Effect of phosphodiesterase-5 inhibition on apoptosis and beta amyloid load in aged mice.

Abstract

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.

• Authors: Daniela Puzzo, Carla Loreto, Salvatore Giunta, Giuseppe Musumeci, Giuseppina Frasca, Maria Vittoria Podda, Ottavio Arancio, Agostino Palmeri
• Journal: Neurobiology of aging (Neurobiol Aging) Vol. 35 Issue 3 Pg. 520-31 (Mar 2014) ISSN: 1558-1497 [Electronic] United States
• PMID: 24112792 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Brain-Derived Neurotrophic Factor
• Cyclic AMP Response Element-Binding Protein
• Deoxyuracil Nucleotides
• Phosphodiesterase 5 Inhibitors
• Piperazines
• Proto-Oncogene Proteins c-bcl-2
• Purines
• Sulfones
• bcl-2-Associated X Protein
• deoxyuridine triphosphate
• Sildenafil Citrate
• Cyclic Nucleotide Phosphodiesterases, Type 5
• Caspase 3

Topics

• Aging (metabolism, pathology)
• Alzheimer Disease (drug therapy, genetics, pathology)
• Amyloid beta-Peptides (metabolism)
• Animals
• Apoptosis (drug effects, genetics)
• Brain (metabolism, pathology)
• Brain-Derived Neurotrophic Factor (metabolism)
• CA1 Region, Hippocampal (metabolism)
• Caspase 3 (metabolism)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 5 (physiology)
• Deoxyuracil Nucleotides (metabolism)
• Disease Models, Animal
• Humans
• Injections, Intraperitoneal
• Mice
• Mice, Inbred C57BL
• Molecular Targeted Therapy
• Neuronal Plasticity (genetics)
• Phosphodiesterase 5 Inhibitors (pharmacology, therapeutic use)
• Phosphorylation
• Piperazines (administration & dosage, pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Purines (administration & dosage, pharmacology)
• Sildenafil Citrate
• Sulfones (administration & dosage, pharmacology)
• bcl-2-Associated X Protein (metabolism)