Non-Selective PDE4 Inhibition Induces a Rapid and Transient Decrease of Serum Potassium in Mice

The phosphodiesterase 4 (PDE4) family of enzymes is a promising drug target for a variety of conditions, including inflammatory conditions such as asthma and chronic obstructive pulmonary disorder (COPD), and neurological conditions such as depression. PDE4 inhibitors include rolipram, which was trialled for the treatment of depression, and roflumilast, which has recently completed clinical trials for the treatment of COPD. Unfortunately, PDE4 inhibitors generally exhibit side effects – mainly, nausea and emesis. The mechanisms underlying these side effects are not fully understood, though several strategies exist in the literature for avoiding them. These strategies usually encourage finding novel structural classes of inhibitors. Here I present work on two structural classes as PDE4 inhibitors. Chapter one introduces the PDE4 enzyme as a drug target and explains the side effects associated with it, and introduces previously studied inhibitor classes. Chapter two describes the synthesis and evaluation of a class of tetrahydrobenzothiophenes as PDE4 inhibitors, with the most potent analogue exhibiting an IC50 of approximately 20 nM. Although this class was serendipitously discovered by my lab and collaborators, a similar compound was recently reported by Kranz et. al. as a selective PDE4B inhibitor. Interestingly, our compounds bind in the active site of PDE4 in a different orientation, as revealed by X-ray co-crystallography. Chapter three builds on this structural information, using molecular docking to design new analogues. Based on docking simulations, the tetrahydrobenzothiophene scaffold was derivatised with different urea groups, with the most potent exhibiting a PDE4 IC50 of 93.03 nM. Additionally, isomeric analogues of the tetrahydrobenzothiophenes of chapter 2 were investigated, though these performed poorly in assays. Chapter four describes flavonoids as a possible source of PDE4 inhibitors. Flavonoids are a class of naturally occurring polyphenolic compounds that display a range of biological activities. There have been some indications that this class may be a useful source of phosphodiesterase inhibitors. Here I investigated a series of chromone compounds bearing a 2-tetrahydopyranyl group. In PDE4 assays, the most potent compounds exhibited IC50s of approximately 0.4 μM.

To determine whether changes in serum glucose, serum potassium, and plasma insulin levels are correlated in a cohort of hypertensive patients. Prespecified subgroup analysis of results from a prospective, multicenter, randomized, open-label, parallel-group study. Setting. Primary care clinics at three tertiary care medical centers. Community-based ambulatory population of 202 patients (age range 17-65 yrs) with a new diagnosis of hypertension, untreated hypertension, or known hypertension, who were previously treated with fewer than three antihypertensive drugs and had no evidence of cardiovascular disease or diabetes mellitus. Intervention. Monotherapy with oral hydrochlorothiazide 12.5 or 25 mg/day for 9 weeks. Fasting serum glucose, serum potassium, and plasma insulin levels were obtained at baseline (before hydrochlorothiazide therapy was started) and after 9 weeks of therapy. Significant elevations were noted in fasting serum glucose (mean +/- SD 3.42 +/- 10.38 mg/dl, p<0.0001) and plasma insulin (2.35 +/- 9.47 microU/ml, p<0.0001) levels, and a significant reduction in serum potassium level (0.30 +/- 0.44 mEq/L, p<0.0001) was noted. No significant correlation was observed between changes in fasting serum glucose and potassium levels (r = 0.022, 95% confidence interval (CI) -0.120-0.164, p=0.757) or between changes in serum potassium and plasma insulin levels (r = -0.112, 95% CI -0.256-0.037, p=0.140). Changes in serum glucose levels did not differ significantly between patients maintaining serum potassium levels of 4.0 mEq/L or greater and those with levels below 4.0 mEq/L. Changes in serum potassium and serum glucose levels were not correlated in individuals receiving hydrochlorothiazide monotherapy; thus maintenance of normal potassium levels may not attenuate the risk of thiazide diuretic-induced hyperglycemia.

