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.
Keywords:
APP processing; Aging; Apoptosis; BDNF; Bax/Bcl-2 ratio; Beta-amyloid; Caspase-3; Sildenafil.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / metabolism*
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Aging / pathology*
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / genetics
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Alzheimer Disease / pathology*
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Amyloid beta-Peptides / metabolism*
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Animals
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Apoptosis / drug effects*
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Apoptosis / genetics
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Brain / metabolism
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Brain / pathology*
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Brain-Derived Neurotrophic Factor / metabolism
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CA1 Region, Hippocampal / metabolism
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Caspase 3 / metabolism
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cyclic Nucleotide Phosphodiesterases, Type 5 / physiology*
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Deoxyuracil Nucleotides / metabolism
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Disease Models, Animal
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Humans
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Injections, Intraperitoneal
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Mice
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Mice, Inbred C57BL
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Molecular Targeted Therapy
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Neuronal Plasticity / genetics
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Phosphodiesterase 5 Inhibitors / pharmacology*
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Phosphodiesterase 5 Inhibitors / therapeutic use
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Phosphorylation
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Piperazines / administration & dosage
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Piperazines / pharmacology*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Purines / administration & dosage
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Purines / pharmacology
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Sildenafil Citrate
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Sulfones / administration & dosage
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Sulfones / pharmacology*
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bcl-2-Associated X Protein / metabolism
Substances
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Amyloid beta-Peptides
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Brain-Derived Neurotrophic Factor
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Cyclic AMP Response Element-Binding Protein
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Deoxyuracil Nucleotides
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Phosphodiesterase 5 Inhibitors
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Piperazines
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Proto-Oncogene Proteins c-bcl-2
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Purines
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Sulfones
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bcl-2-Associated X Protein
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deoxyuridine triphosphate
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Sildenafil Citrate
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Cyclic Nucleotide Phosphodiesterases, Type 5
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Caspase 3