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Phosphodiesterases (PDEs): Therapeutic Targets in Human Health and Disease

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Microenvironment".

Deadline for manuscript submissions: 25 March 2025 | Viewed by 10935

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Special Issue Editors

Dr. Paul M. Epstein

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Guest Editor

Department of Cell Biology, UConn Health, Farmington, CT, USA
Interests: cyclic nucleotide phosphodiesterases; PDEs; cAMP; cGMP; signal transduction; second messengers

Dr. Stefan Brocke

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Guest Editor

Department of Immunology, UConn Health, Farmington, CT, USA
Interests: neuroinflammation; T cells; leukocyte migration; cAMP signaling; phosphodiesterases; immunotherapy; neurodegeneration

Dr. Michy P. Kelly

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Guest Editor

University of Maryland School of Medicine, Baltimore, MD, USA
Interests: 3’,5’-cyclic nucleotide phosphodiesterases (PDEs); learning and memory; social behavior; age-related cognitive decline; Alzheimer’s disease

Dr. Leila Gobejishvili

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Guest Editor

Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, USA
Interests: liver injury; inflammation; fibrogenesis; cAMP signaling; phosphodiesterases; recent photo

Special Issue Information

Dear Colleagues,

In 1957, when Earl Sutherland and Ted Rall discovered cAMP as the first “second messenger” mediating the effects of hormones on liver and skeletal muscle, the field of signal transduction, the way in which cells communicate with each other and respond to external signals, was born. It is apparent now that many diseases result from something going wrong in these signal transduction processes, and correcting the spatial and temporal changes in cAMP levels in subcellular compartments back to normal can therapeutically treat these resultant diseases. An enzymatic activity, cAMP phosphodiesterase (PDE), capable of converting cAMP to 5’-AMP, which terminates the messenger function of cAMP, was reported at the time of its discovery. We now know that PDEs represent a superfamily of enzymes encoded by 21 different genes grouped into 11 gene families. More than 100 different forms of PDE have now been identified, some of which are selectively located in different cell types and in different subcellular compartments. With this degree of complexity, by inhibiting or altering the expression of specific forms of PDE, we can change fundamental physiological processes in one cell type, without affecting others, which is the basis and goal of targeted therapies. To this end, efforts have been focused on which PDEs mediate which cell processes and on developing selective inhibitors of these PDEs to correct a wide variety of disease states. Drugs that target PDEs have now been approved for COPD, psoriasis, atopic dermatitis, erectile dysfunction, pulmonary hypertension, and heart failure. And this is only the tip of the iceberg, as they also show therapeutic benefits for a wide range of cancers, CNS disorders, autoimmune disorders, and metabolic disorders.

The aim of this Special Issue is to highlight recent advances in targeting PDEs for therapeutic benefit, and we would be delighted to have you join us in this by submitting your recent work.

Dr. Paul M. Epstein
Dr. Stefan Brocke
Dr. Michy P. Kelly
Dr. Leila Gobejishvili
Guest Editors

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Keywords

cyclic nucleotide phosphodiesterase
PDE
cAMP
cGMP
signal transduction

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Published Papers (8 papers)

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Research

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15 pages, 10638 KiB

Open AccessArticle

Dual Inhibition of Phosphodiesterase 3 and 4 Enzymes by Ensifentrine Protects against MRSA-Induced Lung Endothelial and Epithelial Dysfunction

by Mohammed Yaman Al Matni, Lucille Meliton, Steven M. Dudek and Eleftheria Letsiou

Cells 2024, 13(21), 1750; https://doi.org/10.3390/cells13211750 - 23 Oct 2024

Viewed by 1365

Abstract

Acute Respiratory Distress Syndrome (ARDS) is a severe lung condition with a high mortality rate for which there are no effective therapeutics. The failure of the alveolar–capillary barrier, composed of lung endothelial (EC) and alveolar epithelial (AEC) cells, is a critical factor leading to excessive inflammation and edema characteristic of acute lung injury (ALI) pathophysiology. Phosphodiesterases (PDE) are enzymes well-recognized for their roles in regulating endothelial permeability and inflammation. Although PDE inhibitors are used as therapeutics for inflammatory diseases like COPD (chronic obstructive pulmonary disease), their efficacy in treating ARDS has not yet been established. In this study, we investigated the effects of ensifentrine, an FDA-approved novel dual PDE 3/4 inhibitor, on lung endothelial and epithelial dysfunction caused by methicillin-resistant S. aureus (MRSA), a pathogen involved in bacterial ARDS. Human primary lung endothelial cells and alveolar epithelial cell lines (A549 and immortalized AEC) were treated with heat-killed MRSA, and their responses were assessed in the presence or absence of ensifentrine. Ensifentrine given either pre- or post-exposure attenuated MRSA-induced increased lung endothelial permeability. VE-cadherin junctions, which serve to stabilize the EC barrier, were disrupted by MRSA; however, ensifentrine effectively prevented this disruption. Pre-treatment with ensifentrine protected against MRSA-induced EC pro-inflammatory signaling by inhibiting the expression of VCAM-1, ICAM-1, and by reducing the IL-6 and IL-8 release. In AEC, MRSA caused the upregulation of ICAM-1, the activation of NF-kB, and the production of IL-8, all of which were inhibited by ensifentrine. These results indicate that the dual inhibition of phosphodiesterases 3 and 4 by ensifentrine is barrier protective and attenuates MRSA-induced inflammation in both lung endothelial and epithelial cells. The PDE3/4 inhibitor ensifentrine may represent a promising novel strategy for the treatment of MRSA-induced ARDS. Full article

