Phosphodiesterase 4 Inhibitor Research Articles

33356 A multinational chart review to examine gastrointestinal symptoms and their management in patients treated with apremilast for plaque psoriasis

Background: Diarrhea and nausea are the most common adverse events observed in phase 3 clinical trials and real-world studies of apremilast, an oral phosphodiesterase-4 inhibitor indicated for moderate-to-severe plaque psoriasis.

33468 Efficacy and safety of once-daily roflumilast cream 0.3% in patients with knee/elbow involvement: Pooled results from phase 3 trials (DERMIS-1 and DERMIS-2)

Roflumilast cream 0.3% is a selective and potent phosphodiesterase-4 inhibitor under investigation as a once-daily treatment for psoriasis. Psoriatic plaques on the knees/elbows can be challenging to treat due to thicker stratum corneum, which impedes topical absorption. We present pooled efficacy results from a post hoc analysis of the subgroup of patients with knee and/or elbow involvement from two identical phase 3 randomized controlled trials of roflumilast (DERMIS-1: NCT04211363 and DERMIS-2: NCT04211389).

31865 Pooled efficacy and safety results from the DERMIS-1 and DERMIS-2 phase 3 trials of once-daily roflumilast cream 0.3% for treatment of chronic plaque psoriasis

Roflumilast cream 0.3% is a selective, highly potent phosphodiesterase-4 inhibitor being investigated as a nonsteroidal, once-daily treatment for psoriasis. Here we describe pooled efficacy and safety results from 2 identical Phase 3 randomized controlled trials of roflumilast cream (DERMIS-1: NCT04211363 and DERMIS-2: NCT04211389). Patients with psoriasis involving 2-20% of body surface area (aged ≥2 years) were randomized to roflumilast (n = 576) or vehicle (n = 305) for 8 weeks. Significantly greater percentages of roflumilast-treated versus vehicle-treated patients achieved the primary efficacy endpoint, Investigator Global Assessment (IGA) Success (Clear or Almost Clear IGA plus ≥2-grade improvement from baseline) at Week 8 (39.9% vs.

An Overview of PDE4 Inhibitors in Clinical Trials: 2010 to Early 2022.

Since the early 1980s, phosphodiesterase 4 (PDE4) has been an attractive target for the treatment of inflammation-based diseases. Several scientific advancements, by both academia and pharmaceutical companies, have enabled the identification of many synthetic ligands for this target, along with the acquisition of precise information on biological requirements and linked therapeutic opportunities. The transition from pre-clinical to clinical phase was not easy for the majority of these compounds, mainly due to their significant side effects, and it took almost thirty years for a PDE4 inhibitor to become a drug i.e., Roflumilast, used in the clinics for the treatment of chronic obstructive pulmonary disease. Since then, three additional compounds have reached the market a few years later: Crisaborole for atopic dermatitis, Apremilast for psoriatic arthritis and Ibudilast for Krabbe disease. The aim of this review is to provide an overview of the compounds that have reached clinical trials in the last ten years, with a focus on those most recently developed for respiratory, skin and neurological disorders.

Rolipram Rescues Memory Consolidation Deficits Caused by Sleep Deprivation: Implication of the cAMP/PKA and cAMP/Epac Pathways.

Over the last few years, the number of people suffering from sleeping disorders has increased significantly despite negative effects on cognition and an association with brain inflammation. We assessed memory deficits caused by Sleep Deprivation (SD) to determine the therapeutic effect of phosphodiesterase 4 (PDE4) inhibitors on SD-induced memory deficits and to investigate whether the modulation of memory deficits by PDE4 inhibitors is mediated by a protein kinase A (PKA)-independent pathway in conjunction with a PKA-dependent pathway. Adult male mice were divided into four groups. Three SD groups were deprived of Rapid Eye Movement (REM) sleep for 12 h a day for six consecutive days. They were tested daily in the Morris water maze to evaluate learning and memory. One of the SD groups was injected with a PDE4 inhibitor, rolipram (1 mg/kg ip), whereas another had rolipram co-administered with chlorogenic acid (CHA, 20 mg/kg ip), an inhibitor of PKA. After 6 days, the mice were sacrificed, and the hippocampi were evaluated for cyclic AMP (cAMP) and nuclear factor Nrf-2 levels. The hippocampal expression of PKA, phosphorylated cAMP Response Element-Binding Protein (CREB), and phosphorylated glycogen synthase 3β (Ser389) were also evaluated. SD caused a significant decrease in cAMP levels in the brain and had a detrimental effect on learning and memory. The administration of rolipram or rolipram+CHA resulted in an improvement in cognitive function. The present study provides evidence that restoration of memory with PDE4 inhibitors occurs through a dual mechanism involving the PKA and Epac pathways.

