Abstract
Increasing human life expectancy prompts the development of novel remedies for cognitive decline: 44 million people worldwide are affected by dementia, and this number is predicted to triple by 2050. Acetylcholinesterase and N-methyl-d-aspartate receptors represent the targets of currently available drugs for Alzheimer’s disease, which are characterized by limited efficacy. Thus, the search for therapeutic agents with alternative or combined mechanisms of action is wide open. Since variations in 3′,5′-cyclic adenosine monophosphate, 3′,5′-cyclic guanosine monophosphate, and/or nitric oxide levels interfere with downstream pathways involved in memory processes, evidence supporting the potential of phosphodiesterase (PDE) inhibitors in contrasting neurodegeneration should be critically considered. For the preparation of this Review, more than 140 scientific papers were retrieved by searching PubMed and Scopus databases. A systematic approach was adopted when overviewing the different PDE isoforms, taking into account details on brain localization, downstream molecular mechanisms, and inhibitors currently under study, according to available in vitro and in vivo data. In the context of drug repurposing, a section focusing on PDE5 was introduced. Original computational studies were performed to rationalize the emerging evidence that suggests the role of PDE5 inhibitors as multi-target agents against neurodegeneration. Moreover, since such compounds must cross the blood–brain barrier and reach inhibitory concentrations in the central nervous system to exert their therapeutic activity, physicochemical parameters were analyzed and discussed. Taken together, literature and computational data suggest that some PDE5 inhibitors, such as tadalafil, represent promising candidates.
Highlights
In the context of cognitive decline, the search for novel efficient diagnostic tools and treatments is wide open, since the human population is constantly aging due to increasing life expectancy
By elevating 3′,5′-cyclic adenosine monophosphate and 3′,5′-cyclic guanosine monophosphate and/or influencing nitric oxide (NO) levels, PDE inhibitors interfere with several pathways that have been reported to be relevant in learning functions in animal models of impaired cognition.[6,7]
In this context, growing evidence suggests that some inhibitors, especially those interfering with the PDE5 isoform, may play a role in influencing cognition-related neural activity and be effective against central nervous system (CNS)-related
Summary
In the context of cognitive decline, the search for novel efficient diagnostic tools and treatments is wide open, since the human population is constantly aging due to increasing life expectancy. PDEs are a family of enzymes encompassing 11 classes, which will be covered of this Review, that physiologically act by hydrolyzing cyclic nucleotide-based second messengers to their corresponding linear derivatives.[3] By elevating 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) and/or influencing nitric oxide (NO) levels, PDE inhibitors interfere with several pathways that have been reported to be relevant in learning functions in animal models of impaired cognition.[6,7] In this context, growing evidence suggests that some inhibitors, especially those interfering with the PDE5 isoform, may play a role in influencing cognition-related neural activity and be effective against central nervous system (CNS)-related. Chemical aspects of selected natural and synthetic PDE5 inhibitors will be discussed in more detail: computational tools, such as molecular docking and pharmacokinetic properties prediction, will support the exploration of their potential as multi-target CNS drugs
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