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Article

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

by
Rita Pepponi
1,
Roberta De Simone
1,
Chiara De Nuccio
2,
Sergio Visentin
1,
Andrea Matteucci
1,
Antonietta Bernardo
1,
Patrizia Popoli
1 and
Antonella Ferrante
1,*
1
National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
2
Research Coordination and Support Service, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(7), 3456; https://doi.org/10.3390/ijms23073456
Submission received: 2 March 2022 / Revised: 17 March 2022 / Accepted: 21 March 2022 / Published: 22 March 2022
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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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.
Keywords: Niemann Pick type C disease; adenosine; A2A receptor; dipyridamole Niemann Pick type C disease; adenosine; A2A receptor; dipyridamole

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MDPI and ACS Style

Pepponi, R.; De Simone, R.; De Nuccio, C.; Visentin, S.; Matteucci, A.; Bernardo, A.; Popoli, P.; Ferrante, A. Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study. Int. J. Mol. Sci. 2022, 23, 3456. https://doi.org/10.3390/ijms23073456

AMA Style

Pepponi R, De Simone R, De Nuccio C, Visentin S, Matteucci A, Bernardo A, Popoli P, Ferrante A. Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study. International Journal of Molecular Sciences. 2022; 23(7):3456. https://doi.org/10.3390/ijms23073456

Chicago/Turabian Style

Pepponi, Rita, Roberta De Simone, Chiara De Nuccio, Sergio Visentin, Andrea Matteucci, Antonietta Bernardo, Patrizia Popoli, and Antonella Ferrante. 2022. "Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study" International Journal of Molecular Sciences 23, no. 7: 3456. https://doi.org/10.3390/ijms23073456

APA Style

Pepponi, R., De Simone, R., De Nuccio, C., Visentin, S., Matteucci, A., Bernardo, A., Popoli, P., & Ferrante, A. (2022). Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study. International Journal of Molecular Sciences, 23(7), 3456. https://doi.org/10.3390/ijms23073456

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