sildenafil-citrate and deoxyuridine-triphosphate

Age-related cognitive decline is accompanied by an increase of neuronal apoptosis and a dysregulation of neuroplasticity-related molecules such as brain-derived neurotrophic factor and neurotoxic factors including beta amyloid (Aβ) peptide. Because it has been previously demonstrated that phosphodiesterase-5 inhibitors (PDE5-Is) protect against hippocampal synaptic dysfunction and memory deficits in mouse models of Alzheimer's disease and physiological aging, we investigated the effect of a treatment with the PDE5-I, sildenafil, on cell death, pro- and antiapoptotic molecules, and Aβ production. We demonstrated that chronic intraperitoneal injection of sildenafil (3 mg/kg for 3 weeks) decreased terminal deoxyuridine triphosphate nick end labeling-positive cells in the CA1 hippocampal area of 26-30-month-old mice, downregulating the proapoptotic proteins, caspase-3 and B-cell lymphoma 2-associated X, and increasing antiapoptotic molecules such as B-cell lymphoma protein-2 and brain-derived neurotrophic factor. Also, sildenafil reverted the shifting of amyloid precursor protein processing toward Aβ42 production and the increase of the Aβ42:Aβ40 ratio in aged mice. Our data suggest that PDE5-I might be beneficial to treat age-related detrimental features in a physiological mouse model of aging.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; bcl-2-Associated X Protein; Brain; Brain-Derived Neurotrophic Factor; CA1 Region, Hippocampal; Caspase 3; Cyclic AMP Response Element-Binding Protein; Cyclic Nucleotide Phosphodiesterases, Type 5; Deoxyuracil Nucleotides; Disease Models, Animal; Humans; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; Neuronal Plasticity; Phosphodiesterase 5 Inhibitors; Phosphorylation; Piperazines; Proto-Oncogene Proteins c-bcl-2; Purines; Sildenafil Citrate; Sulfones