The celecoxib derivatives AR-12 and AR-14 induce autophagy and clear prion-infected cells from prions.
Sci Rep
; 7(1): 17565, 2017 12 14.
Article
em En
| MEDLINE
| ID: mdl-29242534
ABSTRACT
Prion diseases are fatal infectious neurodegenerative disorders that affect both humans and animals. The autocatalytic conversion of the cellular prion protein (PrPC) into the pathologic isoform PrPSc is a key feature in prion pathogenesis. AR-12 is an IND-approved derivative of celecoxib that demonstrated preclinical activity against several microbial diseases. Recently, AR-12 has been shown to facilitate clearance of misfolded proteins. The latter proposes AR-12 to be a potential therapeutic agent for neurodegenerative disorders. In this study, we investigated the role of AR-12 and its derivatives in controlling prion infection. We tested AR-12 in prion infected neuronal and non-neuronal cell lines. Immunoblotting and confocal microscopy results showed that AR-12 and its analogue AR-14 reduced PrPSc levels after only 72 hours of treatment. Furthermore, infected cells were cured of PrPSc after exposure of AR-12 or AR-14 for only two weeks. We partially attribute the influence of the AR compounds on prion propagation to autophagy stimulation, in line with our previous findings that drug-induced stimulation of autophagy has anti-prion effects in vitro and in vivo. Taken together, this study demonstrates that AR-12 and the AR-14 analogue are potential new therapeutic agents for prion diseases and possibly protein misfolding disorders involving prion-like mechanisms.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Autofagia
/
Sulfonamidas
/
Proteínas PrPSc
/
Celecoxib
Limite:
Animals
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article