function in vivo. Furthermore, the ddY/DAO- strain displays behaviors which suggest that it will be a useful tool for evaluation of the clinical benefit of DAO inhibition in schizophrenia.

Topics: Acoustic Stimulation; Animals; Brain Chemistry; Cyclic GMP; D-Amino-Acid Oxidase; Disease Models, Animal; Dose-Response Relationship, Radiation; Excitatory Amino Acid Antagonists; Extremities; Female; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Motor Activity; Neural Inhibition; Neurologic Examination; Phencyclidine; Psychomotor Performance; Quinolones; Reaction Time; Reflex, Startle; Schizophrenia; Sex Factors; Swimming

Topics: Adult; Arousal; Blood Pressure; Cyclic AMP; Cyclic GMP; Dominance, Cerebral; Female; Heart Rate; Humans; Male; Psychomotor Performance; Schizophrenia; Schizophrenic Psychology; Stress, Psychological

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.

Topics: Adolescent; Adult; Blood Platelets; Case-Control Studies; China; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Neuroleptic treatment of schizophrenia reduces CSF cyclic AMP in clinical responders after a mean of 8 weeks of treatment. This is consistent with continued effective dopamine receptor blockade by these drugs. Rat striatal 3H-spiroperidol binding sites increase more after 10 weeks of haloperidol therapy than after 3 weeks, suggesting that physiological equilibrium has not yet been reached by 3 weeks. The rat striatal receptor affinity for 3H-spiroperidol is decreased after 10 weeks but not after 3 weeks. The decreased affinity represents a new phenomenon that may be important in explaining long-term continuing neuroleptic effectiveness despite the increased receptor number. The decreased affinity of rat dopamine binding sites for 3H-spiroperidol after 10 weeks of neuroleptic treatment is consistent with the reduced human CSF cyclic AMP after a similar period of neuroleptic treatment.

Topics: Adolescent; Adult; Animals; Antipsychotic Agents; Corpus Striatum; Cyclic AMP; Cyclic GMP; Female; Haloperidol; Humans; Male; Middle Aged; Rats; Receptors, Dopamine; Schizophrenia

Topics: Cyclic AMP; Cyclic GMP; Dopamine; gamma-Aminobutyric Acid; Homovanillic Acid; Humans; Neurons; Prolactin; Schizophrenia; Sulpiride; Time Factors

Human CSF cyclic nucleotides do not distinguish manic-depresive patients or schizophrenic patients from controls, although a "high CSF cyclic AMP" subgroup of poor-prognosis schizophrenics is still under investigation. Neuroleptic therapy raises CSF cyclic GMP and lowers CSF cyclic AMP, at least in the responder subgroup of a clinically heterogeneous patient population when neuroleptics that are good adenylate cyclase inhibitors in vitro are used in the treatment. This is consistent with the concept that neuroleptic treatment in humans involves blockade of dopamine neurotransmission. Attempts to correlate the decline in CSF cyclic AMP concentration with clinical improvement may be important. Lithium treatment does not alter the level of CSF cyclic AMP, which probably derives largely from dopamine-related neurotransmission that lithium does not affect. However, the plasma cyclic AMP response to epinephrine is inhibited by lithium at therapeutic doses in vivo after chronic treatment. The lithium effect is somewhat specific in that the glucagon-stimulated rise in plasma cyclic AMP is not affected. The results in clinical experiments support the theory that norepinephrine-sensitive adenylate cyclase inhibition in brain is involved in lithium action. Research to attempt to distinguish lithium-responsive from lithium nonresponsive patients on the basis of sensitivity to lithium inhibition of the epinephrine-induced rise in plasma cyclic AMP is of considerable potential practical importance.

Topics: Adolescent; Adult; Bipolar Disorder; Cyclic AMP; Cyclic GMP; Female; Glucagon; Humans; Lithium; Male; Middle Aged; Propranolol; Regression Analysis; Remission, Spontaneous; Schizophrenia

Lumbar CSF HVA, MHPG, 5HIAA, cAMP, and cGMP were measured in 12 chronic schizophrenics with tardive dyskinesia before and 3 weeks after sodium valproate (VPA) or cyproheptadine treatment. HVA levels significantly decreased and cAMP and cGMP levels significantly increased during the administration of VPA or cyproheptadine. There were no significant correlations between the degree of improvement in tardive dyskinesia and the changes of amine metabolities or cyclic nucleotides. None of the pretreatment values for CSF amine metabolites or cyclic nucleotides were different from those of 15 chronic schizophrenics without tardive dyskinesia as controls. Decrease of HVA and increase of cGMP during the treatment might indicate the normalization of dopaminergic-cholinergic imbalance in the brain. Furthermore, significantly low levels of 5HIAA were observed in the patients with drug-induced tremor. It is suggested that neuroleptic-induced tremor may be attributed to serotonergic dysfunction in the brain.

Topics: Adult; Chronic Disease; Cyclic AMP; Cyclic GMP; Cyproheptadine; Dyskinesia, Drug-Induced; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Middle Aged; Neurotransmitter Agents; Schizophrenia; Tremor; Valproic Acid

Topics: Cyclic AMP; Cyclic GMP; Humans; Prognosis; Remission, Spontaneous; Schizophrenia; Social Adjustment

Human CSF cyclic AMP and cyclic GMP have been measured as possible indicators of activity of central neurotransmitter-sensitive adenylate or guanylate cyclase. In an attempt to help to identify the specific neurotransmitter systems of origin of human CSF cyclic AMP and GMP, we studied Parkinson patients with and without L-dopa therapy and schizophrenic patients before and after propranolol therapy. No effect of L-dopa or propranolol was found on CSF cyclic nucleotides. However, Parkinson patients had a 40-50% reduction of CSF cyclic AMP and a 80-90% reduction of CSF cyclic GMP compared with the schizophrenic patients. Implications of this finding are discussed.

Topics: Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Propranolol; Schizophrenia

Topics: Animals; Calcium; Cells, Cultured; Chlorpromazine; Cyclic AMP; Cyclic GMP; Cytotoxicity, Immunologic; DNA; Dose-Response Relationship, Drug; Humans; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Protein Binding; Rosette Formation; Schizophrenia; Spleen; T-Lymphocytes

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.

Topics: Antipsychotic Agents; Cyclic GMP; Dopamine; Humans; Phenothiazines; Schizophrenia