PDE4 Inhibitor Research Articles

Ensifentrine (Ohtuvayre) for COPD.

The FDA has approved ensifentrine (Ohtuvayre – Verona), an inhaled phosphodiesterase (PDE) 3 and 4 inhibitor, for maintenance treatment of chronic obstructive pulmonary disease (COPD) in adults. It is the first dual inhibitor of PDE3 and PDE4 to be approved by the FDA, and the first inhaled drug with a new mechanism of action to be approved for treatment of COPD in more than 20 years.

Real-World Drug Survival of Biologics and Targeted Synthetic Disease-Modifying Anti-rheumatic Drugs Among Patients with Psoriatic Arthritis.

While the variety of biologics (b) and targeted synthetic (ts) disease-modifying anti-rheumatic drugs (DMARDs) available for patients with psoriatic arthritis (PsA) has proved to be efficacious in randomized clinical trials, there is a growing importance to understand the benefits and potential drawbacks of these different therapies in real-world settings, which includes bio-experienced and older patients as well. To evaluate the real-world adherence, drug survival, and discontinuation risk of bDMARDs and tsDMARDs among patients with PsA, comprising both younger and older patients. A retrospective studyusing a computerized database. Treatment-naïve and treatment-experiencedpatients with PsA, younger and older than 60 years, who initiated treatment with bDMARDs [TNF-α inhibitors (TNF-αis), IL-17 inhibitors (IL-17is), IL-12/23 inhibitors (IL-12/23i)] or tsDMARDs (the PDE-4 inhibitor apremilast) during 2015-2018 were included. Adherence was assessed using the proportion of days covered (PDC) method. Time to discontinuation was analyzed using Kaplan-Meier estimates. Risk of discontinuation was estimated by Cox proportional hazard model. We identified 427 eligible patients (22.2 % were older than 60 years), utilizing 673 treatment lines. The proportion of adherent patients (PDC ≥0.8) was similar (62.1-66.5%) across all lines of therapy and across different biologics (70.0-72.0%), while apremilast showed the lowest, in both treatment-naïve and experienced settings (43.6% and 25.5%, respectively). The Kaplan-Meier analysis showed that in the treatment-naïve TNF-αis had higher drug survival compared with apremilast (P = 0.032). Apremilast also had the lowest drug survival in the treatment-experienced group (P < 0.0001). Kaplan-Meier analysis by age groups showed similar drug survival rates in older (≥ 60 years) and younger (age < 60 years) patients, regardless of treatment-experience status. The multivariable model showed that apremilast had increased risk for discontinuation compared with TNF-αis. Adherence, drug survival and risk for discontinuation were similar for all included bDMARDs, regardless of treatment experience status, while apremilast showed lower rates and increased risk. Adherence and discontinuation rate were similar in older and younger patients. With the variety of drug modes of action available for patients with PsA, these findings may assist caregivers in selecting the appropriate treatment.

Abstract Mo139: PDE1, 3 and 4 Inhibition and GPCR Agonism in the Regulation of cAMP Signaling