Roflumilast-Mediated Phosphodiesterase 4D Inhibition Reverses Diabetes-Associated Cardiac Dysfunction and Remodeling: Effects Beyond Glucose Lowering

Patients with type 2 diabetes have a substantial risk of developing cardiovascular disease. Phosphodiesterase 4 (PDE4) dysregulation is of pathophysiological importance in metabolic disorders. For determination of the role of PDE4 in diabetic cardiac dysfunction, mice fed with a high-fat diet (HFD) were treated by pharmacological inhibition of PDE4 or cardiac specific knocking down of PDE4D. Mice on HFD developed diabetes and cardiac dysfunction with increased cardiac PDE4D5 expression. PDE4 inhibitor roflumilast can reverse hyperglycemia and cardiac dysfunction, accompanied by the decrease of PDE4D expression and increase of muscle specific miRNA miR-1 level in hearts. Either cardiac specific PDE4D knockdown or miR-1 overexpression significantly reversed cardiac dysfunction in HFD mice, despite persistence of hyperglycemia. Findings of gain- and loss-of-function studies of PDE4D in cardiomyocytes indicated that inhibition of insulin-induced PDE4D protected cardiac hypertrophy by preserving miR-1 expression in cardiomyocytes through promoting cAMP-CREB-Sirt1 signaling-induced SERCA2a expression. We further revealed that insulin also induced PDE4D expression in cardiac fibroblasts, which causes cardiac fibrosis through TGF-β1 signaling-mediated miR-1 reduction. Importantly, the expression of PDE4D5 was increased in human failing hearts of individuals with diabetes. These studies elucidate a novel mechanism by which hyperinsulinemia-induced cardiac PDE4D expression contributes to diabetic cardiac remodeling through reducing the expression of miR-1 and upregulation of miR-1 target hypertrophy and fibrosis-associated genes. Our study suggests a therapeutic potential of PDE4 inhibitor roflumilast in preventing or treating cardiac dysfunction in diabetes in addition to lowering glucose.

Targeting PDE4B (Phosphodiesterase-4 Subtype B) for Cardioprotection in Acute Myocardial Infarction via Neutrophils and Microcirculation.

Timely and complete restoration of blood flow is the most effective intervention for patients with acute myocardial infarction. However, the efficacy is limited by myocardial ischemia-reperfusion (MI/R) injury. PDE4 (phosphodiesterase-4) hydrolyzes intracellular cyclic adenosine monophosphate and it has 4 subtypes A-D. This study aimed to delineate the role of PDE4B (phosphodiesterase-4 subtype B) in MI/R injury. Mice were subjected to 30-minute coronary artery ligation, followed by 24-hour reperfusion. Cardiac perfusion was assessed by laser Doppler flow. Vasomotor reactivities were determined in mouse and human coronary (micro-)arteries. Cardiac expression of PDE4B, but not other PDE4 subtypes, was increased in mice following reperfusion. PDE4B was detected primarily in endothelial and myeloid cells of mouse and human hearts. PDE4B deletion strikingly reduced infarct size and improved cardiac function 24-hour or 28-day after MI/R. PDE4B in bone marrow-derived cells promoted MI/R injury and vascular PDE4B further exaggerated this injury. Mechanistically, PDE4B mediated neutrophil-endothelial cell interaction and PKA (protein kinase A)-dependent expression of cell adhesion molecules, neutrophil cardiac infiltration, and release of proinflammatory cytokines. Meanwhile, PDE4B promoted coronary microcirculatory obstruction and vascular permeability in MI/R, without affecting flow restriction-induced thrombosis. PDE4B blockade increased flow-mediated vasodilatation and promoted endothelium-dependent dilatation of coronary arteries in a PKA- and nitric oxide-dependent manner. Furthermore, postischemia administration with piclamilast, a PDE4 pan-inhibitor, improved cardiac microcirculation, suppressed inflammation, and attenuated MI/R injury in mice. Incubation with sera from patients with acute myocardial infarction impaired acetylcholine-induced relaxations in human coronary microarteries, which was abolished by PDE4 inhibition. Similar protection against MI/R-related coronary injury was recapitulated in mice with PDE4B deletion or inhibition, but not with the pure vasodilator, sodium nitroprusside. PDE4B is critically involved in neutrophil inflammation and microvascular obstruction, leading to MI/R injury. Selective inhibition of PDE4B might protect cardiac function in patients with acute myocardial infarction designated for reperfusion therapy.

