Effects of sildenafil on nigrostriatal dopamine neurons in a murine model of Parkinson's disease.
The objective of this study was to determine if the phosphodiesterase 5 (PDE-5) inhibitor, sildenafil, could be used as a neuroprotective agent in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson's disease. The underlying hypothesis of these studies is that blockade of PDE-5 catabolism of cGMP will attenuate the loss of nigrostriatal dopamine (NSDA) neurons following chronic neurotoxin exposure. Chronic MPTP-treated mice were administered sildenafil using three different regimens. Animals were: 1) treated with sildenafil and then exposed to chronic MPTP; 2) treated concurrently with sildenafil and MPTP; and 3) first exposed to MPTP and subsequently treated with sildenafil. End points of neurotoxicity included dopamine (DA) and tyrosine hydroxylase (TH) concentrations in NSDA axon terminals in the striatum, and stereological cell counts of TH immunoreactive neurons in the substantia nigra. Results reveal that sildenafil did not prevent neurotoxicity produced by chronic MPTP exposure regardless of the treatment paradigms employed. On the other hand, sildenafil did not produce any deleterious effect on NSDA neuron function nor did it potentiate the neurotoxic effects of MPTP. These results suggest that sildenafil would not accelerate DA cell loss when used as a treatment for erectile dysfunction in men diagnosed with Parkinson's disease.
Janis
Kelly L
KL
Department of Pharmacology, Michigan State University, East Lansing, MI 48824, USA.
Brennan
Ryan T
RT
Drolet
Robert E
RE
Behrouz
Bahareh
B
Kaufman
Sarah K
SK
Lookingland
Keith J
KJ
Goudreau
John L
JL
D000818:Animals; D001369:Axons / Q000378:metabolism; D015153:Blotting, Western; D003342:Corpus Striatum / Q000187:drug effects*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use*; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013378:Substantia Nigra / Q000187:drug effects*; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D014446:Tyrosine 3-Monooxygenase; D017869:Cyclic GMP-Dependent Protein Kinases; D004298:Dopamine