Modulators of cardiac cyclic adenosine 3’5’-monophosphate (cAMP) and/or its effector protein kinase A (PKA) are used to treat heart disease. Elucidating the mechanisms of endogenous and pharmacological modulators of cAMP, including phosphodiesterase (PDE) inhibitors, is key to predicating alternative drug therapies for heart failure (HF). PDEs regulate confined cAMP/PKA signaling pathways, depending on PDE isoform and localization. PDE3 regulates the SR and sarcolemmal membrane cAMP pools, controlling calcium influx and efflux at these domains. PDE1 regulates sarcolemmal cAMP/PKA signaling. Despite these differences, inhibitors of either increase heart contractility. However, inhibition of PDE3 is pro-arrhythmic, unlike that of PDE1. The regulation of localized cAMP signaling is key to controlled regulation of cell function, with ramifications for HF, and which GPCR lies upstream of PDE1 remains unknown. We hypothesized that the three cAMP-hydrolyzing cardiac PDEs (1, 3, 4) that are found in the human heart would regulate distinct cAMP signaling pathways. Using the cAMP biosensor EPAC-SH187, we performed fluorescence resonance energy transfer experiments in healthy guinea pig adult ventricular myocytes. Cells were treated with inhibitors of PDEs 1, 3, and 4 along with GPCR agonists isoproterenol, glucagon (gcg), and amthamine (amt), respectively for β-adrenergic, gcg and histamine H2 receptors at sub-maximal doses. Cell function and calcium data were obtained using IonOptix. We first asked if PDEi would synergistically regulate pools of cAMP, and found that PDE4i does at pools of cAMP generated by beta-agonism. PDE3i regulates that generated by amt at the H2R, with comparable effects observed in simultaneous or prior H2R stimulation. The combination of these sub-saturating doses exerted strong inotropic and lusitropic effects in paced myocytes. In neither of these domains, PDE1i changed cAMP levels. However, PDE1i intriguingly attenuated the level of gcg-stimulated cAMP production, suggesting a feedback loop mechanism. We conclude that PDEs 1, 3, and 4 regulate distinct pools of cAMP. Importantly, we demonstrate this in a species where the myocardial expression of these PDEs match that of humans as opposed to smaller rodent models.

Targeting next-generation PDE4 inhibitors in search of potential management of rheumatoid arthritis and psoriasis

Immune-mediated inflammatory diseases (IMIDs) comprise a broad spectrum of conditions characterized by systemic inflammation affecting various organs and tissues, for which there is no known cure. The isoform-specific inhibition of phosphodiesterase-4B (PDE4B) over PDE4D constitutes an effective therapeutic strategy for the treatment of IMIDs that minimizes the adverse effects associated with non-selective PDE4 inhibitors. Thus, we report a new class of isoquinolone derivatives as next-generation PDE4 inhibitors for effective management of rheumatoid arthritis (RA) and psoriasis. Among the series, 8 compounds i.e. 1e, 1l, 1m, 1n, 1o, 2m, 2o and 3o showed promising PDE4B inhibition (>80 %) in vitro with IC50 ∼ 1.4–6.2 µM. The compound 1l was identified as an initial hit and was pursued for further studies. According to structure–activity relationship (SAR), an allyl group at C-4 position improved PDE4B inhibition. The correlation between in vitro activity data and binding affinities obtained via molecular docking suggested that the high-affinity binding to PDE4B is a prerequisite for the effective inhibition of PDE4B. Notably, the hit 1l showed selectivity towards PDE4B over PDE4D in vitro. Furthermore, 1l treatment (30 mg/kg) in the adjuvant-induced arthritis (AIA) rat model induced by complete Freund’s adjuvant (CFA) demonstrated anti-arthritic potential via ameliorating paw swelling and body weight, narrowing joint space, reducing excessive immune cells infiltration and pannus formation in addition to reducing mRNA expression of pro-inflammatory cytokines such as TNF-α and IL-6 in synovial tissues of experimental rats. Additionally, 1l reduced the hyper-proliferative state and colony forming potential of IMQ-induced psoriatic keratinocytes. The treatment of these cells with 1l markedly reduced the protein levels of Ki67 and mRNA levels of pro-inflammatory cytokines e.g. IL-17A and TNF-α suggesting its potent anti-psoriatic potential. Furthermore, 1l did not show any significant adverse effects when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at the tested concentrations (1–100 µM) and the NOAEL (no-observed-adverse-effect level) was found to be 100 µM. Thus, with promising anti-inflammatory effects both in vitro and in vivo along with PDE4B selectivity with an acceptable safety margin, 1l emerged as a new and promising inhibitor for further studies.