SARS-CoV-2 nucleocapsid protein triggers hyperinflammation via protein-protein interaction-mediated intracellular Cl− accumulation in respiratory epithelium

SARS-CoV-2, the culprit pathogen of COVID-19, elicits prominent immune responses and cytokine storms. Intracellular Cl− is a crucial regulator of host defense, whereas the role of Cl− signaling pathway in modulating pulmonary inflammation associated with SARS-CoV-2 infection remains unclear. By using human respiratory epithelial cell lines, primary cultured human airway epithelial cells, and murine models of viral structural protein stimulation and SARS-CoV-2 direct challenge, we demonstrated that SARS-CoV-2 nucleocapsid (N) protein could interact with Smad3, which downregulated cystic fibrosis transmembrane conductance regulator (CFTR) expression via microRNA-145. The intracellular Cl− concentration ([Cl−]i) was raised, resulting in phosphorylation of serum glucocorticoid regulated kinase 1 (SGK1) and robust inflammatory responses. Inhibition or knockout of SGK1 abrogated the N protein-elicited airway inflammation. Moreover, N protein promoted a sustained elevation of [Cl−]i by depleting intracellular cAMP via upregulation of phosphodiesterase 4 (PDE4). Rolipram, a selective PDE4 inhibitor, countered airway inflammation by reducing [Cl−]i. Our findings suggested that Cl− acted as the crucial pathological second messenger mediating the inflammatory responses after SARS-CoV-2 infection. Targeting the Cl− signaling pathway might be a novel therapeutic strategy for COVID-19.

Past, Present, and Future in Dermatomyositis Therapeutics.

This review highlights current and emerging pharmacologic therapies for the treatment of dermatomyositis (DM). Current clinical evidence, in addition to recently published and ongoing clinical trials for various drugs in development, are summarized in this review. There has been significant progress in the research and development of potential treatments in DM. The FDA recently approved Octagam® 10% Immune Globulin Intravenous (IVIg) for the treatment of DM. Several drug targets are being explored as viable therapeutic options in phase 2 and phase 3 clinical trials; at the forefront of these are JAK inhibitors (tofacitinib and baricitinib) and T-cell co-stimulation blockers (i.e. abatacept). In addition, clinical trials are currently under way for therapeutics targeting novel molecular pathways, including immunoproteasome inhibitors, anti-B cell therapy, anti-interferon drugs, complement inhibitors, and phosphodiesterase-4 inhibitors. With the large number of clinical trials, multiple novel therapeutics in development, and improved classification and outcome measures, the treatment landscape for DM will continue to rapidly evolve in the coming years as more options become available.

Can Phosphodiesterase 4 Inhibitor Therapy Be Used in Respiratory Diseases Other Than Chronic Obstructive Pulmonary Disease?

Selective phosphodiesterase 4 (PDE4) inhibitors have been extensively studied for the treatment of various respiratory diseases due to their broad anti-inflammatory and/or bronchodilator effects. Roflumilast, an oral selective PDE4 inhibitor, is currently used as a second-line treatment in patients with chronic obstructive pulmonary disease (COPD) with chronic bronchitis. Despite its proven efficacy in other respiratory disorders, including asthma, no other PDE4 inhibitor is approved for respiratory pathologies. This systematic review summarizes the therapeutic action of PDE4 inhibitors, their limitations, recent therapeutic success, and future targets for their use in respiratory diseases other than COPD. An electronic literature search was conducted on four databases, namely, PubMed, PubMed Central, Google Scholar, and ScienceDirect, to collect data on related studies done in humans and published in the English language in the last five years. After extensive analysis and quality appraisal, 11 studies were eligible and thus included in this review, consisting of two randomized controlled trials (RCT), one systematic review and meta-analysis, and eight literature reviews. Roflumilast is not approved for the treatment of asthma due to associated adverse effects and comparable efficacy to inhaled corticosteroids, which are considered the mainstay of asthma maintenance therapy. Hence, the importance of balancing the efficacy with minimizing the side effects is highlighted. Tanimilast (CHF6001), an inhalational selective PDE4 inhibitor, and ensifentrine, a combined PDE3/4 inhibitor, demonstrate the recent therapeutic success in asthma and warrant further large-scale clinical studies. Future researchers will focus on the specific endotype than the phenotype in asthma as a meaningful therapeutic approach due to the high heterogeneity noted in asthma. Current evidence suggests the possibility of PDE4 inhibitors as a novel therapeutic option for chronic cough, allergic rhinitis, and cystic fibrosis. Further evidence from new studies is eagerly anticipated to better understand the efficacy and safety of PDE4 inhibitors in these respiratory diseases.

