Phosphodiesterase inhibitors say NO to Alzheimer's disease. (December 2019)

• Record Type: Journal Article
• Authors: Nabavi, Seyed Mohammad; Talarek, Sylwia; Listos, Joanna; Nabavi, Seyed Fazel; Devi, Kasi Pandima; Roberto de Oliveira, Marcos; Tewari, Devesh; Argüelles, Sandro; Mehrzadi, Saeed; Hosseinzadeh, Azam; D'onofrio, Grazia; Orhan, Ilkay Erdogan; Sureda, Antoni; Xu, Suowen; Momtaz, Saeedeh; Farzaei, Mohammad Hosein
• Is Part Of: Food and chemical toxicology. Volume 134(2019)
• Publication Date: 2019-12
• Subjects: Phosphodiesterase -- Subtype -- Isoform -- Alzheimer's disease -- cAMP -- cGMP; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2019.110822
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Phosphodiesterases (PDEs) consisted of 11 subtypes (PDE1 to PDE11) and over 40 isoforms that regulate levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), the second messengers in cell functions. PDE inhibitors (PDEIs) have been attractive therapeutic targets due to their involvement in diverse medical conditions, e.g. cardiovascular diseases, autoimmune diseases, Alzheimer's disease (AD), etc. Among them; AD with a complex pathology is a progressive neurodegenerative disorder which affect mostly senile people in the world and only symptomatic treatment particularly using cholinesterase inhibitors in clinic is available at the moment for AD. Consequently, novel treatment strategies towards AD are still searched extensively. Since PDEs are broadly expressed in the brain, PDEIs are considered to modulate neurodegenerative conditions through regulating cAMP and cGMP in the brain. In this sense, several synthetic or natural molecules inhibiting various PDE subtypes such as rolipram and roflumilast (PDE4 inhibitors), vinpocetine (PDE1 inhibitor), cilostazol and milrinone (PDE3 inhibitors), sildenafil and tadalafil (PDE5 inhibitors), etc have been reported showing encouraging results for the treatment of AD. In this review, PDE superfamily will be scrutinized from the view point of structural features, isoforms, functions and pharmacology particularly attributed to PDEs as target for AD therapy. Graphical abstract: Image 1 Highlights: Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP as well as cGMP controlling many physiological processes. AD is one of the most prevalent age-related neurodegenerative diseases typically associated with neuroinflammation. Pharmacological targets which are involved in blocking PDEs can be considered as new medicinal approaches in cognitive disorders and dementia. Several neuropsychopharmacological mechanisms are involved in therapeutic effect of PDEs inhibitors in AD. Numerous cellular signaling pathways are involved in beneficial effects of PDEs in AD such as PKA/PKG and cAMP/CREB/BDNF.