(This article belongs to the Special Issue Phosphodiesterases (PDEs): Therapeutic Targets in Human Health and Disease)

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21 pages, 2415 KiB

Open AccessFeature PaperArticle

A Novel PDE10A Inhibitor for Tourette Syndrome and Other Movement Disorders

by Randall D. Marshall, Frank S. Menniti and Mark A. Tepper

Cells 2024, 13(14), 1230; https://doi.org/10.3390/cells13141230 - 22 Jul 2024

Cited by 1 | Viewed by 1455

Abstract

Background: Tourette syndrome is a neurodevelopmental movement disorder involving basal ganglia dysfunction. PDE10A inhibitors modulate signaling in the striatal basal ganglia nuclei and are thus of interest as potential therapeutics in treating Tourette syndrome and other movement disorders. Methods: The preclinical pharmacology and toxicology, human safety and tolerability, and human PET striatal enzyme occupancy data for the PDE10A inhibitor EM-221 are presented. Results: EM-221 inhibited PDE10A with an in vitro IC50 of 9 pM and was >100,000 selective vs. other PDEs and other CNS receptors and enzymes. In rats, at doses of 0.05–0.50 mg/kg, EM-221 reduced hyperlocomotion and the disruption of prepulse inhibition induced by MK-801, attenuated conditioned avoidance, and facilitated novel object recognition, consistent with PDE10A’s inhibition. EM-221 displayed no genotoxicity and was well tolerated up to 300 mg/kg in rats and 100 mg/kg in dogs. In single- and multiple-day ascending dose studies in healthy human volunteers, EM-221 was well tolerated up to 10 mg, with a maximum tolerated dose of 15 mg. PET imaging indicated that a PDE10A enzyme occupancy of up to 92.8% was achieved with a ~24 h half-life. Conclusions: The preclinical and clinical data presented here support the study of EM-221 in phase 2 trials of Tourette syndrome and other movement disorders. Full article

(This article belongs to the Special Issue Phosphodiesterases (PDEs): Therapeutic Targets in Human Health and Disease)

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21 pages, 2664 KiB

Open AccessArticle

Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice

by Ben Rombaut, Melissa Schepers, Assia Tiane, Femke Mussen, Lisa Koole, Sofie Kessels, Chloë Trippaers, Ruben Jacobs, Kristiaan Wouters, Emily Willems, Lieve van Veggel, Philippos Koulousakis, Dorien Deluyker, Virginie Bito, Jos Prickaerts, Inez Wens, Bert Brône, Daniel L. A. van den Hove and Tim Vanmierlo

Cells 2024, 13(12), 1000; https://doi.org/10.3390/cells13121000 - 8 Jun 2024

Viewed by 1890

Abstract

Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer’s disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter. The effects on cognitive function of prolonged A33 treatment from 20 days to 4 months of age, was assessed at 7–8 months. PDE4B inhibition significantly improved both the working and spatial memory of APPswe/PSdE9 mice after treatment ended. At the cellular level, in vitro inhibition of PDE4B induced microglial filopodia formation, suggesting that regulation of PDE4B activity can counteract microglia activation. Further research is needed to investigate if this could prevent microglia from adopting their ‘disease-associated microglia (DAM)’ phenotype in vivo. These findings support the possibility that PDE4B is a potential target in combating AD pathology and that early intervention using A33 may be a promising treatment strategy for AD. Full article

(This article belongs to the Special Issue Phosphodiesterases (PDEs): Therapeutic Targets in Human Health and Disease)

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25 pages, 4396 KiB

Open AccessArticle

Effects of the Phosphodiesterase 10A Inhibitor MR1916 on Alcohol Self-Administration and Striatal Gene Expression in Post-Chronic Intermittent Ethanol-Exposed Rats

by Luísa B. Bertotto, Dolly Lampson-Stixrud, Anushka Sinha, Nicki K. Rohani, Isabella Myer and Eric P. Zorrilla