573 ME3183, a novel phosphodiesterase-4 (PDE4) inhibitor, showed potent suppressive effects on pathogenic cytokine expression in cultures of peripheral blood mononuclear cells (PBMC) from psoriasis patients and on psoriatic features in mouse models

Introduction & Objectives: PDE4 plays an important role in the immune system. ME3183, an oral PDE4 inhibitor, has shown anti-inflammatory effects in non-clinical studies. Here, we evaluated the therapeutic potency of ME3183 for psoriasis both in vitro and in vivo and compared it with apremilast, a marketed oral PDE4 inhibitor. Methods: In the in vitro assay, cultures of PBMC from 10 psoriasis (Ps) patients were stimulated with lipopolysaccharide (LPS) in the presence of ME3183 or apremilast, and the level of tumor necrosis factor-alpha (TNF-α) was measured. In the psoriasis model, imiquimod was applied on shaved dorsal skin for 6 consecutive days. In the arthritis model, collagen antibody was injected on Day 0 and LPS on Day 3. In both models, ME3183 or apremilast was administered twice daily, and clinical score and histological findings were evaluated. Gene expression by real-time polymerase chain reaction and cell population were analyzed in the psoriasis model and paw thickness in the arthritis model. Results: In cultures of PBMC from Ps patients, ME3183 showed a 114-fold inhibitory activity against TNF-α production than apremilast. We next evaluated the effects of ME3183 on psoriasis and arthritis in vivo. In the psoriasis model, ME3183 significantly ameliorated the psoriatic score, epidermal thickness, gene expressions of interleukin (IL)-17A and IL-23p19 and skin infiltration of IL-17A+ cells. In the arthritis model, ME3183 significantly suppressed the arthritis score and paw thickness. In both models, ME3183 was effective at low doses compared to apremilast. Conclusions: Our results indicated that ME3183 had potent anti-psoriatic effects via suppression of pathogenic cytokine expression. ME3183 may have higher therapeutic effects on Ps and psoriatic arthritis compared to the current oral PDE4 inhibitor. The clinical efficacy of ME3183 will be evaluated in the P2a study with Ps patients.

440 Topical phosphodiesterase 4 (PDE4) inhibitor crisaborole (crisa) improves skin transcriptomic and proteomic biomarkers of mild-to-moderate AD towards normal skin

This study was conducted to identify changes in genomic and proteomic skin profiles of 40 patients with AD lesions treated with crisa, a nonsteroidal PDE4 inhibitor, and vehicle and compare them to those of nonlesional (NL) and normal (N) skin. 2 randomly assigned (1:1 intrapatient manner) target lesions were treated with crisa or vehicle BID for 14 days. Punch biopsies were collected from lesional and nonlesional skin from patients with AD and 20 healthy controls at baseline and days 8/15 of treatment.

593 Krafft temperature of surfactants in vehicles for roflumilast and pimecrolimus cream and effects on skin tolerability

Creams and lotions use emulsifiers to create a physically stable vehicle for topically applied dosage forms. The minimum temperature required for an anionic emulsifier to form micelles, which can cause lipid extraction from skin and result in irritation, is known as the Krafft temperature (TK). A cream or lotion formulated with emulsifiers having a TK above safe water exposure temperatures (approximately 50°C) cannot irritate skin due to epidermal lipid extraction. Roflumilast cream, a novel, once-daily, topical formulation of a highly potent phosphodiesterase-4 inhibitor in development for treatment of several dermatologic conditions, demonstrated favorable tolerability in clinical trials.

Phosphodiesterase-4 Inhibitor Roflumilast-Mediated Protective Effect in Sepsis-Induced Late-Phase Event of Acute Kidney Injury: A Narrative Review

Severe infections such as viral, bacterial, or fungal sepsis can cause an inflammatory response in the host, leading to organ failure and septic shock—phosphodiesterase-4 (PDE-4) inhibiting related agents from suppressing cyclic adenosine monophosphate (cAMP) degradation. Regulatory organisations have approved some substances in this category to reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with chronic bronchitis and a history of COPD exacerbations. Roflumilast has been shown to alleviate inflammatory responses, thus regulating airway inflammation. Additionally, roflumilast therapy dramatically enhanced B-cell lymphoma 2 (Bcl-2) expression, an anti-apoptotic marker lowered in septic animals. Previous research has indicated that roflumilast may help reverse sepsis-induced liver and lung harm, but whether it is also effective in reversing sepsis-induced renal impairment remains unknown. Therefore, this review determines whether roflumilast protects against renal dysfunction, inflammatory response, and apoptosis in sepsis-induced kidney damage. Additionally, we discussed the molecular mechanism through which roflumilast exerts its protective effect to uncover a possible treatment agent for sepsis-induced renal impairment.