Abstract Tu029: Effects of the phosphodiesterase inhibitors, cilostazol and ensifentrine, on alveolar-capillary dysfunction caused by MRSA

Background: Acute lung injury (ALI) is characterized by excessive inflammation and dysfunction of the alveolar-capillary barrier, which consists of lung vascular endothelial and alveolar epithelial cells. Therapeutic interventions that protect this barrier are promising strategies for ALI treatment. Phosphodiesterase (PDE) inhibitors are potent modulators of inflammation. These include cilostazol, a PDE3 inhibitor, and ensifentrine, a dual PED3/4 inhibitor, which are both clinically available compounds that exhibit cytoprotective and anti-inflammatory properties. However, their roles in regulating alveolar-capillary function in ALI are unknown. The aim of this study is to investigate the effects of cilostazol and ensifentrine on lung endothelial and epithelial dysfunction caused by methicillin-resistant Staphylococcus aureus (MRSA), a common bacterial pathogen involved in ALI pathogenesis. Methods: Human primary lung endothelial cells (EC) and A549 (alveolar epithelial cell line) were pre-treated with cilostazol (CZ; 15 μM) or ensifentrine (Ens; 10 μΜ) for 1 hour and then challenged with heat-killed MRSA (2.5 x10 8 /ml). The Electrical Cell Impedance Sensing (ECIS) assay was used to assess EC barrier integrity. Pro-inflammatory signaling markers were measured by western blotting (WB) and qPCR. Cell conditioned media was analyzed for extracellular vesicle release by flow cytometry and WB. Results: MRSA-induced EC barrier disruption was attenuated by both CZ and Ens, although Ens exhibited superior barrier protective properties. CZ and Ens suppressed MRSA-induced upregulation of the inflammatory adhesion molecules, VCAM-1 and ICAM-1, in EC. Ens, but not CZ, reduced MRSA-induced ICAM-1 upregulation in A549. MRSA caused a significant increase in the release of EC-derived extracellular vesicles, which was partially inhibited by CZ or Ens pretreatment. Conclusions: Both cilostazol and ensifentrine exert anti-inflammatory properties in MRSA-treated lung EC. Compared to cilostazol, ensifentrine exhibits enhanced endothelial barrier protection and inhibits inflammation in both lung endothelial and epithelial cells. Future in vivo studies will evaluate the therapeutic efficacy of these inhibitors in bacterial-induced ALI.

Anti-Inflammatory Effects of miR-369-3p via PDE4B in Intestinal Inflammatory Response.

Cyclic nucleotide phosphodiesterases (PDEs) consist of a family of enzymes expressed in several types of cells, including inflammatory cells, that play a pivotal role in inflammation. Several studies have demonstrated that the inhibition of PDE4 results in a reduced inflammatory response via PKA and CREB signaling. Hence, PDE4 suppression improves the inflammatory feedback typical of several diseases, such as inflammatory bowel disease (IBD). In our previous studies, we have demonstrated that miR-369-3p regulates inflammatory responses, modulating different aspects of the inflammatory process. The aim of this study was to demonstrate an additional anti-inflammatory effect of miR-369-3p targeting PDE4B, one of the widely expressed isoforms in immune cells. We found that miR-369-3p was able to reduce the expression of PDE4B, elevating the intracellular levels of cAMP. This accumulation increased the expression of PKA and pCREB, mitigating the release of pro-inflammatory cytokines and promoting the release of anti-inflammatory cytokines. To prove that PDE4B is a good therapeutic target in IBD, we also demonstrate that the expression of PDE4B was increased in UC patients compared to healthy controls, affecting the immune infiltrate. PDE4B is considered an important player in inflammatory progression; hence, our results show the ability of miR-369-3p to ameliorate inflammation by targeting PDE4B, supporting its future application as a new therapeutic approach in IBD.

