Polypharmacological Potential of Phosphodiesterase 5 Inhibitors for the Treatment of Neurocognitive Disorders.

The prevalence of neurocognitive disorders (NCD) increases every year as the population continues to age, leading to significant global health concerns. Overcoming this challenge requires identifying biomarkers, risk factors, and effective therapeutic interventions that might provide meaningful clinical benefits. For Alzheimer's disease (AD), one of the most studied NCD, approved drugs include acetylcholinesterase inhibitors (rivastigmine, donepezil, and galantamine), an NMDA receptor antagonist (memantine), and anti-amyloid monoclonal antibodies (aducanumab and lecanemab). These drugs offer limited relief, targeting singular pathological processes of the AD. Given the multifactorial nature of the NCDs, a poly-pharmacological strategy may lead to improved outcomes compared to the current standard of care. In this regard, phosphodiesterase 5 (PDE5) inhibitors emerged as promising drug candidates for the treatment of neurocognitive disorders. These inhibitors increase cGMP levels and CREB signaling, thus enhancing learning, memory and neuroprotection, while reducing Aβ deposition, tau phosphorylation, oxidative stress, and neuroinflammation. In the present article, we evaluate the therapeutic potential of different PDE5 inhibitors to outline their multifaceted impact in the NCDs.