The chronic autoimmune disease known as psoriasis creates major life-quality problems for affected patients. The disease evolves through genetic and environmental triggers that trigger continuous keratinocyte multiplication with persistent inflammation. Research into psoriasis treatment now emphasizes phosphodiesterase-4 (PDE4) inhibitors because they manage cyclic adenosine monophosphate (cAMP) signaling to reduce inflammatory cytokine production. This review examines the PDE4 inhibitor potential for psoriasis treatment through investigation of their therapeutic functions alongside their mechanism of action and clinical response, safety data, and novel treatment approaches. The review gathered detailed information about clinical research and pharmaceutical operations of PDE4 inhibitors, specifically for apremilast, roflumilast, and crisaborole. This review also analyzes experimental PDE4 inhibitors alongside the advantages that appear when combining these drugs with biologics or phototherapy, together with methotrexate. The administration of PDE4 inhibitors creates higher intracellular cAMP levels that decrease TNF-α and IL-17 production as pro-inflammatory cytokines. The research on Apremilast, as the most prominent oral PDE4 inhibitor, shows that it both improves PASI scores and maintains good safety results. These medications treat psoriasis symptoms specifically through creams and gels, thus reducing the risk of whole-body side effects. The combined administration of PDE4 inhibitors and biologics leads to better therapeutic effects, which may lower both drug resistance rates and side effects. PDE4 inhibitors function as a valuable alternative therapeutic approach to both standard immunosuppressants and biologic medications in psoriasis treatment. New drug dosage methods connected to personalized treatment plans have the potential to raise patient care effectiveness. Researchers need to study ways to improve PDE4 inhibitor formulations, along with developing new combination therapy approaches to enhance sustained psoriasis disease treatment.

Major depressive disorder (MDD) is a mental disease characterized by depressed mood, lifetime anxiety, and deficits of learning and memory. Inhibition of phosphodiesterase 9 (PDE9) has been reported to improve rodent cognitive and memory function. However, the role of PDE9 in MDD, in particular its manifestations of depression and anxiety, has not been investigated. We examined the protective effects of WYQ-C36D (C36D), a novel PDE9 inhibitor, against corticosterone-induced cytotoxicity, pCREB/CREB and BDNF expression by cell viability, and immunoblot assays in HT-22 cells. The potential effects of C36D at doses of 0.1, 0.5, and 1mg/kg on stress-induced depression- and anxiety-like behaviors and memory deficits were also examined in mice. C36D significantly protected HT-22 cells against corticosterone-induced cytotoxicity and rescued corticosterone-induced decreases in cGMP, CREB phosphorylation, and BDNF expression. All these effects were otherwise blocked by the PKG inhibitor Rp-8-Br-PET-cGMPS (Rp8). In addition, when tested in vivo in stressed mice, C36D produced antidepressant-like effects on behavior, as shown by decreased immobility time both in the forced swimming and tail suspension tests. C36D also showed anxiolytic-like and memory-enhancing effects in the elevated plus-maze and novel object recognition tests. Our results show that inhibition of PDE9 by C36D produces antidepressant- and anxiolytic-like behavioral effects and memory enhancement by activating cGMP/PKG signaling pathway. PDE9 inhibitors may have the potential as a novel class of drug to treat MDD.