Heterocyclic Nitrogen Compounds as Potential PDE4B Inhibitors in Activated Macrophages

Cyclic-nucleotide phosphodiesterases (PDEs) represent a superfamily of enzymes playing a pivotal role in cell signaling by controlling cAMP and cGMP levels in response to receptor activation. PDE activity and expression are linked to many diseases including inflammatory diseases. In light of their specific biochemical properties, PDE inhibition has attracted the interest of several researrs In this context, PDE4 inhibition induces anti-inflammatory effects. Piclamilast and rolipram, well-known PDE4 inhibitors, are endowed with common side effects. The selective phosphodiesterase 4B (PDE4B) inhibitors could be a promising approach to overcome these side effects. In the present study, six potential PDE4B inhibitors have been investigated. Through this study, we identified three PDE4B inhibitors in human macrophages activated by lipopolysaccharide. Interestingly, two of them reduced reactive oxygen species production in pro-inflammatory macrophages.

Phosphodiesterase 2 and Its Isoform A as Therapeutic Targets in the Central Nervous System Disorders.

Cyclic adenosine monophosphates (cAMP) and cyclic guanosine monophosphate (cGMP) are two essential second messengers, which are hydrolyzed by phosphodiesterase's (PDEs), such as PDE-2. Pharmacological inhibition of PDE-2 (PDE2A) in the central nervous system improves cAMP and cGMP signaling, which controls downstream proteins related to neuropsychiatric, neurodegenerative, and neurodevelopmental disorders. Considering that there are no specific treatments for these disorders, PDE-2 inhibitors' development has gained more attention in the recent decade. There is high demand for developing new-generation drugs targeting PDE2 for treating diseases in the central nervous and peripheral systems. This review summarizes the relationship between PDE-2 with neuropsychiatric, neurodegenerative, and neurodevelopmental disorders as well as its possible treatment, mainly involving inhibitors of PDE2.

THE ANALYSIS STUDY OF EFFECTIVENESS AND SAFETY OF ORAL SILDENAFIL CITRATE FOR TREATMENT OF ERECTILE DYSFUNCTION : A COMPREHENSIVE SYSTEMATIC REVIEW

Background: Erectile dysfunction (ED) is a medical condition affecting men's sexual performance and well-being. Sildenafil citrate, a specific inhibitor of phosphodiesterase type 5, is approved for treating ED. The efficacy and safety of oral sildenafil citrate in treating ED are crucial for successful treatment procedures. Understanding the relationship between the efficacy and safety of oral sildenafil citrate can help develop successful treatment procedures for ED patients. Methods: This systematic review adhered to the PRISMA 2020 guidelines and primarily examined entire English literature published between 2000 and 2024. Only editorials and review articles published in the same publication as the submission were accepted if they possessed a Digital Object Identifier (DOI). A variety of online platforms, including ScienceDirect, PubMed, and SagePub, were utilized to gather the relevant literature. Result: The study analyzed more than 2000 papers from reputable sources such as Science Direct, SagePub, and PubMed. After deciding to subject eight publications to additional inspection, a thorough evaluation of the entire body of literature was carried out. Conclusion: Sildenafil, a potent treatment for erectile dysfunction (ED), has been found to be effective in improving men's psychosocial aspects. It is an inhibitor of PDE5, a condition that affects men's emotional well-being. The study also found that the firmness of erections was linked to improvements in psychosocial aspects. Sildenafil can be used interchangeably with tablets, providing a convenient alternative for those with difficulty swallowing. However, follow-up for men with ED is often inadequate due to improper doses and lack of understanding.

Penile Replantation: A Review of Microsurgical Techniques, Patient Outcomes, and Solutions to Complex Reconstructive Challenges

