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Phosphodiesterase 7 inhibition preserves dopaminergic neurons in cellular and rodent models of Parkinson disease

AuthorsMorales-García, José A. ; Redondo, Miriam ; Alonso-Gil, Sandra ; Gil, Carmen ; Pérez, Concepción; Martínez, Ana ; Santos, Ángel; Pérez Castillo, Ana
KeywordsCyclic-nucleotide phosphodiesterases
Nonsteroidal antiinflammatory drugs
Neuroblastoma sh-sy5y cells
Dependent neuroprotection
Pde7 inhibitors
Issue Date24-Feb-2011
PublisherPublic Library of Science
CitationPLoS ONE 6(2): e17240 (2011)
Abstract[Background]: Phosphodiesterase 7 plays a major role in down-regulation of protein kinase A activity by hydrolyzing cAMP in many cell types. This cyclic nucleotide plays a key role in signal transduction in a wide variety of cellular responses. In the brain, cAMP has been implicated in learning, memory processes and other brain functions. [Methodology/Principal Findings]: Here we show a novel function of phosphodiesterase 7 inhibition on nigrostriatal dopaminergic neuronal death. We found that S14, a heterocyclic small molecule inhibitor of phosphodiesterase 7, conferred significant neuronal protection against different insults both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures. S14 treatment also reduced microglial activation, protected dopaminergic neurons and improved motor function in the lipopolysaccharide rat model of Parkinson disease. Finally, S14 neuroprotective effects were reversed by blocking the cAMP signaling pathways that operate through cAMP-dependent protein kinase A. [Conclusions/Significance]: Our findings demonstrate that phosphodiesterase 7 inhibition can protect dopaminergic neurons against different insults, and they provide support for the therapeutic potential of phosphodiesterase 7 inhibitors in the treatment of neurodegenerative disorders, particularly Parkinson disease.
DescriptionThis is an open-access article distributed under the terms of the Creative Commons Attribution License.
Publisher version (URL)http://dx.doi.org/10.1371/journal.pone.0017240
Appears in Collections:(IIBM) Artículos
(IQM) Artículos
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