Electrolyte disturbances are relatively common in patients with depression, but they are often overlooked, and the relationship between electrolyte changes and adverse outcomes in depression is not yet clear. This study aims to explore the impact of serum electrolyte levels on the all-cause and cardiovascular disease (CVD) mortality rates in patients with depression. This prospective cohort study included 3127 patients with depression who participated in the National Health and Nutrition Examination Survey (NHANES) from 2005 through 2018. Depression was assessed using the Patient Health Questionnaire (PHQ-9), with a PHQ-9 score ≥10 defined as depression. The data were analyzed from April 1 to July 30, 2024. Multivariable Cox proportional hazards regression model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) between serum sodium, potassium, and chloride levels and the CVD risk and all-cause mortality in patients with depression. Three multivariable models were constructed. We further stratified the analysis by age, gender, hypertension, smoking, alcohol consumption, diabetes, and drinking status. Interaction significance was estimated using P-values for the product terms between serum sodium, potassium, chloride, and stratification factors. This cohort study included data from 2946 participants in the analysis (mean [SD] age, 50.13 [16.48] years; 1116 men [37.88]); During a median (IQR) follow-up of 7.2 (3.6-10.5) years, 398 deaths were recorded, of which 117 were attributed to CVD.After multivariable adjustment, compared with participants in the first quartile of serum sodium levels, the HRs of CVD mortality were 0.90(95% CI, 0.53-1.53) in the fourth quartile (p for trend = 0.484). The HRs of all-cause mortality were 0.73(95% CI, 0.55-0.99) for the fourth quartile (p for trend = 0.003). A nonlinear association was observed between serum sodium levels and all-cause mortality in patients with depression (p for overall = 0.003, p for nonlinear = 0.047). Compared with participants in the first quartile of serum potassium levels, the HRs of CVD mortality were and 1.58(95% CI, 0.98-2.54) in the fourth quartile (p for trend = 0.050), the HRs of all-cause mortality were 1.52(95% CI, 1.16-1.99) for the fourth quartile (p for trend <0.001). A nonlinear association was observed between serum potassium levels and all-cause (p for overall<0.001, p for nonlinear = 0.005) and CVD (p for nonlinear = 0.003) mortality in patients with depression. Compared with participants in the first quartile of serum chlorine levels, the HRs of CVD mortality were 0.84(95% CI, 0.49-1.46) in the fourth quartile(p for trend = 0.284). The HRs of all-cause mortality were 0.70(95% CI, 0.51-0.95) for the fourth quartile(p for trend <0.001). A nonlinear association was observed between serum chlorine levels and all-cause (p for nonlinear<0.001) and CVD (p for nonlinear<0.001) mortality in patients with depression. This cohort study found that in patients with depression, higher sodium is significantly correlated with lower all-cause mortality, higher potassium is significantly correlated with higher all-cause and CVD mortality, and higher chloride is significantly correlated with lower all-cause and CVD mortality.

Hyperkalemia is a commonly encountered problem in dialysis patients with end-stage renal disease. In this study we evaluated the effect of mineralocorticoid therapy (MCT; fludrocortisone 0.1-0.3 mg per os daily) on serum potassium of hyperkalemic end-stage renal disease patients. Consecutive monthly clinical and biochemical profiles 3-6 months before and after MCT were compared. Twenty-one patients with a mean age (+/- SE) of 54 +/- 4 years (11 male and 10 female) were studied. Two patients were dropped from this study because they required a change in prescription of dialysis after starting MCT. Mean serum potassium levels significantly fell (p < 0.001) during the post-MCT period (4.9 +/- 0.1 mEq/l) compared with potassium levels during the pre-MCT (5.6 +/- 0.1 mEq/l) period. All patients except 1 showed a reduction in serum potassium levels after MCT. Pre- and post-MCT values were not different for body weight, mean blood pressure, blood urea nitrogen, serum glutamic-oxaloacetic transaminase, lactate dehydrogenase, sodium, chloride, bicarbonate, creatinine and albumin. Since the majority of the patients were anuric (n = 15), a decrease in serum potassium values in the post-MCT period was not due to loss of potassium in the urine. MCT appears to decrease serum potassium values in patients with end-stage renal disease by extrarenal mechanisms. We conclude that MCT can be used safely to lower serum potassium in patients with end-stage renal disease.

Phosphodiesterase-4 (PDE4) inhibitors are reshaping the treatment landscape for chronic inflammatory skin diseases by offering effective, non-steroidal options for conditions like psoriasis, atopic dermatitis, and seborrheic dermatitis. This perspective translates recent structural biology and biochemical findings into clinically meaningful guidance. Among available agents, roflumilast stands out for its high potency and selectivity, with a half-maximal inhibitory concentration of 0.7 nM compared to 140 nM for apremilast (200-fold less) and 750 nM for crisaborole (1071-fold less). This higher potency enables lower dosing and improved tolerability, particularly in topical formulations. Unlike earlier PDE4 inhibitors, roflumilast's structural similarity to the second signal messenger cyclic adenosine monophosphate (cAMP) results in stronger binding to and inhibition of PDE4 and more effective suppression of inflammation. Clinically, this translates into rapid improvements in skin erythema, scaling, and itch, with minimal systemic side effects. Roflumilast is especially valuable for patients who are steroid-averse, pediatric, elderly, or have contraindications to systemic therapy. It can also be integrated into combination regimens, offering flexibility for refractory cases. As ongoing research explores its use in other skin conditions such as vitiligo and lichen planus, understanding the molecular differences among PDE4 inhibitors becomes increasingly relevant to the practicing dermatology provider. By connecting molecular pharmacology with therapeutic decision-making, this article supports dermatology clinicians in selecting targeted therapies that improve patient outcomes, adherence, and quality of life. J Drugs Dermatol. 2025;24(6):631-633. doi:10.36849/JDD.9089Citation: Issa NT, Obagi S, Damiani G, et al. PDE4 inhibitors: bridging molecular insights with clinical impact. J Drugs Dermatol. 2025;24(6):631-633. doi:10.36849/JDD.9089.

Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders

Long-term exposure to drugs of abuse causes an up-regulation of the cAMP-signaling pathway in the nucleus accumbens and other forebrain regions, this common neuroadaptation is thought to underlie aspects of drug tolerance and dependence. Phosphodiesterase 4 (PDE4) is an enzyme that the selective hydrolyzes intracellular cAMP. It is expressed in several brain regions that regulate the reinforcing effects of drugs of abuse. Here, we review the current knowledge about central nervous system (CNS) distribution of PDE4 isoforms and the effects of systemic and brain-region specific inhibition of PDE4 on behavioral models of drug addiction. A systematic literature search was performed using the Pubmed. Using behavioral sensitization, conditioned place preference and drug self-administration as behavioral models, a large number of studies have shown that local or systemic administration of PDE4 inhibitors reduce drug intake and/or drug seeking for psychostimulants, alcohol, and opioids in rats or mice. Preclinical studies suggest that PDE4 could be a therapeutic target for several classes of substance use disorder. We conclude by identifying opportunities for the development of subtype-selective PDE4 inhibitors that may reduce addiction liability and minimize the side effects that limit the clinical potential of non-selective PDE4 inhibitors. Several PDE4 inhibitors have been clinically approved for other diseases. There is a promising possibility to repurpose these PDE4 inhibitors for the treatment of drug addiction as they are safe and well-tolerated in patients.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterised by irreversible fibrosis of the lung parenchyma and a steady decline in respiratory function. Its pathogenesis remains incompletely understood, and despite advances in diagnosis and disease management, therapeutic options remain limited and largely palliative. Emerging evidence suggests that phosphodiesterase-4 (PDE4) inhibitors may represent a novel therapeutic approach in IPF through modulation of cyclic adenosine monophosphate-dependent signalling pathways. Preclinical and clinical studies indicate that PDE4 inhibition can attenuate key pathological processes implicated in IPF, including macrophage-driven inflammatory responses, dysregulated epithelial repair, and fibroblast proliferation and differentiation. Through these mechanisms, PDE4 inhibitors demonstrate combined anti-inflammatory and antifibrotic effects in experimental models of lung fibrosis. Among this class, the PDE4B-selective inhibitor nerandomilast has shown encouraging signals of efficacy in clinical trials of IPF, supporting continued investigation of subtype-selective targeting strategies. Other PDE4 inhibitors, including roflumilast, rolipram, and structurally novel derivatives such as 2-arylbenzofurans, have also demonstrated antifibrotic activity, predominantly in preclinical studies. This review synthesises current evidence on the role of PDE4 signalling in IPF pathogenesis and critically evaluates the pharmacological rationale, therapeutic potential, and translational challenges of PDE4 inhibitors in the treatment of IPF. Future perspectives, including subtype-selective inhibition and optimised drug delivery strategies, are discussed as potential avenues to improve efficacy and tolerability in this patient population.

