cyclic-gmp and Mental-Disorders

The focus of this chapter is on the cyclic nucleotide phosphodiesterase 1 (PDE1) family. PDE1 is one member of the 11 PDE families (PDE 1-11). It is the only phosphodiesterase family that is calcium/calmodulin activated. As a result, whereas other families of PDEs 2-11 play a dominant role controlling basal levels of cyclic nucleotides, PDE1 is involved when intra-cellular calcium levels are elevated and, thus, has an "on demand" or activity-dependent involvement in the control of cyclic nucleotides in excitatory cells including neurons, cardiomyocytes and smooth muscle. As a Class 1 phosphodiesterase, PDE1 hydrolyzes the 3' bond of 3'-5'-cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Here, we review evidence for this family of enzymes as drug targets for development of therapies aimed to address disorders of the central nervous system (CNS) and of degenerative diseases. The chapter includes sections on the potential for cognitive enhancement in mental disorders, as well as a review of PDE1 enzyme structure, enzymology, tissue distribution, genomics, inhibitors, pharmacology, clinical trials, and therapeutic indications. Information is taken from public databases. A number of excellent reviews of the phosphodiesterase family have been written as well as reviews of the PDE1 family. References cited here are not comprehensive, rather pointing to major reviews and key publications.

Topics: Cognitive Dysfunction; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 1; Humans; Mental Disorders; Neurodegenerative Diseases; Phosphodiesterase Inhibitors

Cyclic nucleotide PDEs are a super-family of enzymes responsible for regulating intracellular levels of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Through their catalysis, PDEs are able to exert tight regulation over these important intracellular signaling cascades. Previously, PDEs have been implicated in learning and memory, as well as in mood disorders, such as anxiety and depression. PDE2 is of special interest due to its high level of expression in the forebrain, specifically in the isocortex, entorhinal cortex, striatum, hippocampus, amygdala, and medial habenula. Many of these brain regions are considered participants of the limbic system, which is known as the emotional regulatory center of the brain, and is important for modulating emotion and long-term memory. Therefore, PDE2s coincidental expression in these areas suggests an important role for PDE2 in these behaviors, and researchers are continuing to uncover the complex connections. It was shown that PDE2 inhibitors have pro-cognitive effects in tests of memory, including the object recognition test. PDE2 inhibitors are also protective against cognitive deficits in various models of cognitive impairment. Additionally, PDE2 inhibitors are protective against many different forms of stress-induced anxiety-like and depression-like behaviors. Currently, there is a great need for novel therapeutics for the treatment of mood and cognitive disorders, especially anxiety and depression, and other neurodegenerative diseases, such as Alzheimer's disease, and PDE2 is emerging as a viable target for future drug development for many of these diseases.

Topics: Alzheimer Disease; Anxiety Disorders; Brain; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Depressive Disorder; Humans; Mental Disorders; Neurodegenerative Diseases; Phosphodiesterase Inhibitors; Stress, Psychological

Topics: Adenylyl Cyclases; Animals; Anti-Inflammatory Agents; Antiviral Agents; Asthma; Cardiovascular Diseases; Cricetinae; Cyclic AMP; Cyclic GMP; Disease; Enzyme Activation; Extracellular Space; Guanylate Cyclase; Humans; Hypoglycemic Agents; Isoenzymes; Kinetics; Mental Disorders; Mice; Neoplasms; Obesity; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Psoriasis; Rats

Topics: Cyclic AMP; Cyclic GMP; Humans; Lithium; Mental Disorders; Skin