Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyse the intracellular second messengers cAMP and cGMP to their inactive forms 5'AMP and 5'GMP. Some members of the PDE family display specificity towards a single cyclic nucleotide messenger, and PDE4, PDE7, and PDE8 specifically hydrolyse cAMP. While the role of PDE4 and its use as a therapeutic target have been well studied, less is known about PDE7 and PDE8. This review aims to collate the present knowledge on human PDE7 and outline its potential use as a therapeutic target. Human PDE7 exists as two isoforms PDE7A and PDE7B that display different expression patterns but are predominantly found in the central nervous system, immune cells, and lymphoid tissue. As a result, PDE7 is thought to play a role in T cell activation and proliferation, inflammation, and regulate several physiological processes in the central nervous system, such as neurogenesis, synaptogenesis, and long-term memory formation. Increased expression and activity of PDE7 has been detected in several disease states, including neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's disease, autoimmune diseases such as multiple sclerosis and COPD, and several types of cancer. Early studies have shown that administration of PDE7 inhibitors may ameliorate the clinical state of these diseases. Targeting PDE7 may therefore provide a novel therapeutic strategy for targeting a broad range of disease and possibly provide a complementary alternative to inhibitors of other cAMP-selective PDEs, such as PDE4, which are severely limited by their side-effects.

01 Jul 2023·Biochemistry and Biophysics Reports

cAMP-PDE signaling in COPD: Review of cellular, molecular and clinical features

Review

Author: Azimzadeh Jamalkandi, Sadegh ; Emamvirdizadeh, Alireza ; Ghanei, Mostafa ; Ahmadi, Ali ; Nourian, Yazdan Hasani ; Karimi, Mehrdad ; Salehi, Zahra ; Salimian, Jafar

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death among non-contagious diseases in the world. PDE inhibitors are among current medicines prescribed for COPD treatment of which, PDE-4 family is the predominant PDE isoform involved in hydrolyzing cyclic adenosine monophosphate (cAMP) that regulates the inflammatory responses in neutrophils, lymphocytes, macrophages and epithelial cells The aim of this study is to investigate the cellular and molecular mechanisms of cAMP-PDE signaling, as an important pathway in the treatment management of patients with COPD. In this review, a comprehensive literature review was performed about the effect of PDEs in COPD. Generally, PDEs are overexpressed in COPD patients, resulting in cAMP inactivation and decreased cAMP hydrolysis from AMP. At normal amounts, cAMP is one of the essential agents in regulating metabolism and suppressing inflammatory responses. Low amount of cAMP lead to activation of downstream inflammatory signaling pathways. PDE4 and PDE7 mRNA transcript levels were not altered in polymorphonuclear leukocytes and CD8 lymphocytes originating from the peripheral venous blood of stable COPD subjects compared to healthy controls. Therefore, cAMP-PDE signaling pathway is one of the most important signaling pathways involved in COPD. By examining the effects of different drugs in this signaling pathway critical steps can be taken in the treatment of this disease.

02 May 2023·International journal of molecular sciences

Unleashing Spinal Cord Repair: The Role of cAMP-Specific PDE Inhibition in Attenuating Neuroinflammation and Boosting Regeneration after Traumatic Spinal Cord Injury.

Review

Author: Schepers, Melissa ; Vanmierlo, Tim ; Broeckhoven, Jana Van ; Mussen, Femke ; Hellings, Niels

A review.Traumatic spinal cord injury (SCI) is characterized by severe neuroinflammation and hampered neuroregeneration, which often leads to permanent neurol. deficits.Current therapies include decompression surgery, rehabilitation, and in some instances, the use of corticosteroids.However, the golden standard of corticosteroids still achieves minimal improvements in functional outcomes.Therefore, new strategies tackling the initial inflammatory reactions and stimulating endogenous repair in later stages are crucial to achieving functional repair in SCI patients.Cyclic adenosine monophosphate (cAMP) is an important second messenger in the central nervous system (CNS) that modulates these processes.A sustained drop in cAMP levels is observed during SCI, and elevating cAMP is associated with improved functional outcomes in exptl. models. cAMP is regulated in a spatiotemporal manner by its hydrolyzing enzyme phosphodiesterase (PDE).Growing evidence suggests that inhibition of cAMP-specific PDEs (PDE4, PDE7, and PDE8) is an important strategy to orchestrate neuroinflammation and regeneration in the CNS.Therefore, this review focuses on the current evidence related to the immunomodulatory and neuroregenerative role of cAMP-specific PDE inhibition in the SCI pathophysiol.

News (Medical) associated with PDE7 x PDE4

11 Jul 2024

·www.biospace.com

FDA Approved PDE4 Inhibitor Roflumilast for Atopic Dermatitis

On July 9th, 2024, the U.S. FDA approved Arcutis Biotherapeutics' ZORYVE® (roflumilast) for treating atopic dermatitis (AD), the most common type of eczema affecting millions in the U.S. This once-daily, steroid-free cream could become a new standard of care for AD. The approval underscores the growing importance of researching Phosphodiesterase 4 (PDE4) and other PDEs as immunomodulatory targets for various inflammatory diseases. Sino Biological, and its subsidiary SignalChem Biotech, support drug discovery and development targeting PDEs by providing a broad range of PDE families and isoforms. Mechanism of Action Roflumilast is a phosphodiesterase-4 (PDE4) inhibitor that reduces inflammation by increasing cyclic adenosine monophosphate (cAMP) levels, an important molecule in regulating inflammation. PDE4, which breaks down cAMP, has four subtypes (PDE4A, PDE4B, PDE4C, PDE4D) and about 20 isoforms. The anti-inflammatory effects of PDE4 inhibitors are mainly due to inhibiting PDE4B and PDE4D, which are highly expressed in immune cells. By inhibiting these subtypes, roflumilast raises cAMP levels, decreasing pro-inflammatory mediators (e.g., TNF alpha, IL-4, IL-5, IL-13, IL-17A, IL-17F, IL-22) and increasing the anti-inflammatory mediator IL-10. This helps manage inflammatory conditions like atopic dermatitis, alleviating symptoms such as redness, itching, and swelling. PDE4 inhibitors mechanism of action. DOI:10.1517/13543784.2015.1094054 Phosphodiesterases (PDEs) as drug targets PDE enzymes control essential body functions by managing cAMP and cGMP levels. Various PDE inhibitors are developed for diseases: PDE1/2 for cardiovascular and neurological disorders; PDE4 for COPD and atopic dermatitis; PDE5 for erectile dysfunction and pulmonary arterial hypertension; PDE6 for retinal diseases; and PDE7 for inflammatory and autoimmune problems. In summary, PDE inhibitors are powerful tools and hold great promise as drug targets for wide-ranging therapeutic applications. Sino Biological’s Offering to Support Phosphodiesterases (PDEs) Research Sino Biological, along with its subsidiary SignalChem Biotech, is at the forefront of advancing drug development, offering a wide variety of recombinant PDE families and isoforms, to facilitate research on PDEs. Partner with us and visit our website to learn more about how we can best work together to accelerate the PDEs research.

Drug ApprovalImmunotherapy

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