cyclic-gmp and Depressive-Disorder

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

Depression results in a tremendous burden to individuals suffering from the disorder and to the global health economy. Available pharmacologic treatments for depression target monoamine levels and monoamine receptors. However, delayed onset of effect, partial or inadequate treatment response, and side-effects are significant limitations of current therapies. The search for a better understanding of mechanisms of depression and for new treatment targets has turned attention to intracellular mediators. Phosphodiesterases (PDEs) are enzymes that break down the intracellular second messenger mononucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Recent data from animal and human studies indicate that PDEs may play a role in depression and in related stress conditions. PDE genes have been linked directly to depression and to other genes associated with psychiatric disorders.

Topics: Animals; Antidepressive Agents; Cyclic AMP; Cyclic GMP; Depression; Depressive Disorder; Genetic Predisposition to Disease; Humans; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases

Inflammation, oxidative and nitrosative stress underlie depression being assessed in rodents by the systemic administration of lipopolysacharide (LPS). There is an increasing body of evidence of an involvement of nitric oxide (NO) pathway in depression, but this issue was not investigated in LPS-induced model. Thus, herein we evaluated the effects of NO-pathway-modulating drugs, named aminoguanidine, l-NAME, sildenafil and l-arginine, on the behavioral (forced swimming test [FST], sucrose preference [SPT] and prepulse inhibition [PPI] of the startle) and neurochemical (glutathione [GSH], lipid peroxidation, IL-1β) alterations in the prefrontal cortex, hippocampus and striatum as well as in BDNF levels in the hippocampus 24h after LPS (0.5mg/kg, i.p.) administration, a time-point related to depressive-like behavior. Twenty-four hours post LPS there was an increase in immobility time in the FST, decrease in sucrose preference and PPI levels accompanied by a decrease in GSH levels and an increase in lipid peroxidation, IL-1β and hippocampal BDNF levels suggestive of a depressive-like state. The pretreatment with the NOS inhibitors, l-NAME and aminoguanidine as well as sildenafil prevented the behavioral and neurochemical alterations induced by LPS, although sildenafil and l-NAME were not able to prevent the increase in hippocampal BDNF levels induced by LPS. The iNOS inhibitor, aminoguanidine, and imipramine prevented all behavioral and neurochemical alterations induced by LPS. l-arginine did not prevent the alterations in immobility time, sucrose preference and GSH induced by LPS. Taken together our results show that the NO-cGMP pathway is important in the modulation of the depressive-like alterations induced by LPS.

Topics: Animals; Antidepressive Agents; Arginine; Behavior, Animal; Brain; Brain-Derived Neurotrophic Factor; Cyclic GMP; Depressive Disorder; Disease Models, Animal; Enzyme Inhibitors; Guanidines; Imipramine; Interleukin-1beta; Lipopolysaccharides; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Sulfones

Stress occurs in everyday life, but the relationship between stress and the onset or development of depression/anxiety remains unknown. Increasing evidence suggests that the impairment of antioxidant defense and the neuronal cell death are important in the process of emotional disorders. Chronic stress impairs the homeostasis of antioxidants/oxidation, which results in the aberrant stimulation of the cell cycle proteins where cGMP-PKG signaling is thought to have an inhibitory role. Phosphodiesterase 2 (PDE2) is linked to cGMP-PKG signaling and highly expressed in the limbic brain regions including hippocampus and amygdala, which may play important roles in the treatment of depression and anxiety. To address the possible effects of PDE2 inhibitors on depression-/anxiety-like behaviors and the underlying mechanisms, Bay 60-7550 (0.75, 1.5 and 3 mg/kg, i.p.) was administered 30 min before chronic stress. The results suggested that Bay 60-7550 not only restored the behavioral changes but also regulated Cu/Zn superoxide dismutase (SOD) levels differentially in hippocampus and amygdala, which were increased in the hippocampus while decreased in the amygdala. It was also significant that Bay 60-7550 regulated the abnormalities of pro- and anti-apoptotic components, such as Bax, Caspase 3 and Bcl-2, and the indicator of PKG signaling characterized by pVASP(ser239), in these two brain regions. The results suggested that Bay 60-7550 is able to alleviate oxidative stress and mediate part of the apoptotic machinery in neuronal cells possibly through SOD-cGMP/PKG-anti-apoptosis signaling and that inhibition of PDE2 may represent a novel therapeutic target for psychiatric disorders, such as depression and anxiety.

Topics: Amygdala; Animals; Anxiety Disorders; Apoptosis; Caspase 3; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Depressive Disorder; Hippocampus; Imidazoles; Male; Mice, Inbred ICR; Neurons; Oxidative Stress; Phosphodiesterase Inhibitors; Psychotropic Drugs; Signal Transduction; Stress, Psychological; Superoxide Dismutase; Triazines

Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are synthesized by adenylate cyclase and guanylyl cyclase and degraded by phosphodiesterases. Antidepressant treatment action is hypothesized to occur through increased cAMP signaling; however, antidepressants are also reported to increase phosphodiesterase-4 expression. We addressed this paradox by systematically studying elements of intracellular signaling in the hippocampus of rats chronically treated with imipramine. We observed decreases in cAMP levels, which were congruent with our findings of increased gene expression for phosphodiesterases and decreased adenylate cyclase. Immunoassay results showed unchanged cGMP and brain-derived neurotrophic factor levels. We conclude that in contrast with the assumption of antidepressant-mediated increases in cAMP levels, longterm imipramine treatment may have the opposite effect, namely decreased hippocampal cAMP.