Newly discovered biologic agent used for psoriasis treatment

Psoriasis is an autoimmune inflammatory skin disorder that affects 2–3% of the world's population. It has distinct features, such as accelerated keratinocyte proliferation and proinflammatory cytokines secretion. Topical, systemic, phototherapy, and biologic therapies are used in the treatment. Topical therapies are preferred over systemic medicines for mild to moderate psoriasis. Systemic therapies are best for severe pathological conditions. Immunosuppressants, biological agents, and recently licensed phosphodiesterase-4 (PDE4) inhibitors are some of the systemic therapies. Present therapies have a lot of drawbacks, and new discoveries in the pathogenesis of psoriasis are opening the way for novel therapeutics that target the disease at the molecular level. Multiple small molecules, PDE-4 inhibitors, biologics, and immunomodulators, as well as newly discovered Janus kinases (JAK) inhibitors, were found to be effective. This article focuses on many emerging treatments as well as presently approved psoriasis medications.

Roflumilast, a Phosphodiesterase-4 Inhibitor, Ameliorates Sleep Deprivation-Induced Cognitive Dysfunction in C57BL/6J Mice

Sleep deprivation (SD) interferes with long-term memory and cognitive functions by overactivation of phosphodiesterase (PDEs) enzymes. PDE4, a nonredundant regulator of the cyclic nucleotides (cAMP), is densely expressed in the hippocampus and is involved in learning and memory processes. In the present study, we investigated the effects of Roflumilast (ROF), a PDE4B inhibitor, on sleep deprivation-induced cognitive dysfunction in a mouse model. Memory assessment was performed using a novel object recognition task, and the hippocampal cAMP level was estimated by the ELISA method. The alterations in the expressions of PDE4B, amyloid-β (Aβ), CREB, BDNF, and synaptic proteins (Synapsin I, SAP 97, PSD 95) were assessed to gain insights into the possible mechanisms of action of ROF using the Western blot technique. Results show that ROF reversed SD-induced cognitive decline in mice. ROF downregulated PDE4B and Aβ expressions in the brain. Additionally, ROF improved the cAMP level and the protein expressions of synapsin I, SAP 97, and PSD 95 in the hippocampal region of SD mice. Taken together, these results suggest that ROF can suppress the deleterious effects of SD-induced cognitive dysfunction via the PDE4B-mediated cAMP/CREB/BDNF signaling cascade.

Long-Acting β2 Adrenergic Receptor Agonist Ameliorates Imiquimod-Induced Psoriasis-Like Skin Lesion by Regulating Keratinocyte Proliferation and Apoptosis.

Psoriasis is a chronic inflammatory disease that affects approximately 1%–5% of the population worldwide. Considering frequent relapse, adverse drug reactions, and large costs of treatment, it is urgent to identify new medications for psoriasis. Keratinocytes play an essential role during psoriasis development, and they express high levels of β2-Adrenergic receptor (β2-AR), which increases intracellular cAMP levels when activated. Increased level of cAMP is associated with the inhibition of epidermal cell proliferation. In the present study, we observed the effect of salmeterol, a long-acting β2-AR agonist, on the proliferation and apoptosis of keratinocytes as well as imiquimod-induced psoriasis-like skin lesions in mice. As phosphodiesterase 4 (PDE4) inhibitors increases intracellular cAMP concentration by inhibiting its inactivation, we further explored the synergetic effect of a PDE4 inhibitor and salmeterol on psoriasis-like skin lesions in mice. Our results indicated that salmeterol effectively inhibited the proliferation of HaCaT cells induced by TNF-α and serum, and this effect was accompanied by significantly increased apoptosis and CREB phosphorylation, which were reversed by the PKA inhibitor, H89. Salmeterol ameliorated imiquimod-induced psoriasis-like skin lesions in mice, but salmeterol combined with a PDE4 inhibitor had no synergetic effect in improving skin lesions in mice. Of note, the synergistic effects of anti-proliferation and induction of apoptosis in HaCaT cells appeared by inhibiting ERK signaling. In summary, salmeterol, a long-acting β2-AR agonist, alleviates the severity of psoriasis via inhibiting the proliferation and promoting apoptosis of keratinocytes, partially by activating the cAMP/PKA signaling pathway.

