Phosphodiesterase inhibitors in psychiatric disorders

Sadeghi, Maryam; Nassireslami, Ehsan; Zoshk, Mojtaba Yousefi; Hosseini, Yasaman; Abbasian, Kourosh; Chamanara, Mohsen

doi:10.1007/s00213-023-06361-3

Cited by 11 publications

(5 citation statements)

References 164 publications

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“…The activation of the TGR5-cAMP-protein kinase A (PKA) axis exerts an anti-inflammatory effect on microglia, which in turn promotes the phosphorylation of the target protein CREB. The cAMP/PKA/CREB signaling pathway is closely associated with anxiety (63)(64)(65)(66). The anti-anxiety effect of INT-777 is elicited through the activation of microglial cells, which modulate the TGR5/cAMP/PKA/CREB axis.…”

Section: Bile Acids Transmit Signals That Affect Anxiety Via the Dire...mentioning

confidence: 99%

Bile acid signalling and its role in anxiety disorders

Chen,

Shao,

Chen

et al. 2023

Front. Endocrinol.

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Anxiety disorder is a prevalent neuropsychiatric disorder that afflicts 7.3%~28.0% of the world’s population. Bile acids are synthesized by hepatocytes and modulate metabolism via farnesoid X receptor (FXR), G protein-coupled receptor (TGR5), etc. These effects are not limited to the gastrointestinal tract but also extend to tissues and organs such as the brain, where they regulate emotional centers and nerves. A rise in serum bile acid levels can promote the interaction between central FXR and TGR5 across the blood-brain barrier or activate intestinal FXR and TGR5 to release fibroblast growth factor 19 (FGF19) and glucagon-like peptide-1 (GLP-1), respectively, which in turn, transmit signals to the brain via these indirect pathways. This review aimed to summarize advancements in the metabolism of bile acids and the physiological functions of their receptors in various tissues, with a specific focus on their regulatory roles in brain function. The contribution of bile acids to anxiety via sending signals to the brain via direct or indirect pathways was also discussed. Different bile acid ligands trigger distinct bile acid signaling cascades, producing diverse downstream effects, and these pathways may be involved in anxiety regulation. Future investigations from the perspective of bile acids are anticipated to lead to novel mechanistic insights and potential therapeutic targets for anxiety disorders.

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Section: Bile Acids Transmit Signals That Affect Anxiety Via the Dire...mentioning

confidence: 99%

Bile acid signalling and its role in anxiety disorders

Chen,

Shao,

Chen

et al. 2023

Front. Endocrinol.

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show abstract

“…No PKA inhibitors have been approved in the clinic. However, phosphodiesterases (PDEs) inhibitors, which prevent cAMP or cGMP hydrolysis and thereby elevate cAMP/cGMP levels, are developed for the treatment of obstructive respiratory diseases, neuroinflammation, ischemia/reperfusion injury, atopic dermatitis, erectile dysfunction, depression and hypertension [ 13 – 15 ]. Preclinical studies demonstrate that PDE inhibitors may have tumor-suppressive effects, especially when combined with chemotherapeutic agents [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment

Zhang,

Liu,

Liu

et al. 2024

J Hematol Oncol

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Cancer is a complex disease resulting from abnormal cell growth that is induced by a number of genetic and environmental factors. The tumor microenvironment (TME), which involves extracellular matrix, cancer-associated fibroblasts (CAF), tumor-infiltrating immune cells and angiogenesis, plays a critical role in tumor progression. Cyclic adenosine monophosphate (cAMP) is a second messenger that has pleiotropic effects on the TME. The downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), exchange protein activated by cAMP (EPAC) and ion channels. While cAMP can activate PKA or EPAC and promote cancer cell growth, it can also inhibit cell proliferation and survival in context- and cancer type-dependent manner. Tumor-associated stromal cells, such as CAF and immune cells, can release cytokines and growth factors that either stimulate or inhibit cAMP production within the TME. Recent studies have shown that targeting cAMP signaling in the TME has therapeutic benefits in cancer. Small-molecule agents that inhibit adenylate cyclase and PKA have been shown to inhibit tumor growth. In addition, cAMP-elevating agents, such as forskolin, can not only induce cancer cell death, but also directly inhibit cell proliferation in some cancer types. In this review, we summarize current understanding of cAMP signaling in cancer biology and immunology and discuss the basis for its context-dependent dual role in oncogenesis. Understanding the precise mechanisms by which cAMP and the TME interact in cancer will be critical for the development of effective therapies. Future studies aimed at investigating the cAMP-cancer axis and its regulation in the TME may provide new insights into the underlying mechanisms of tumorigenesis and lead to the development of novel therapeutic strategies.

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“…PDEs regulate a variety of intracellular signal transduction pathways, particularly through cAMP and cGMP ( Delhaye and Bardoni, 2021 ). PDEs play an important role in regulating the functions of the central nervous system (CNS), as well as PDE inhibitors have anti-inflammatory, antioxidant, vasodilator, antidepressant, and memory-enhancing effects ( Sadeghi et al, 2023 ). In addition, many studies have expanded the correlation between PDE4 and the pathogenesis of CNS diseases, demonstrating the beneficial effects of PDE4 inhibitors on CNS diseases such as stroke, Alzheimer’s disease, and depression ( Richter et al, 2013 ; Blokland et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase 7 inhibitor reduces stress-induced behavioral and cytoarchitectural changes in C57BL/6J mice by activating the BDNF/TrkB pathway

Dong,

Wei,

Zong

et al. 2024

Front. Pharmacol.

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BackgroundPhosphodiesterase 7 (PDE7) plays a role in neurological function. Increased expression and activity of PDE7 has been detected in several central nervous system diseases. However, the role of PDE7 in regulating stress levels remains unclear. Thus, this study aimed to determine whether and how PDE7 involved in the stress-induced behavioral and neuron morphological changes.MethodsThe single prolonged stress (SPS) was used to build a stress exposure model in C57BL/6 J mice and detected PDE7 activity in hippocampus, amygdala, prefrontal cortex and striatum. Next, three doses (0.2, 1, and 5 mg/kg) of the PDE7 inhibitor BRL-50481 were intraperitoneally administered for 10 days, then behavioral, biochemical, and morphological tests were conducted.ResultsPDE7 activity in hippocampus of mice significantly increased at all times after SPS. BRL-50481 significantly attenuated SPS induced anxiety-like behavior and fear response in both context and cue. In addition, BRL-50481 increased the levels of key molecules in the cAMP signaling pathway which were impaired by SPS. Immunofluorescent staining and Sholl analysis demonstrated that BRL-50481 also restored the nucleus/cytoplasm ratio of hippocampal neurons and improved neuronal plasticity. These effects of BRL-50481 were partially blocked by the TrkB inhibitor ANA-12.ConclusionPDE7 inhibitors attenuate stress-induced behavioral changes by protecting the neuron cytoarchitecture and the neuronal plasticity in hippocampus, which is mediated at least partly through the activation of BDNF/TrkB signaling pathway. These results proved that PDE7 is a potential target for treating stress-induced behavioral and physiological abnormalities.

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Phosphodiesterase inhibitors in psychiatric disorders

Cited by 11 publications

References 164 publications

Bile acid signalling and its role in anxiety disorders

Bile acid signalling and its role in anxiety disorders

cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment

Phosphodiesterase 7 inhibitor reduces stress-induced behavioral and cytoarchitectural changes in C57BL/6J mice by activating the BDNF/TrkB pathway

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