Phosphodiesterase 7 Regulation in Cellular and Rodent Models of Parkinson’s Disease

Parkinson’s disease is characterized by a loss of dopaminergic neurons in the ventral midbrain. This disease is diagnosed when around 50% of these neurons have already died; consequently, therapeutic treatments start too late. Therefore, an urgent need exists to find new targets involved in the onse...

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Bibliographic Details
Published in:Molecular neurobiology 2020-02, Vol.57 (2), p.806-822
Main Authors: Morales-Garcia, Jose A., Alonso-Gil, Sandra, Santos, Ángel, Perez-Castillo, Ana
Format: Article
Language:English
Subjects:
6-Hydroxydopamine
AMP
Animal models
Anti-inflammatory agents
Biomedical and Life Sciences
Biomedicine
Brain injury
Cell Biology
Disease
Dopamine receptors
Enzymes
Inflammation
Intracellular levels
Lipopolysaccharides
Mesencephalon
Microglia
Movement disorders
Neurobiology
Neurodegeneration
Neurodegenerative diseases
Neurology
Neuroprotection
Neurosciences
Parkinson's disease
Phosphodiesterase
Substantia nigra
Therapeutic applications
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Summary:Parkinson’s disease is characterized by a loss of dopaminergic neurons in the ventral midbrain. This disease is diagnosed when around 50% of these neurons have already died; consequently, therapeutic treatments start too late. Therefore, an urgent need exists to find new targets involved in the onset and progression of the disease. Phosphodiesterase 7 (PDE7) is a key enzyme involved in the degradation of intracellular levels of cyclic adenosine 3′, 5′-monophosphate in different cell types; however, little is known regarding its role in neurodegenerative diseases, and specifically in Parkinson’s disease. We have previously shown that chemical as well as genetic inhibition of this enzyme results in neuroprotection and anti-inflammatory activity in different models of neurodegenerative disorders, including Parkinson’s disease. Here, we have used in vitro and in vivo models of Parkinson’s disease to study the regulation of PDE7 protein levels. Our results show that PDE7 is upregulated after an injury both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures and after lipopolysaccharide or 6-hidroxydopamine injection in the Substantia nigra pars compacta of adult mice. PDE7 increase takes place mainly in degenerating dopaminergic neurons and in microglia cells. This enhanced expression appears to be direct since 6-hydroxydopamine and lipopolysaccharide increase the expression of a 962-bp fragment of its promoter. Taking together, these results reveal an essential function for PDE7 in the pathways leading to neurodegeneration and inflammatory-mediated brain damage and suggest novel roles for PDE7 in neurodegenerative diseases, specifically in PD, opening the door for new therapeutic interventions.
ISSN:0893-7648
1559-1182
DOI:10.1007/s12035-019-01745-z