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Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study.

Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study.

Authors :
Pepponi, Rita
De Simone, Roberta
De Nuccio, Chiara
Visentin, Sergio
Matteucci, Andrea
Bernardo, Antonietta
Popoli, Patrizia
Ferrante, Antonella
Source :
International Journal of Molecular Sciences. Apr2022, Vol. 23 Issue 7, p3456-N.PAG. 16p.
Publication Year :
2022

Abstract

Niemann Pick type C disease (NPC) is a rare disorder characterized by lysosomal lipid accumulation that damages peripheral organs and the central nervous system. Currently, only miglustat is authorized for NPC treatment in Europe, and thus the identification of new therapies is necessary. The hypothesis addressed in this study is that increasing adenosine levels may represent a new therapeutic approach for NPC. In fact, a reduced level of adenosine has been shown in the brain of animal models of NPC; moreover, the compound T1-11, which is able to weakly stimulate A2A receptor and to increase adenosine levels by blocking the equilibrative nucleoside transporter ENT1, significantly ameliorated the pathological phenotype and extended the survival in a mouse model of the disease. To test our hypothesis, fibroblasts from NPC1 patients were treated with dipyridamole, a clinically-approved drug with inhibitory activity towards ENT1. Dipyridamole significantly reduced cholesterol accumulation in fibroblasts and rescued mitochondrial deficits; the mechanism elicited by dipyridamole relies on activation of the adenosine A2AR subtype subsequent to the increased levels of extracellular adenosine due to the inhibition of ENT1. In conclusion, our results provide the proof of concept that targeting adenosine tone could be beneficial in NPC. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
16616596
Volume :
23
Issue :
7
Database :
Academic Search Index
Journal :
International Journal of Molecular Sciences
Publication Type :
Academic Journal
Accession number :
156291860
Full Text :
https://doi.org/10.3390/ijms23073456