Structure-based optimization of Toddacoumalone as highly potent and selective PDE4 inhibitors with anti-inflammatory effects

Phosphodiesterase-4 (PDE4) is an important drug target for inflammatory diseases. Previously, we identified a series of novel PDE4 inhibitors derived from the natural Toddacoumalone, among which the hit compound 2 with a naphthyridine scaffold showed moderate potency with the IC50 value of 400 nM. Based on the co-crystal structure of PDE4D-2, further structural optimizations and structure–activity relationship studies led to a highly potent PDE4 inhibitor 23a with the IC50 value of 0.25 nM and excellent selectivity profiles over other PDEs (>4000-fold). The co-crystal structure of PDE4D-23a elucidated that 23a has strong interactions with the M and Q pocket of PDE4D. Importantly, compound 23a significantly inhibits the release of inflammatory cytokines TNF-α and IL-6 in lipopolysaccharide-stimulated RAW264.7 cells. Thus, compound 23a with a naphthyridine scaffold is a promising PDE4 inhibitor for the treatment of inflammatory diseases.

ZL-n-91, a specific Phosphodiesterase-4 inhibitor, suppresses the growth of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that frequently develops resistance to chemotherapy. A new approach to treating TNBC is required to improve patient survival. Phosphodiesterase-4 (PDE4) is an enzyme that is predominantly involved in the modulation of intracellular signaling mediated by cAMP. Although the efficacy of PDE4 inhibitors in several human inflammatory diseases is well documented, their clinical utility has been limited by side effects, including nausea and emesis. Recently, PDE4 has been used as a potential therapeutic target for different cancer types. In the present study, we investigated the anticancer effects of a novel PDE4 inhibitor ZL-n-91 on TNBC and the underlying mechanism. We showed that ZL-n-91 inhibited the proliferation of TNBC cells, induced cell apoptosis, and caused cell cycle arrest. Western blot analysis showed that ZL-n-91 increased Bax level and reduced Bcl-2 expression. Furthermore, downregulation of the cell cycle-related proteins, such as CDK2, CDK4, cyclin D1, PCNA, p-RB, and ZL-n-91, significantly inhibited the transcription of DNA repair genes and triggered an intracellular DNA damage response. Moreover, ZL-n-91 prevented the growth of the transplanted MDA-MB-231 tumor xenograft in nude mice and increased the γ-H2AX expression. These data demonstrate the anticancer effects of ZL-n-91 on TNBC cells and suggest its potential use in anticancer therapy.

Roflumilast, a cyclic nucleotide phosphodiesterase 4 inhibitor, protects against cerebrovascular endothelial injury following cerebral ischemia/reperfusion by activating the Notch1/Hes1 pathway

The loss of tight junction (TJ) and adherens junction (AJ) proteins leads to the damage of the blood-brain barrier (BBB) during cerebral ischemia. Inhibition of cyclic nucleotide phosphodiesterase 4 (PDE4) by roflumilast (Roflu) protects against ischemic stroke-induced neuronal damage. However, the effects of Roflu on vascular endothelial injury and BBB integrity remain unknown. Here, we investigated whether and how Roflu protects against cerebrovascular endothelial injury caused by cerebral ischemia/reperfusion. We demonstrated that PDE4B knocking-down increased the expression of TJ and AJ proteins in human brain microvascular endothelial cells (HBMECs) subjected to oxygen-glucose deprivation reperfusion (OGD/R). Inhibition of PDE4 by Roflu (1.0 μM) showed similar effects as PDE4B knocking-down. We then found that Roflu activated Notch1/Hairy and enhancer of split 1 (Hes1) signaling. Consistently, the effects of Roflu on TJ and AJ proteins were reversed by the γ-secretase inhibitor DAPT or Hes1 knocking-down. Furthermore, Roflu (1.0 mg/kg) improved neurobehavioral outcomes and ameliorated BBB disruption in rats following ischemic stroke. Roflu also increased the levels of TJ proteins and AJ proteins in vivo. Collectively, these data suggest that Roflu is a promising compound for the prevention of BBB damage. The protective effects of Roflu are mediated through activation of the Notch1/Hes1 pathway.