cyclic-gmp and Central-Nervous-System-Diseases

Phosphodiesterase 10A (PDE10A) is a double substrate enzyme that hydrolyzes second messenger molecules such as cyclic-3',5'-adenosine monophosphate (cAMP) and cyclic-3',5'-guanosine monophosphate (cGMP). Through this process, PDE10A controls intracellular signaling pathways in the mammalian brain and peripheral tissues. Pharmacological, biochemical, and anatomical data suggest that disorders in the second messenger system mediated by PDE10A may contribute to impairments in the central nervous system (CNS) function, including cognitive deficits as well as disturbances of behavior, emotion processing, and movement. This review provides a detailed description of PDE10A and the recent advances in the design of selective PDE10A inhibitors. The results of preclinical studies regarding the potential utility of PDE10A inhibitors for the treatment of CNS-related disorders, such as schizophrenia as well as Huntington's and Parkinson's diseases are also summarized.

Topics: Animals; Brain; Central Nervous System Diseases; Cognition Disorders; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Signal Transduction; Treatment Outcome

The development of small molecule modulators of NO/cGMP signaling for use in the CNS has lagged far behind the use of such clinical agents in the periphery, despite the central role played by NO/cGMP in learning and memory, and the substantial evidence that this signaling pathway is perturbed in neurodegenerative disorders, including Alzheimer's disease. The NO-chimeras, NMZ and Nitrosynapsin, have yielded beneficial and disease-modifying responses in multiple preclinical animal models, acting on GABA

Topics: Animals; Central Nervous System Agents; Central Nervous System Diseases; Cyclic GMP; Drug Discovery; Humans; Nitric Oxide; Signal Transduction; Small Molecule Libraries

A wide diversity of perturbations of the central nervous system (CNS) result in structural damage to the neuroarchitecture and cellular defects, which in turn are accompanied by neurological dysfunction and abortive endogenous neurorepair. Altering intracellular signaling pathways involved in inflammation and immune regulation, neural cell death, axon plasticity and remyelination has shown therapeutic benefit in experimental models of neurological disease and trauma. The second messengers, cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), are two such intracellular signaling targets, the elevation of which has produced beneficial cellular effects within a range of CNS pathologies. The only known negative regulators of cyclic nucleotides are a family of enzymes called phosphodiesterases (PDEs) that hydrolyze cyclic nucleotides into adenosine monophosphate (AMP) or guanylate monophosphate (GMP). Herein, we discuss the structure and physiological function as well as the roles PDEs play in pathological processes of the diseased or injured CNS. Further we review the approaches that have been employed therapeutically in experimental paradigms to block PDE expression or activity and in turn elevate cyclic nucleotide levels to mediate neuroprotection or neurorepair as well as discuss both the translational pathway and current limitations in moving new PDE-targeted therapies to the clinic.

Topics: Animals; Central Nervous System; Central Nervous System Diseases; Cyclic AMP; Cyclic GMP; Humans; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Regeneration; Second Messenger Systems; Signal Transduction

The discovery of nitric oxide (NO) as an activator of soluble guanylate cyclase (sGC) has stimulated extensive research on the NO-sGC-3':5'-cyclic guanosine monophosphate (cGMP)-cGMP-dependent protein kinase (PKG) pathway. However, the restricted localization of pathway components and the lack of information on PKG substrates have hindered research seeking to examine the physiological roles of the NO-sGC-cGMP-PKG pathway. An excellent substrate for PKG is the G-substrate, which was originally discovered in the cerebellum. The role of G-substrate in the cerebellum and other brain structures has been revealed in recent years. This review discusses the relationship between the G-substrate and other components of the NO-sGC-cGMP-PKG pathway and describes the characteristics of the G-substrate gene and protein related to diseases. Finally, we discuss the physiological role of G-substrate in the cerebellum, where it regulates cerebellum-dependent long-term memory, and its role in the ventral tegmental area and retina, where it acts as an effective neuroprotectant.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aging; Amacrine Cells; Amino Acid Sequence; Animals; Central Nervous System Diseases; Cerebellum; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide-Gated Cation Channels; Gene Expression Regulation, Developmental; Guanylate Cyclase; Humans; Hyperlipoproteinemia Type II; Long-Term Synaptic Depression; Memory, Long-Term; Molecular Sequence Data; Nerve Tissue Proteins; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphorylation; Protein Isoforms; Protein Processing, Post-Translational; Receptors, Cytoplasmic and Nuclear; Second Messenger Systems; Sequence Alignment; Sequence Homology, Amino Acid; Soluble Guanylyl Cyclase; Ventral Tegmental Area; Vocalization, Animal