Atopic dermatitis (AD) is a chronic inflammatory condition that affects 15% of children and 7.3% of adults in the USA. While topical corticosteroids (TCs) and topical calcineurin inhibitors (TCIs) are considered the mainstay of topical treatments for AD management, long-term use is cautioned due to possible adverse effects (AEs). We present and review the efficacy and safety of new FDA-approved topical agents, topical agents currently in clinical trials, and TCs and TCIs that are currently available for AD management. We also present and compare the safety and efficacy of new and old FDA-approved topical agents, along with other topical treatments that are currently in clinical trials for AD management. An extensive review of the literature was performed using the PubMed, Cochrane, Scopus and ClinicalKey databases with year parameters set between 2014 and 2022. Search keywords included ‘atopic dermatitis’, ‘topical treatments’, ‘comparison’, ‘effectiveness’, ‘new topical treatments for AD’, ‘JAK inhibitors’, ‘PDE-4 inhibitors’, ‘delgocitinib’, ‘crisaborole’ and ‘tapinarof’. We identified four topical drug classes that are efficacious in treating AD: corticosteroids, calcineurin inhibitors, phosphodiesterase-4 (PDE-4) inhibitors and aryl hydrocarbon receptor agonists. Criteria for treatment success were an IGA score of 0 or 1 and improvement ≥2 grades from baseline. Treatment varied among studies from 2 to 24 weeks. Topical corticosteroids were the most effective after adjusting for vehicle (0.05% clobetasol propionate emulsion foam, 38%; 0.1% clocortolone pivalate, 31.6% IGA reduction), followed by tapinarof 1% cream with 29% of patients achieving treatment success, TCIs (0.03% tacrolimus ointment, 24.8%; 1% pimecrolimus cream, 32.1% vehicle-adjusted achieving IGA of ≤2) and PDE-4 inhibitors (2% crisaborole ointment, 10.4%). Tapinarof was the most efficacious in treating AD. There is a lack of head-to-head trials for topical treatments for AD. Due to the tremendous burden of AD on patients’ physical and mental health, there is a need for additional therapies.

PDE4 is one of eleven known cyclic nucleotide phosphodiesterase families and plays a pivotal role in mediating hydrolytic degradation of the important cyclic nucleotide second messenger, cyclic 3′5′ adenosine monophosphate (cAMP). PDE4 inhibitors are known to have anti-inflammatory properties, but their use in the clinic has been hampered by mechanism-associated side effects that limit maximally tolerated doses. In an attempt to initiate the development of better-tolerated PDE4 inhibitors we have surveyed existing approved drugs for PDE4-inhibitory activity. With this objective, we utilised a high-throughput computational approach that identified moexipril, a well tolerated and safe angiotensin-converting enzyme (ACE) inhibitor, as a PDE4 inhibitor. Experimentally we showed that moexipril and two structurally related analogues acted in the micro molar range to inhibit PDE4 activity. Employing a FRET-based biosensor constructed from the nucleotide binding domain of the type 1 exchange protein activated by cAMP, EPAC1, we demonstrated that moexipril markedly potentiated the ability of forskolin to increase intracellular cAMP levels. Finally, we demonstrated that the PDE4 inhibitory effect of moexipril is functionally able to induce phosphorylation of the small heat shock protein, Hsp20, by cAMP dependent protein kinase A. Our data suggest that moexipril is a bona fide PDE4 inhibitor that may provide the starting point for development of novel PDE4 inhibitors with an improved therapeutic window.

Our previous studies show that inhibition of phosphodiesterase 4 (PDE4) augments agonist-induced renovascular 3',5'-cAMP secretion more in isolated, perfused kidneys from spontaneously hypertensive rats (SHR) versus Wistar-Kyoto normotensive rats (WKY); however, whether this is because of PDE4 inhibition in renovascular smooth muscle cells or endothelial cells is unknown. Therefore, we examined the effects of 3-isobutyl-1-methylxanthine (broad-spectrum PDE inhibitor) and RO 20-1724 (selective PDE4 inhibitor) on isoproterenol-induced 3',5'-cAMP levels in cultured WKY and SHR preglomerular vascular smooth muscle and endothelial cells. 3-Isobutyl-1-methylxanthine and RO 20-1724 augmented isoproterenol-induced 3',5'-cAMP levels similarly in WKY versus SHR endothelial cells. In contrast, 3-isobutyl-1-methylxanthine and RO 20-1724 augmented isoproterenol-induced 3',5'-cAMP levels significantly more in SHR, compared to WKY, smooth muscle cells (P<0.0001). In both cell types from both rat strains, mRNA levels for the PDE4B subtype exceeded levels for the PDE4A, PDE4C, and PDE4D subtypes, and small interfering RNA knockdown of PDE4B mRNA in SHR smooth muscle cells increased isoproterenol-induced 3',5'-cAMP. mRNA levels for the PDE4B2 variant exceeded levels for the PDE4B1, PDE4B3, PDE4B4, and PDE4B5 variants. In vivo, infusions of RO 20-1724 increased the urinary excretion of 3',5'-cAMP more in SHR than WKY (P=0.0211). We conclude that (1) the greater effect of PDE4 inhibition on renovascular 3',5'-cAMP is mediated by inhibition of PDE4 in renovascular smooth muscle cells, not endothelial cells; (2) the major PDE4 subtype in both renovascular smooth muscle and endothelial cells is PDE4B with variant PDE4B2 likely being dominant; and (3) inhibition of PDE4 in vivo increases renal 3',5'-cAMP levels more in genetically hypertensive rats.

