Increasing 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 (AChE) and N-methyl-D-aspartate (NMDA) receptors represent the targets of currently available drugs for Alzheimer’s disease (AD), that are anyway characterized by limited efficacy. Thus, the search for therapeutic agents with alternative or combined mechanisms of action is wide open. Since variations in cAMP, cGMP and/or NO levels interfere with downstream pathways involved in memory processes, evidences 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 evidences that suggest the role of PDE5 inhibitors as multi-target agents against neurodegeneration. Moreover, since such compounds must cross the blood brain barrier (BBB) and reach inhibitory concentrations in CNS 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.

Due to high oxygen consumption, the brain is particularly vulnerable to oxidative stress, which is considered an important element in the etiopathogenesis of several mental disorders, including schizophrenia, depression and dependencies. Despite the fact that it is not established yet whether oxidative stress is a cause or a consequence of clinic manifestations, the intake of antioxidant supplements in combination with the psychotropic therapy constitutes a valuable solution in patients’ treatment. Anyway, some drugs possess antioxidant capacity themselves and this aspect is discussed in this review, focusing on antipsychotics and antidepressants. In the context of a collection of clinical observations, in vitro and in vivo results are critically reported, often highlighting controversial aspects. Finally, a new challenge is discussed, i.e., the possibility of assessing in silico the antioxidant potential of these drugs, exploiting computational chemistry methodologies and machine learning. Despite the physiological environment being incredibly complex and the detection of meaningful oxidative stress biomarkers being all but an easy task, a rigorous and systematic analysis of the structural and reactivity properties of antioxidant drugs seems to be a promising route to better interpret therapeutic outcomes and provide elements for the rational design of novel drugs.

Background: Phosphodiesterase 5 inhibitors (PDE5-Is) sildenafil, vardenafil, tadalafil and the recently approved avanafil represent the first-line choice for both on-demand and chronic treatment of erectile dysfunction (ED). In addition to this, sildenafil and tadalafil, have also been approved for the treatment of pulmonary arterial hypertension. Due to its expression and localization in many tissues, PDE5 and its regulation has been reported to be involved in several other diseases. Objective: We aim to provide an updated overview of the emerging therapeutic applications of PDE5-Is besides ED, taking into account the latest ongoing research reports. Methods: We searched online databases (Pubmed, Reaxys, Scopus) to lay the bases for an accurate, quality criteria-based literature update. We focused our attention on most recent research reports, in particular when supported by pre-clinical and clinical data. Results: The regulation of PDE5 may influence pathological conditions such as, among the others, heart failure, cystic fibrosis, cancer, CNS-related diseases, diabetes and dysfunctions affecting male urinary/reproductive system. Conclusion: Sildenafil, vardenafil, tadalafil and the other chemical entities considered PDE5-Is showed overall positive results and significant improvements in the studied disease, thus some discordant results, in particular when comparing pre-clinical and clinical data, have to be pointed out, suggesting that further insights are needed especially to assess the exact molecular pathway underlying.