Phosphodiesterases (PDEs) represent important cornerstones of cGMP signaling in various tissues. Since the discovery of PDE activity in 1962, it has become clear that the functional characteristics of PDEs and their role in cyclic nucleotide signaling are fairly complex. On the one hand, members of the PDE family responsible for the hydrolysis of cGMP affect cellular responses by shaping cGMP signals derived from the activation of soluble cytosolic and/or membrane bound particulate guanylyl cyclases. Conversely, PDEs may function as downstream effectors in the cGMP signaling cascade. To make things even more sophisticated, cGMP modulates the activity of several PDEs either directly, by binding to a regulatory domain, or indirectly, through phosphorylation, and the result can be either inhibition or stimulation of the enzyme, depending on the subtype. Furthermore, cross-talk between cGMP and cAMP signaling is achieved by cGMP-dependent modulation of PDEs hydrolyzing cAMP and vice versa. Mammals possess at least 21 PDE genes and often express a set of PDEs in a tissue- and differentiation-dependent manner. Given these premises, it is still a challenging task to elucidate the physiological function(s) of individual PDE genes. The present chapter focuses on the role of PDEs as regulators of neuronal functions. Useful information regarding this topic has been gained by studying (1) the expression pattern of PDEs in the CNS, (2) the association of PDEs with specific macromolecular signaling complexes and (3) the phenotypes associated with mutations or ablation of PDE genes in man, mice and fruit flies, respectively. PDEs degrading cGMP and/or being regulated by cGMP have been implicated in cognition and learning, Parkinson's disease, attention deficit hyperactivity disorder, psychosis and depression. Correspondingly, modulators of PDEs have become attractive tools for treatment of these disorders of CNS function.

Topics: Animals; Central Nervous System; Central Nervous System Diseases; Cyclic AMP; Cyclic GMP; Gene Expression; Humans; Phosphoric Diester Hydrolases; Signal Transduction; Substrate Specificity

Phosphodiesterase type 2A (PDE2A) has received considerable interest as a molecular target for treating central nervous system diseases that affect memory, learning, and cognition. In this paper, the authors present the discovery of small molecules that have a novel modality of PDE2A inhibition. PDE2A possesses GAF-A and GAF-B domains and is a dual-substrate enzyme capable of hydrolyzing both cGMP and cAMP, and activation occurs through cGMP binding to the GAF-B domain. Thus, positive feedback of the catalytic activity to hydrolyze cyclic nucleotides occurs in the presence of appropriate concentrations of cGMP, which binds to the GAF-B domain, resulting in a "brake" that attenuates downstream cyclic nucleotide signaling. Here, we studied the inhibitory effects of some previously reported PDE2A inhibitors, all of which showed impaired inhibitory effects at a lower concentration of cGMP (70 nM) than a concentration effective for the positive feedback (4 μM). This impairment depended on the presence of the GAF domains but was not attributed to binding of the inhibitors to these domains. Notably, we identified PDE2A inhibitors that did not exhibit this behavior; that is, the inhibitory effects of these inhibitors were as strong at the lower concentration of cGMP (70 nM) as they were at the higher concentration (4 μM). This suggests that such inhibitors are likely to be more effective than previously reported PDE2A inhibitors in tissues of patients with lower cGMP concentrations.

Topics: Catalysis; Central Nervous System Diseases; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Enzyme Inhibitors; Humans; Protein Domains

Cyclic-GMP (C-GMP), a normal constituent of the central nervous system, was found to be present in increased amounts in the cerebrospinal fluid (CSF) of systemic lupus erythematosus (SLE) patients with active neurologic disease. Twenty-four CSF samples from 17 patients with SLE were evaluated for C-GMP concentration by radioimmunoassay. This study extends our initial observations and examines three groups of SLE patients based on their clinical status at the time of each lumbar puncture: those with active neurologic and psychologic abnormalities (group I), active neurologic abnormalities (group II), and psychologic abnormalities without active neurologic involvement (group III). Groups I and II had mean CSF C-GMP values of 3.1 nM +/- 0.64 (SE) and 4.1 nM +/- 0.10 respectively, which were both significantly higher than the mean for group III (1.2 nM +/- 0.43) (P less than 0.05). Other CSF findings did not display this close correlation with activity of neurologic disease. In 4 SLE patients, significantly higher levels of CSF C-GMP were found on serial sampling during times when neurologic abnormalities were active. Thus elevated CSF C-GMP concentration may be a marker of active neurologic disease in SLE.

Topics: Adult; Blood Sedimentation; Central Nervous System Diseases; Cerebrospinal Fluid; Complement System Proteins; Cyclic GMP; Female; Hemoglobins; Humans; Leukocyte Count; Leukopenia; Lupus Erythematosus, Systemic; Male; Neurocognitive Disorders; Neurologic Manifestations; Prednisone; Psychotropic Drugs; Radioimmunoassay; Spinal Puncture; Thrombocytopenia

Topics: Animals; Central Nervous System Diseases; Cyclic AMP; Cyclic GMP; Female; Male; Phosphodiesterase Inhibitors; Rats; Rats, Inbred Strains