Abstract
BackgroundPhosphodiesterase 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 FindingsHere 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/SignificanceOur 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.
Highlights
Parkinson disease (PD) is one of the most common progressive neurodegenerative disorder, affecting around 1% of the elderly population
We have demonstrated, for the first time, that inhibition of PDE7 induces neuroprotection of human dopaminergic neuronal cells SH-SY5Y and of primary mesencephalic cultures and attenuates the production of nitrites and proinflammatory agents
Human neuroblastoma cells exposed to 6-OHDA are used as in vitro model for PD, due to similar cellular processes that occur in the degenerating dopaminergic neurons [31]
Summary
Parkinson disease (PD) is one of the most common progressive neurodegenerative disorder, affecting around 1% of the elderly population. Typical symptoms of this disease are muscle rigidity, bradykinesia, resting tremor and postural instability. The cell death leads to the loss of dopamine in areas where these neurons project, causing the described symptoms. 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. CAMP has been implicated in learning, memory processes and other brain functions
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