Phosphodiesterase 7 (PDE7), a cAMP-specific PDE family, insensitive to rolipram, is present in many immune cells, including T lymphocytes. Two genes of PDE7 have been identified: PDE7A and PDE7B with three or four splice variants, respectively. Both PDE7A and PDE7B are expressed in T cells, and the predominant splice variant in these cells is PDE7A1. PDE7 is one of several PDE families that terminates biological functions of cAMP—a major regulating intracellular factor. However, the precise role of PDE7 in T cell activation and function is still ambiguous. Some authors reported its crucial role in T cell activation, while according to other studies PDE7 activity was not pivotal to T cells. Several studies showed that inhibition of PDE7 by its selective or dual PDE4/7 inhibitors suppresses T cell activity, and consequently T-mediated immune response. Taken together, it seems quite likely that simultaneous inhibition of PDE4 and PDE7 by dual PDE4/7 inhibitors or a combination of selective PDE4 and PDE7 remains the most interesting therapeutic target for the treatment of some immune-related disorders, such as autoimmune diseases, or selected respiratory diseases. An interesting direction of future studies could also be using a combination of selective PDE7 and PDE3 inhibitors.

Objectives: This study aimed to analyse the impact of serum sodium and potassium levels on sensorineural hearing loss and tinnitus. Material and Methods: A total of 616 individuals participated-248 with sensorineural hearing loss and tinnitus, 136 with tinnitus only, and 232 controls. All patients received thorough examinations by specialists in otorhinolaryngology and audiology. Additionally, all participants underwent laboratory testing. Results: Serum sodium levels were slightly elevated in the tinnitus group with sensorineural hearing loss compared to both the tinnitus group and the control group, although these differences were not statistically significant (p = 0.27 and p = 0.89). Additionally, this trend was not observed when comparing the tinnitus group to the control group (p = 0.32). The serum potassium levels did not show a significant difference among the three groups (p = 0.155). In the group experiencing sensorineural hearing loss and tinnitus, a significant positive correlation was found between serum sodium levels and the onset of sensorineural hearing loss (p = 0.000, rho = 0.223). Additionally, there was a significant correlation between age and the onset of symptoms (p = 0.000, rho = 0.235). No significant correlations were found regarding serum potassium levels. Patients with hearing levels exceeding 40 dB exhibited slightly higher serum sodium levels (p = 0.56). Both the groups with tinnitus and sensorineural hearing loss, as well as the tinnitus-only group, showed a trend indicating that higher serum sodium levels were associated with greater tinnitus intensities (p = 0.43 and p = 0.62, respectively). A logistic regression analysis indicated that the development of sensorineural hearing loss and tinnitus was significantly associated with changes in serum sodium levels (p = 0.030; OR: 0.186, 95% CI = 0.027-5.550). Additionally, serum sodium levels were found to be significant predictors of more severe hearing loss, defined as hearing levels exceeding 40 dB (p = 0.019; OR: 1.950, 95% CI = 0.504-7.540). Conclusions: The findings of this investigation suggest that changes in serum sodium levels may influence the development and severity of tinnitus and sensorineural hearing loss. Further studies involving more cases are needed to solidify these results.