Abstract
In this study we tested whether phosphodiesterase 5 (PDE5) inhibitors, sildenafil and vardenafil, would afford protection against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of Huntington's Disease (HD). The neurotoxin was given over 5 days by constant systemic infusion using osmotic minipumps. Animals treated with PDE5 inhibitors (sildenafil or vardenafil) showed improved neurologic scores, reduced the loss of striatal DARPP-32 protein levels and lesion volumes, and decreased calpain activation produced by 3NP. This protective effect was independent of changes in 3NP-induced succinate dehydrogenase inhibition. Furthermore, striatal p-CREB levels along with the expression of BDNF were significantly increased in sildenafil-treated rats. In summary, PDE5 inhibitors protected against 3NP-induced striatal degeneration by reducing calpain activation and by promoting survival pathways. These data encourage further evaluation of PDE5 inhibitors in transgenic mouse models of HD.
Copyright 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Blotting, Western
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Brain-Derived Neurotrophic Factor / metabolism*
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Calpain / metabolism*
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Corpus Striatum / drug effects*
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Corpus Striatum / metabolism
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Corpus Striatum / pathology
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism
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Male
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Motor Activity / drug effects
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Neurons / drug effects
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Neurons / metabolism
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Neurons / pathology
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Neurotoxicity Syndromes / drug therapy*
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Neurotoxicity Syndromes / metabolism
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Neurotoxicity Syndromes / pathology
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Neurotoxins / pharmacology
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Nitro Compounds / pharmacology*
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Phosphodiesterase Inhibitors / pharmacology
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Piperazines / pharmacology*
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Propionates / pharmacology*
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Purines / pharmacology
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Rats
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Rats, Inbred Lew
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Reverse Transcriptase Polymerase Chain Reaction
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Sildenafil Citrate
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Succinate Dehydrogenase / metabolism
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Sulfones / pharmacology*
Substances
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Brain-Derived Neurotrophic Factor
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Cyclic AMP Response Element-Binding Protein
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Dopamine and cAMP-Regulated Phosphoprotein 32
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Neurotoxins
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Nitro Compounds
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Phosphodiesterase Inhibitors
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Piperazines
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Propionates
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Purines
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Sulfones
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Sildenafil Citrate
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Succinate Dehydrogenase
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Calpain
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3-nitropropionic acid