Sildenafil (Viagra) is a selective inhibitor of phosphodiesterase type 5 (PDE5), which degrades cyclic guanosine monophosphate (cGMP) to the linear nucleotide. Sildenafil is acutely used in erectile dysfunction and chronically in pulmonary hypertension.
Evidence in the last decade shows that sildenafil may have potential as a therapeutic option for Alzheimer's disease or other neurodegenerative disorders. The purpose of this work was to explore whether sildenafil crosses the blood-brain barrier (BBB). Pharmacokinetic properties of sildenafil in rodents were investigated using (11) C-radiolabelling followed by in vivo positron emission tomography (PET) and ex vivo tissue dissection and gamma counting. PET results in rats suggest penetration into the central nervous system (CNS). Ex vivo data in perfused animals suggest that trapping of [(11) C]sildenafil within the cerebral vascular endothelium limits accumulation in the CNS parenchyma. Peroral sildenafil administration to Macaca fascicularis and subsequent chemical analysis of plasma and cerebrospinal fluid (CSF) using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) showed that drug content in the cerebrospinal fluid (CSF) was high enough to achieve PDE5 inhibition, which was also demonstrated by the significant increases in CSF cGMP levels. Central actions of sildenafil include both relaxation of the cerebral vasculature and inhibition of PDE5 in neurons and glia. This central action of sildenafil may underlie its efficacy in neuroprotection models, and may justify the continued search for a PDE5 ligand suitable for PET imaging. This article is protected by copyright. All rights reserved.
Journal of neurochemistry. 2015 Dec 07 [Epub ahead of print]
Vanessa Gómez-Vallejo, Ana Ugarte, Carolina García-Barroso, Mar Cuadrado-Tejedor, Boguslaw Szczupak, Iria G Dopeso-Reyes, José L Lanciego, Ana García-Osta, Jordi Llop, Julen Oyarzabal, Rafael Franco
Radiochemistry Platform, CIC biomaGUNE, San Sebastian, Spain. , Small Molecule Discovery Platform, Molecular Therapeutics Program, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. , Neurobiology of Alzheimer's disease, Neurosciences Division, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. , Neurobiology of Alzheimer's disease, Neurosciences Division, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. , Nuclear Imaging Platform, CIC biomaGUNE, San Sebastian, Spain. , Neurosciences Division, Centre for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain. , Neurosciences Division, Centre for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain. , Neurobiology of Alzheimer's disease, Neurosciences Division, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. , Radiochemistry and Nuclear Imaging Group, CIC biomaGUNE, San Sebastian, Spain. , Small Molecule Discovery Platform, Molecular Therapeutics Program, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. , Neurobiology of Alzheimer's disease, Neurosciences Division, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.