Cells 2024, 13(4), 321; https://doi.org/10.3390/cells13040321 - 9 Feb 2024

Viewed by 1534

Abstract

Alcohol use disorder (AUD) requires new neurobiological targets. Problematic drinking involves underactive indirect pathway medium spiny neurons (iMSNs) that subserve adaptive behavioral selection vs. overactive direct pathway MSNs (dMSNs) that promote drinking, with a shift from ventromedial to dorsolateral striatal (VMS, DLS) control of EtOH-related behavior. We hypothesized that inhibiting phosphodiesterase 10A (PDE10A), enriched in striatal MSNs, would reduce EtOH self-administration in rats with a history of chronic intermittent ethanol exposure. To test this, Wistar rats (n = 10/sex) with a history of chronic intermittent EtOH (CIE) vapor exposure received MR1916 (i.p., 0, 0.05, 0.1, 0.2, and 0.4 µmol/kg), a PDE10A inhibitor, before operant EtOH self-administration sessions. We determined whether MR1916 altered the expression of MSN markers (Pde10a, Drd1, Drd2, Penk, and Tac1) and immediate-early genes (IEG) (Fos, Fosb, ΔFosb, and Egr1) in EtOH-naïve (n = 5–6/grp) and post-CIE (n = 6–8/grp) rats. MR1916 reduced the EtOH self-administration of high-drinking, post-CIE males, but increased it at a low, but not higher, doses, in females and low-drinking males. MR1916 increased Egr1, Fos, and FosB in the DLS, modulated by sex and alcohol history. MR1916 elicited dMSN vs. iMSN markers differently in ethanol-naïve vs. post-CIE rats. High-drinking, post-CIE males showed higher DLS Drd1 and VMS IEG expression. Our results implicate a role and potential striatal bases of PDE10A inhibitors to influence post-dependent drinking. Full article

(This article belongs to the Special Issue Phosphodiesterases (PDEs): Therapeutic Targets in Human Health and Disease)

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25 pages, 3813 KiB

Open AccessArticle

The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme

by Irina Sbornova, Emilie van der Sande, Snezana Milosavljevic, Elvis Amurrio, Steven D. Burbano, Prosun K. Das, Helen H. Do, Janet L. Fisher, Porschderek Kargbo, Janvi Patel, Latarsha Porcher, Chris I. De Zeeuw, Magda A. Meester-Smoor, Beerend H. J. Winkelman, Caroline C. W. Klaver, Ana Pocivavsek and Michy P. Kelly

Cells 2023, 12(24), 2839; https://doi.org/10.3390/cells12242839 - 14 Dec 2023

Cited by 1 | Viewed by 1952

Abstract

Recently, a Y727C variant in the dual-specific 3′,5′-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if (1) PDE11A protein is expressed in the retina or other eye segments in mice, (2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and (3) Pde11a deletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes of Pde11a WT, but not KO mice, that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this, Pde11a deletion does not alter age-related changes in retinal or lens thickness or axial length, nor vitreous or anterior chamber depth. Further, Pde11a deletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia. Full article

(This article belongs to the Special Issue Phosphodiesterases (PDEs): Therapeutic Targets in Human Health and Disease)

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Review

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14 pages, 695 KiB

Open AccessReview

Phosphodiesterase 4 Inhibition in Neuropsychiatric Disorders Associated with Alzheimer’s Disease

by Jiming Chen, Zhengyao Zhu, Fu Xu, Baomin Dou, Zhutao Sheng and Ying Xu

Cells 2025, 14(3), 164; https://doi.org/10.3390/cells14030164 - 22 Jan 2025

Viewed by 425

Abstract

Cognitive disorders and psychiatric pathologies, particularly Alzheimer’s disease (AD) and Major depressive disorder (MDD), represent a considerable health burden, impacting millions of people in the United States and worldwide. Notably, comorbidities of MDD and anxiety are prevalent in the early stages of mild cognitive impairment (MCI), which is the preceding phase of Alzheimer’s disease and related dementia (ADRD). The symptoms of MDD and anxiety affect up to 80% of individuals in the advanced stages of the neurodegenerative conditions. Despite overlapping clinical manifestations, the pathogenesis of AD/ADRD and MDD remains inadequately elucidated. Until now, dozens of drugs for treating AD/ADRD have failed in clinical trials because they have not proven beneficial in reversing or preventing the progression of these neuropsychiatric indications. This underscores the need to identify new drug targets that could reverse neuropsychiatric symptoms and delay the progress of AD/ADRD. In this context, phosphodiesterase 4 (PDE4) arises as a primary enzyme in the modulation of cognition and mood disorders, particularly through its enzymatic action on cyclic adenosine monophosphate (cAMP) and its downstream anti-inflammatory pathways. Despite the considerable cognitive and antidepressant potential of PDE4 inhibitors, their translation into clinical practice is hampered by profound side effects. Recent studies have focused on the effects of PDE4 and its subtype-selective isoform inhibitors, aiming to delineate their precise mechanistic contributions to neuropsychiatric symptoms with greater specificity. This review aims to analyze the current advances regarding PDE4 inhibition—specifically the selective targeting of its isoforms and elucidate the therapeutic implications of enhanced cAMP signaling and the consequent anti-inflammatory responses in ameliorating the symptomatology associated with AD and ADRD. Full article

