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This review will illustrate the principal roles of the signaling systems of cyclic adenosine and guanosine 3\u2032,5\u2032\u2010monophosphates (cAMP and cGMP) in the neuronal functions, and summarize expression\/activity changes of the associated enzymes in the ND patients, including cyclases, protein kinases, and phosphodiesterases (PDEs). As the sole enzymes hydrolyzing cAMP and cGMP, PDEs are logical targets for modification of neurodegeneration. We will focus on PDE inhibitors and their potentials as disease\u2010modifying therapeutics for the treatment of Alzheimer's disease, Parkinson's disease, and Huntington's disease. For the overlapped but distinct contributions of cAMP and cGMP to NDs, we hypothesize that dual PDE inhibitors, which simultaneously regulate both cAMP and cGMP signaling pathways, may have complementary and synergistic effects on modifying neurodegeneration and thus represent a new direction on the discovery of ND drugs.<\/jats:p>","DOI":"10.1002\/med.22017","type":"journal-article","created":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T15:54:02Z","timestamp":1706370842000},"page":"1404-1445","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Emerging phosphodiesterase inhibitors for treatment of neurodegenerative diseases"],"prefix":"10.1002","volume":"44","author":[{"given":"Yu","family":"Xiang","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences &amp; Sichuan Provincial People's Hospital, School 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