PDE5 Inhibitors as Modulators of Alzheimer's-Associated Inflammation and Oxidative Stress: A Meta-Analytical Assessment of Preclinical Studies.

Neuroinflammation and oxidative stress contribute significantly to cognitive decline, a hallmark of neurodegenerative diseases such as Alzheimer's disease (AD). Addressing cognitive decline is a critical medical need, and phosphodiesterase-5 inhibitors (PDE5Is) may offer a promising solution. This meta-analysis highlights the anti-inflammatory and antioxidant actions of PDE5Is, which may help counter neuroinflammation and oxidative stress in neurodegenerative diseases including AD. We reviewed over 1,258 studies and considered 34 preclinical rodent studies of inflammation or oxidative stress. Quantitative data on biomarkers such as Tumor necrosis factor alpha (TNF-α), Interleukin 1 beta (IL-1β), IL-6, NF-κB, IL-10, Superoxide dismutase (SOD), Catalase (CAT), Glutathione peroxidase (GPx), Glutathione (GSH), Malondialdehyde (MDA), Myeloperoxidase (MPO), and caspase-3 was extracted and analyzed using a random-effects model. Study quality was evaluated with a modified CAMARADES checklist, and heterogeneity was assessed using the I2 statistic. PDE5Is treatment significantly lowered pro-inflammatory cytokines and oxidative stress markers, while boosting the levels of critical anti-inflammatory and antioxidant molecules. The pooled standardized mean differences (SMDs) indicated treatment efficacy for nearly all biomarkers. Notably, the studies on Alzheimer's models confirmed similar therapeutic benefits in reducing amyloid burden and enhancing cognitive outcomes. With a strong safety profile and ability to modulate Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Nuclear erythroid-related factor 2 (Nrf2) pathways, PDE5Is offer promising neuroprotective potential. Thus, repurposing PDE5Is may develop new disease-modifying therapies for Alzheimer's, making clinical investigation crucial.