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-␥ coactivator-1␣ (PGC1␣). cAMP/PKA and cGMP/PKG activate Sirtuin-1, which activates PGC1␣. PGC1␣ induces mitochondrial biogenesis and antioxidant genes (e.g.,Nrf2) and represses BACE1. cAMP and cGMP inhibit BACE1-inducing NFκB and tau-phosphorylating GSK3␤. 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 severity, activities of daily living, and global assessment in mild-to-moderate AD patients on multiple scales, including the ADAS-Cogand the CIBIC-Plus in an 18-month phase III clinical trial. However, two books claimed based on a MedScape article an 18-month phase III trial failed, so propentofylline was discontinued. Now, propentofylline is used to treat canine cognitive dysfunction, which, like AD, involves age-associated wild-type A␤ deposition. Conclusion: Phosphodiesterase inhibitors may prevent and treat AD.

Nitric oxide/cyclic guanosine monophosphate (cGMP) signaling is compromised in Alzheimer's disease (AD), and phosphodiesterase 5 (PDE5), which degrades cGMP, is upregulated. Sildenafil inhibits PDE5 and increases cGMP levels. Integrating previous findings, we determine that most doses of sildenafil (especially low doses) likely activate peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC1␣) via protein kinase G-mediated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) phosphorylation and/or Sirtuin-1 activation and PGC1␣ deacetylation. Via PGC1␣ signaling, low-dose sildenafil likely suppresses ␤-secretase 1 expression and amyloid-␤ (A␤) generation, upregulates antioxidant enzymes, and induces mitochondrial biogenesis. Plus, sildenafil should increase brain perfusion, insulin sensitivity, long-term potentiation, and neurogenesis while suppressing neural apoptosis and inflammation. A systematic review of sildenafil in AD was undertaken. In vitro, sildenafil protected neural mitochondria from A␤ and advanced glycation end products. In transgenic AD mice, sildenafil was found to rescue deficits in CREB phosphorylation and memory, upregulate brain-derived neurotrophic factor, reduce reactive astrocytes and microglia, decrease interleukin-1␤, interleukin-6, and tumor necrosis factor-␣, decrease neural apoptosis, increase neurogenesis, and reduce tau hyperphosphorylation. All studies that tested A␤ levels reported significant improvements except the two that used the highest dosage, consistent with the doselimiting effect of cGMP-induced phosphodiesterase 2 (PDE2) activation and cAMP depletion on PGC1␣ signaling. In AD patients, a single dose of sildenafil decreased spontaneous neural activity, increased cerebral blood flow, and increased the cerebral metabolic rate of oxygen. A randomized control trial of sildenafil (ideally with a PDE2 inhibitor) in AD patients is warranted.

Increasing basal energy expenditure via uncoupling protein 1 (UCP1)-dependent non-shivering thermogenesis is an attractive therapeutic strategy for treatment of obesity. Transient receptor potential melastatin 8 (TRPM8) channel activation by cold and cold mimetics induces UCP1 transcription and prevents obesity in animals, but the clinical relevance of this relationship remains incompletely understood. A review of TRPM8 channel agonism for treatment of obesity focusing on menthol was undertaken. Adipocyte TRPM8 activation results in Ca 2+ influx and protein kinase A (PKA) activation, which induces mitochondrial elongation, mitochondrial localization to lipid droplets, lipolysis, β-oxidation, and UCP1 expression. Ca 2+ -induced mitochondrial reactive oxygen species activate UCP1. In animals, TRPM8 agonism increases basal metabolic rate, non-shivering thermogenesis, oxygen consumption, exercise endurance, and fatty acid oxidation and decreases abdominal fat percentage. Menthol prevents high-fat diet-induced obesity, glucose intolerance, insulin resistance, and liver triacylglycerol accumulation. Hypothalamic TRPM8 activation releases glucagon, which activates PKA and promotes catabolism. TRPM8 polymorphisms are associated with obesity. In humans, oral menthol and other TRPM8 agonists have little effect. However, topical menthol appears to increase core body temperature and metabolic rate. A randomized clinical control trial of topical menthol in obese patients is warranted.

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