Topics: Adenylyl Cyclases; Animals; Antidepressive Agents, Tricyclic; Brain-Derived Neurotrophic Factor; Cyclic AMP; Cyclic GMP; Depressive Disorder; Down-Regulation; Drug Administration Schedule; Hippocampus; Imipramine; Male; Phosphoric Diester Hydrolases; Rats; Rats, Sprague-Dawley; RNA, Messenger

In this report, we investigated the relationship between depressive symptoms and plasma interferon (IFN)-alpha-like immunoreactivity, cyclic GMP (cGMP) and soluble interleukin-2 receptor (sIL-2R) levels during IFN therapy. An altered mood state was observed in 5 of 26 patients. IFN-alpha-like immunoreactivity in the depressed group tended to be elevated. cGMP levels of depressed patients were significantly greater than those of control subjects before and 6 weeks after IFN therapy. However, sIL-2R levels were not different between the two groups. These results suggest that a number of patients suffered from depression during IFN therapy and that patients had greater concentrations of cGMP levels.

Topics: Aged; Cyclic GMP; Depressive Disorder; Humans; Immunohistochemistry; Interferons; Japan; Male; Middle Aged; Prospective Studies

Concentrations of cAMP and cGMP in plasma were measured in 20 drug-free melancholic patients during a simulated electroconvulsive treatment (SECT) and a bilateral ECT session. Blood samples were taken every 15 min beginning 15 min before and ending 60 min after the SECT or the ECT. Two-way ANOVA and paired t-test demonstrated a significant and greater fall in cAMP over time following SECT. ECT induced a marginal increase (P less than 0.05) at 45 min postictally. It is postulated that ECT causes an increase in cAMP levels which is masked by the decrease observed during SECT, caused presumably by the anaesthetic medication. The plasma cGMP levels were increased gradually and significantly after SECT and the same rise was observed during ECT. These effects are discussed in relation to changes in adrenergic-cholinergic activities induced by the medication and the electrical stimulus.

Topics: Adult; Bipolar Disorder; Cyclic AMP; Cyclic GMP; Depressive Disorder; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales

Topics: Adult; Affective Disorders, Psychotic; Aged; Bipolar Disorder; Carbamazepine; Cyclic AMP; Cyclic GMP; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Mood Disorders

Although numerous studies have suggested that depression may be associated with a reduction in synaptic noradrenaline in the brain, direct beta-adrenergic receptor agonists have not been tested in the treatment of depression until recently. Moreover, newer theories of antidepressant action suggest that a reduction in beta-adrenergic receptor sensitivity is a better correlate of antidepressant treatment than noradrenaline turnover changes. It is possible to evaluate the beta-adrenergic receptor-adenylate cyclase complex in the human periphery by measuring the plasma cyclic AMP rise after adrenergic agonists. A clinical trial of the beta-2 adrenergic agonist salbutamol in depression provided an opportunity to test whether adrenergic receptor subsensitivity does occur during clinical antidepressant treatment. Plasma cyclic AMP before treatment with salbutamol rose 26% in response to salbutamol 0.25 mg iv. After 1 and 3 weeks of oral salbutamol treatment, depression scores declined significantly in 11 depressed patients, while the plasma cyclic AMP response to iv salbutamol declined over 60%. The beta-adrenergic adenylate cyclase remained subsensitive 4 days after cessation of salbutamol therapy. The results support the concept that receptor sensitivity changes occur during human antidepressant therapy. Data are presented that Li, too, markedly reduces activity of beta-adrenergic adenylate cyclase in humans. The effect was evaluated by studying the effect of Li at therapeutic serum concentrations on the plasma cyclic AMP response to subcutaneous epinephrine. The Li effect is specific, since the plasma cyclic AMP response to glucagon is not inhibited. The plasma cyclic GMP response to subcutaneous epinephrine, suggested as a model for presynaptic alpha-noradrenergic mechanisms, is also partially inhibited by Li therapy. Since cyclic AMP and cyclic GMP may be viewed as balancing substances, their interaction may provide a mechanism for Li's dual clinical effects in mania and depression. It is important that in vivo techniques be developed for evaluating receptor changes. The plasma cyclic AMP response to adrenergic stimulation provides an in vivo measure of receptor function that can be useful in studying drug effects during the clinical treatment of humans.

Topics: Adenylyl Cyclases; Albuterol; Bipolar Disorder; Cyclic AMP; Cyclic GMP; Depressive Disorder; Epinephrine; Humans; Lithium; Norepinephrine; Receptors, Adrenergic; Receptors, Adrenergic, beta