Introduction: Penile amputation is a rare urological emergency with varying etiologies, ranging from psychiatric disorders to traumatic injuries, and requires precise microsurgical replantation techniques to restore function and appearance. The popularization of microsurgery has greatly improved outcomes by enabling accurate vascular and nerve reattachments, which are crucial for erectile function and sensation. This comprehensive study reviews advancements in microsurgical penile replantation, perioperative, and postoperative care, focusing on the nuances of surgical interventions and potential complications such as ischemia and necrosis. Methods: The PubMed, EMBASE, and Cochrane databases, were queried for studies published between 2015 and 2023 that discussed preoperative conditions, surgical techniques, and postoperative outcomes in penile replantation cases. Resulting studies that reported preoperative and postoperative outcomes of at least one case of penile replantation after amputation were included. Case parameters of interest were then extracted and categorized to determine the most common complications as well as solutions utilized in penile replantation. Results: Our findings from 46 cases across 37 studies revealed a common occurrence of postoperative necrosis (56.5%) and highlighted the importance of timely vascular reconnection and innovative surgical strategies to manage complications. Three cases were complicated by scrotal hematomas and 23 cases reported at least one psychiatric comorbidity. Some innovative solutions mentioned include hyperbaric oxygen therapy, laser angiography, leech therapy, PDE inhibitors, and penile splints. Conclusion: The outcomes suggest a critical need for standardized protocols and further research into optimizing techniques and therapies to enhance the success rates as well as quality of life post-replantation. This review aims to guide future practices and encourage collaborative efforts to refine the complex microsurgical procedures involved in penile replantation.

Insights into bioactive constituents of onion (Allium cepa L.) waste: a comparative metabolomics study enhanced by chemometric tools

BackgroundOnion waste was reported to be a valuable source of bioactive constituents with potential health-promoting benefits. This sparked a surge of interest among scientists for its valorization. This study aims to investigate the chemical profiles of peel and root extracts of four onion cultivars (red, copper-yellow, golden yellow and white onions) and evaluate their erectogenic and anti-inflammatory potentials.MethodsUPLC-QqQ-MS/MS analysis and chemometric tools were utilized to determine the chemical profiles of onion peel and root extracts. The erectogenic potential of the extracts was evaluated using the PDE-5 inhibitory assay, while their anti-inflammatory activity was determined by identifying their downregulating effect on the gene expression of IL-6, IL-1β, IFN-γ, and TNF-α in LPS-stimulated WBCs.ResultsA total of 103 metabolites of diverse chemical classes were identified, with the most abundant being flavonoids. The organ’s influence on the chemical profiles of the samples outweighed the influence of the cultivar, as evidenced by the close clustering of samples from the same organ compared to the distinct separation of root and peel samples from the same cultivar. Furthermore, the tested extracts demonstrated promising PDE-5 and anti-inflammatory potentials and effectively suppressed the upregulation of pro-inflammatory markers in LPS-stimulated WBCs. The anti-inflammatory activities exerted by peel samples surpassed those of root samples, highlighting the importance of selecting the appropriate organ to maximize activity. The main metabolites correlated with PDE-5 inhibition were cyanidin 3-O-(malonyl-acetyl)-glucoside and quercetin dimer hexoside, while those correlated with IL-1β inhibition were γ-glutamyl-methionine sulfoxide, γ-glutamyl glutamine, sativanone, and stearic acid. Taxifolin, 3’-hydroxymelanettin, and oleic acid were highly correlated with IL-6 downregulation, while quercetin 4’-O-glucoside, isorhamnetin 4’-O-glucoside, and p-coumaroyl glycolic acid showed the highest correlation to IFN-γ and TNF-α inhibition.ConclusionThis study provides a fresh perspective on onion waste as a valuable source of bioactive constituents that could serve as the cornerstone for developing new, effective anti-PDE-5 and anti-inflammatory drug candidates.

Phosphodiesterase Inhibition to Sensitize Non-Small-Cell Lung Cancer to Pemetrexed: A Double-Edged Strategy.

Phosphosidesterases (PDEs) are key regulators of cyclic nucleotide signaling, controlling many hallmarks of cancer and playing a role in resistance to chemotherapy in non-small-cell lung cancer (NSCLC). We evaluated the anti-tumor activity of the anti-folate agent pemetrexed (PMX), alone or combined with biochemical inhibitors of PDE5, 8, 9, or 10, against squamous and non-squamous NCSLC cells. Genomic alterations to PDE genes (PDEmut) or PDE biochemical inhibition (PDEi) can sensitize NSCLC to PMX in vitro (observed in 50% NSCLC evaluated). The synergistic activity of PDEi with PMX required microdosing of the anti-folate drug. As single agents, none of the PDEis evaluated have anti-tumor activity. PDE biochemical inhibitors, targeting either cAMP or cGMP signaling (or both), resulted in significant cross-modulation of downstream pathways. The use of PDEi may present a new strategy to overcome PMX resistance of PDEwt NSCLC tumors but comes with important caveats, including the use of subtherapeutic PMX doses.

