Contents lists available at ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox Review Phosphodiesterase inhibitors say NO to Alzheimer's disease Seyed Mohammad Nabavi a , Sylwia Talarek b , Joanna Listos b , Seyed Fazel Nabavi a , Kasi Pandima Devi c , Marcos Roberto de Oliveira d , Devesh Tewari e , Sandro Argüelles f , Saeed Mehrzadi g , Azam Hosseinzadeh g , Grazia D'onofrio h , Ilkay Erdogan Orhan i , Antoni Sureda j , Suowen Xu k , Saeedeh Momtaz l,m , Mohammad Hosein Farzaei n,∗ a Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran b Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Chodźki 4a St, 20-093, Lublin, Poland c Department of Biotechnology, Alagappa University, Karaikudi, 630003, Tamil Nadu, India d Departamento de Química (DQ), Instituto de Ciências Exatas e da Terra (ICET), Universidade Federal de Mato Grosso (UFMT), Cuiabá, Brazil e Department of Pharmacognosy, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, 144411, Punjab, India f Department of Physiology, Faculty of Pharmacy, University of Seville, Seville, Spain g Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran h Geriatric Unit and Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS “Casa Sollievo della Sofferenza”, Viale Cappuccini 1, 71013, San Giovanni Rotondo, FG, Italy i Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkey j Research Group on Community Nutrition and Oxidative Stress, University of Balearic Islands, CIBEROBN (Physiopathology of Obesity and Nutrition), E-07122, Palma de Mallorca, Balearic Islands, Spain k Aab Cardiovascular Research Institute, University of Rochester, Rochester, NY, 14623, USA l Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran m Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran n Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran ARTICLE INFO Keywords: Phosphodiesterase Subtype Isoform Alzheimer's disease cAMP cGMP 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 mes- sengers in cell functions. PDE inhibitors (PDEIs) have been attractive therapeutic targets due to their involve- ment 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 ex- tensively. 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 in- hibitor), 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 scruti- nized from the view point of structural features, isoforms, functions and pharmacology particularly attributed to PDEs as target for AD therapy. 1. Introduction Phosphodiesterases (PDEs) are a large family of enzymes whose main role is to produce 5′-cyclic nucleotides through hydrolysing the 3′- phosphodiester bond in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) involved in signal-transduc- tion pathways. Therefore, they possess a critical contribution in the important pathways in various pharmacological processes including https://doi.org/10.1016/j.fct.2019.110822 Received 27 April 2019; Received in revised form 13 September 2019; Accepted 14 September 2019 ∗ Corresponding author. E-mail addresses: Nabavi208@gmail.com (S.M. Nabavi), Sylwia.Talarek@umlub.bl (S. Talarek), a.listos@umlub.pl (J. Listos), Nabavisf@gmail.com (S.F. Nabavi), devikasi@yahoo.com (K.P. Devi), marcos.oliveira@uniuv.edu.br (M. Roberto de Oliveira), dtewari3@gmail.com (D. Tewari), sarguelles1@us.es (S. Argüelles), mehrzadi.s@iums.ac.ir (S. Mehrzadi), donofrio@operapadrepio.it (G. D'onofrio), iorhan@gazi.edu.tr (I.E. Orhan), tosugo@hotmail.com (A. Sureda), suowen.xu@gmail.com (S. Xu), mh.farzaei@gmail.com (M.H. Farzaei). Food and Chemical Toxicology 134 (2019) 110822 Available online 16 September 2019 0278-6915/ © 2019 Elsevier Ltd. All rights reserved. T