(This article belongs to the Special Issue Phosphodiesterases (PDEs): Therapeutic Targets in Human Health and Disease)

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27 pages, 833 KiB

Open AccessReview

Phosphodiesterase Type 5 Inhibitors in Male Reproduction: Molecular Mechanisms and Clinical Implications for Fertility Management

by Aris Kaltsas, Fotios Dimitriadis, Athanasios Zachariou, Nikolaos Sofikitis and Michael Chrisofos

Cells 2025, 14(2), 120; https://doi.org/10.3390/cells14020120 - 15 Jan 2025

Viewed by 615

Abstract

Phosphodiesterases, particularly the type 5 isoform (PDE5), have gained recognition as pivotal regulators of male reproductive physiology, exerting significant influence on testicular function, sperm maturation, and overall fertility potential. Over the past several decades, investigations have expanded beyond the original therapeutic intent of PDE5 inhibitors for erectile dysfunction, exploring their broader reproductive implications. This narrative review integrates current evidence from in vitro studies, animal models, and clinical research to clarify the roles of PDEs in effecting the male reproductive tract, with an emphasis on the mechanistic pathways underlying cyclic nucleotide signaling, the cellular specificity of PDE isoform expression, and the effects of PDE5 inhibitors on Leydig and Sertoli cell functions. Although certain findings suggest potential improvements in sperm motility, semen parameters, and a more favorable biochemical milieu for spermatogenesis, inconsistencies in study design, limited sample sizes, and inadequate long-term data temper definitive conclusions. Addressing these gaps through standardized protocols, larger and more diverse patient cohorts, and explorations of mechanistic biomarkers could pave the way for incorporating PDE5 inhibitors into evidence-based fertility treatment strategies. In the future, such targeted approaches may inform individualized regimens, optimize male reproductive outcomes, and refine the clinical application of PDE5 inhibitors as part of comprehensive male fertility management. Full article

(This article belongs to the Special Issue Phosphodiesterases (PDEs): Therapeutic Targets in Human Health and Disease)

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15 pages, 2264 KiB

Open AccessReview

Modulation of Second Messenger Signaling in the Brain Through PDE4 and PDE5 Inhibition: Therapeutic Implications for Neurological Disorders

by Min Kyu Park, Hyun Wook Yang, Seo Young Woo, Dong Yeon Kim, Dae-Soon Son, Bo Young Choi and Sang Won Suh

Cells 2025, 14(2), 86; https://doi.org/10.3390/cells14020086 - 9 Jan 2025

Viewed by 533

Abstract

Phosphodiesterase (PDE) enzymes regulate intracellular signaling pathways crucial for brain development and the pathophysiology of neurological disorders. Among the 11 PDE subtypes, PDE4 and PDE5 are particularly significant due to their regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling, respectively, which are vital for learning, memory, and neuroprotection. This review synthesizes current evidence on the roles of PDE4 and PDE5 in neurological health and disease, focusing on their regulation of second messenger pathways and their implications for brain function. Elevated PDE4 activity impairs synaptic plasticity by reducing cAMP levels and protein kinase A (PKA) activity, contributing to cognitive decline, acute brain injuries, and neuropsychiatric conditions such as bipolar disorder and schizophrenia. Similarly, PDE5 dysregulation disrupts nitric oxide (NO) signaling and protein kinase G (PKG) pathways, which are involved in cerebrovascular homeostasis, recovery after ischemic events, and neurodegenerative processes in Alzheimer’s, Parkinson’s, and Huntington’s diseases. PDE4 and PDE5 are promising therapeutic targets for neurological disorders. Pharmacological modulation of these enzymes offers potential to enhance cognitive function and mitigate pathological mechanisms underlying brain injuries, neurodegenerative diseases, and psychiatric disorders. Further research into the regulation of PDE4 and PDE5 will advance therapeutic strategies for these conditions. Full article

(This article belongs to the Special Issue Phosphodiesterases (PDEs): Therapeutic Targets in Human Health and Disease)

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