Immunohistochemical Assessment of Phosphodiesterase 4A and Phosphodiesterase 4D in Relation to Serum Levels of Phosphodiesterase 4 in Patients with Chronic Plaque Psoriasis

Abstract Psoriasis is an immune-mediated genetic skin disease. The underlying pathomechanisms involve complex interaction between the innate and adaptive immune system. T-cells interact with dendritic cells, macrophages, and keratinocytes, which can be mediated by their secreted cytokines. Dysregulation of the immune response is thought to result in a chronic imbalance in the production of pro-inflammatory and anti-inflammatory cytokines. Phosphodiesterase (PDE4) act as proinflammatory enzymes via degradation of cAMP, whereas PDE4 inhibitors play an anti-inflammatory role in vitro and in vivo. In particular, topical and systemic PDE4 inhibitor has been approved for the treatment of psoriasis and psoriatic arthritis. However, little is known on the expression pattern of PDE4 in psoriasis. We report that serum PDE4 are overexpressed in blood of patients with chronic plaque psoriasis, as compared with normal controls. PDE4 expression is up-regulated in psoriatic dermis as compared with normal skin, with particular regard to dermal lymphocytes. Taken together, these results indicate that PDE4 play an important role in psoriasis pathogenesis and supports promises put on topical PDE4 inhibitors in treatment of psoriasis.

A novel phosphodiesterase inhibitor for the treatment of chronic liver injury and metabolic diseases.

Chronic liver disease (CLD) leads to approximately two million deaths annually. Cyclic adenosine monophosphate (cAMP) signaling has long been studied in liver injury, particularly in the regulation of fatty acid (FA) β-oxidation and pro-inflammatory polarization of tissue-resident lymphocytes. Phosphodiesterase 4B (PDE4B) inhibition has been explored as a therapeutic modality, but these drugs have had limited success and are known to cause significant adverse effects. The PDE4 inhibitor 2-(4-([2-(5-Chlorothiophen-2-yl)-5-ethyl-6-methylpyrimidin-4-yl]amino)phenyl)acetic acid) (known as A-33) has yet to be explored for the treatment of metabolic diseases. Herein, we evaluated the efficacy of A-33 in the treatment of animal models of alcohol-associated liver disease (ALD) and steatotic liver disease (SLD). We demonstrated that A-33 effectively ameliorated the signs and symptoms of CLD, resulting in significant decreases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, decreased overall fat and collagen deposition in the liver, decreased intrahepatic triglyceride (TG) concentrations, and normalized expression of genes related to β-oxidation of fatty acids, inflammation, and extracellular matrix (ECM) deposition. We also designed and synthesized a novel analog of A-33, termed MDL3, which inhibited both PDE4B and PDE5A and was more effective in ameliorating pathophysiological signs and symptoms of liver injury and inflammation. In addition, MDL3 re-sensitized obese mice to glucose and significantly inhibited the pathological remodeling of adipose tissue, which was not observed with A-33 administration. In conclusion, we synthesized and demonstrated that MDL3, a novel PDE4B and PDE5A inhibitor, presents a promising avenue of exploration for treating CLD.

