Phosphodiesterase Inhibitors for Alzheimer’s Disease: A Systematic Review of Clinical Trials and Epidemiology with a Mechanistic Rationale
Abstract
Background: Preclinical studies, clinical trials, and reviews suggest increasing 3’,5’-cyclic adenosine monophosphate (cAMP) and 3’,5’-cyclic guanosine monophosphate (cGMP) with phosphodiesterase inhibitors is disease-modifying in Alzheimer’s disease (AD). cAMP/protein kinase A (PKA) and cGMP/protein kinase G (PKG) signaling are disrupted in AD. cAMP/PKA and cGMP/PKG activate cAMP response element binding protein (CREB). CREB binds mitochondrial and nuclear DNA, inducing synaptogenesis, memory, and neuronal survival gene (e.g., brain-derived neurotrophic factor) and peroxisome proliferator-activated receptor- γ coactivator-1 α (PGC1 α). cAMP/PKA and cGMP/PKG activate Sirtuin-1, which activates PGC1 α. PGC1 α induces mitochondrial biogenesis and antioxidant genes (e.g.,Nrf2) and represses BACE1. cAMP and cGMP inhibit BACE1-inducing NF κB and tau-phosphorylating GSK3β. Objective and Methods: We review efficacy-testing clinical trials, epidemiology, and meta-analyses to critically investigate whether phosphodiesteraseinhibitors prevent or treat AD. Results: Caffeine and cilostazol may lower AD risk. Denbufylline and sildenafil clinical trials are promising but preliminary and inconclusive. PF-04447943 and BI 409,306 are ineffective. Vinpocetine, cilostazol, and nicergoline trials are mixed. Deprenyl/selegiline trials show only short-term benefits. Broad-spectrum phosphodiesterase inhibitor propentofylline has been shown in five phase III trials to improve cognition, dementia…
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