Reno-protective effect of Roflumilast against kidney injury induced by ischemia/reperfusion in rats: Evidence from biochemical and histological investigations

Oxidative stress, inflammation, and apoptosis are major contributors to renal ischemia/reperfusion (I/R) injury. This study aimed to investigate the effects of pretreatment with the PDE4 inhibitor roflumilast (Rof) on renal I/R and its underlying mechanisms. Sprague-Dawley rats were subjected to 30 minutes of unilateral renal ischemia followed by 45 minutes of reperfusion. Rof (1.5 and 3 mg/kg) was administered for seven days prior to I/R induction. The findings showed that Rof significantly and dose-dependently attenuated kidney damage by reducing blood urea nitrogen and creatinine levels. Rof also exhibited antioxidant and anti-inflammatory effects, as evidenced by improved glutathione and malondialdehyde levels and decreased proinflammatory cytokines (IL-6 and TNF-α). Furthermore, Rof prevented the downregulation of HO-1 and Nrf2 expression. These results suggest that Rof therapy could protect the kidneys from I/R-induced injury through its antioxidant and anti-inflammatory properties, providing a potential therapeutic approach for the management of renal I/R damage.

The PDE4 inhibitor apremilast modulates ethanol responses in Gabrb1-S409A knock-in mice via PKA-dependent and independent mechanisms

We previously showed that the PDE4 inhibitor apremilast reduces ethanol consumption in mice by protein kinase A (PKA) and GABAergic mechanisms. Preventing PKA phosphorylation of GABAA β3 subunits partially blocked apremilast-mediated decreases in drinking. Here, we produced Gabrb1-S409A mice to render GABAA β1 subunits resistant to PKA-mediated phosphorylation. Mass spectrometry confirmed the presence of the S409A mutation and lack of changes in β1 subunit expression or phosphorylation at other residues. β1-S409A male and female mice did not differ from wild-type C57BL/6J mice in expression of Gabrb1, Gabrb2, or Gabrb3 subunits or in behavioral characteristics. Apremilast prolonged recovery from ethanol ataxia to a greater extent in Gabrb1-S409A mice but prolonged recovery from zolpidem and propofol to a similar extent in both genotypes. Apremilast shortened recovery from diazepam ataxia in wild-type but prolonged recovery in Gabrb1-S409A mice. In wild-type mice, the PKA inhibitor H89 prevented apremilast modulation of ataxia by ethanol and diazepam, but not by zolpidem. In Gabrb1-S409A mice, inhibiting PKA or EPAC2 (exchange protein directly activated by cAMP) partially reversed apremilast potentiation of ethanol, diazepam, and zolpidem ataxia. Apremilast prevented acute tolerance to ethanol ataxia in both genotypes, but there were no genotype differences in ethanol consumption before or after apremilast. In contrast to results in Gabrb3-S408A/S409A mice, PKA phosphorylation of β1-containing GABAA receptors is not required for apremilast's effects on acute tolerance or on ethanol consumption but is required for its ability to decrease diazepam intoxication. Besides PKA we identified EPAC2 as an additional cAMP-dependent mechanism by which apremilast regulates responses to GABAergic drugs.

Discovery of 7-alkoxybenzofurans as PDE4 inhibitors with hepatoprotective activity in D-GalN/LPS-induced hepatic sepsis

Sepsis can quickly result in fatality for critically ill individuals, while liver damage can expedite the progression of sepsis, necessitating the exploration of new strategies for treating hepatic sepsis. PDE4 has been identified as a potential target for the treatment of liver damage. The scaffold hopping of lead compounds FCPR16 and Z19153 led to the discovery of a novel 7-methoxybenzofuran PDE4 inhibitor 4e, demonstrating better PDE4B (IC50 = 10.0 nM) and PDE4D (IC50 = 15.2 nM) inhibitor activity as a potential anti-hepatic sepsis drug in this study. Compared with FCPR16 and Z19153, 4e displayed improved oral bioavailability (F = 66 %) and longer half-life (t1/2 = 2.0 h) in SD rats, which means it can be more easily administered and has a longer-lasting effect. In the D-GalN/LPS-induced liver injury model, 4e exhibited excellent hepatoprotective activity against hepatic sepsis by decreasing ALT and AST levels and inflammatory infiltrating areas.

Research progress on phosphodiesterase 4 inhibitors in central nervous system diseases.

Phosphodiesterases (PDE) are involved in the regulation of cellular physiological processes and neurological functions, including neuronal plasticity, synapto-genesis, synaptic transmission, memory formation and cognitive functions by catalyzing the hydrolysis of intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Many basic and clinical studies have shown that PDE4 inhibitors block or ameliorate the occurrence and development of central nervous system (CNS) diseases by inhibiting cAMP hydrolysis, increasing cAMP content and enhancing its downstream effects. PDE4 inhibitors have long-term potentiation effect, which can enhance phosphorylation of cAMP response element binding protein (CREB) and upregulate expression of memory related Arc genes in hippocampal neurons, thereby improving cognitive impairment and Alzheimer's disease-like symptoms. They can also delay the occurrence and development of Parkinson's disease by reducing the cytotoxicity induced by α-syn and increasing the effect of miR-124-3p on cell functions. Alteration of PDE4 activity is the molecular basis for psychosis and some cognitive disorders, therefore it is considered as a therapeutic target for schizophrenia. PDE4 inhibitors play a role in depression by inhibiting the advanced glycation end product receptor (RAGE), TLR4 and NLRP3 pathways in the hippocampus, reducing the activation of microglia and the production of IL-1β, down-regulating HMGB1/RAGE signaling pathway and inhibiting inflammatory factors. PDE4 inhibitor plays a role in the treatment of autism spectrum disorder by reducing the damage of cerebellar glial cells, increasing nociceptive threshold, and improving mutual learning and memory deficits. PDE4 inhibitors might be used in the treatment of fragile X syndrome by regulating the level of cAMP and affecting the expression of fragile X mental retardation protein (FMRP). PDE4 inhibitors can also promote the differentiation of oligodendrocyte progenitor cells and enhance myelination, which has potential in the treatment of multiple sclerosis. PDE4 is also related to bipolar disorder, which may be one of the therapeutic targets. At present, several PDE4 inhibitors are in clinical trials for the treatment of CNS diseases. This article reviews and discusses the progress on basic research and clinical trials of PDE4 inhibitors in CNS diseases, providing a reference for the prevention and treatment of CNS diseases and the development of new drugs.

FDA-approved PDE4 inhibitors reduce the dominant toxicity of ALS-FTD-associated CHCHD10 S59L.

Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10( CHCHD10 ) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing C2C10H S81L , and human cell models expressing CHCHD10 S59L , we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10 S59L . Evidences using in vitro/ in vivo genetic and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10 S59L -induced diseases. Therefore, we have investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10 S59L -induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10 S59L -induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H S81L . Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10 S59L . These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10 S59L -induced ALS-FTD and possibly other related diseases.

Cyclic nucleotide phosphodiesterases: therapeutic targets incardiac hypertrophy and failure

Cyclic nucleotide phosphodiesterases (PDEs) modulate neurohormonal regulation of cardiac function by degrading cAMP and cGMP. In cardiomyocytes, multiple isoforms of PDEs with different enzymatic properties and subcellular locally regulate cyclic nucleotide levels and associated cellular functions. This organisation is severely disrupted during hypertrophy and heart failure (HF), which may contribute to disease progression. Clinically, PDE inhibition has been seen as a promising approach to compensate for the catecholamine desensitisation that accompanies heart failure. Although PDE3 inhibitors such as milrinone or enoximone can be used clinically to improve systolic function and relieve the symptoms of acute CHF, their chronic use has proved detrimental. Other PDEs, such as PDE1, PDE2, PDE4, PDE5, PDE9 and PDE10, have emerged as potential new targets for the treatment of HF, each with a unique role in local cyclic nucleotide signalling pathways. In this review, we describe cAMP and cGMP signalling in cardiomyocytes and present the different families of PDEs expressed in the heart and their modifications in pathological cardiac hypertrophy and HF. We also review results from preclinical models and clinical data indicating the use of specific PDE inhibitors or activators that may have therapeutic potential in CI.