Véronique Gayrard | PubMed Health

PubMed2006

Prion protein in the cerebrospinal fluid of healthy and naturally scrapie-affected sheep.

The aim of this study was to characterize the cerebrospinal fluid (CSF) prion protein (PrP) of healthy and naturally scrapie-affected sheep. The soluble form of CSF PrP(C) immunoblotted with an anti-octarepeat and an anti-C terminus mAb showed two isoforms of approximately 33 and 26 kDa, corresponding to the biglycosylated and unglycosylated isoforms of brain PrP(C). Neither the mean concentration nor the electrophoretic profile of CSF PrP differed between healthy and scrapie-affected sheep, whereas a slightly increased resistance of CSF PrP to mild proteolysis by proteinase K was evident in the CSF of scrapie-affected sheep. No difference in susceptibility to proteolysis was observed between the two ARR and VRQ genetic variants of the purified prokaryote recombinant PrP. It was concluded that the physicochemical properties of PrP(C) in the CSF could be altered during scrapie and that these changes might reflect the physiopathological process of prion disease.

Animals↗

PubMed2005

A possible pharmacological explanation for quinacrine failure to treat prion diseases: pharmacokinetic investigations in a ovine model of scrapie.

Quinacrine was reported to have a marked in vitro antiprion action in mouse neuroblastoma cells. On compassionate grounds, quinacrine was administered to Creutzfeldt-Jakob disease patients, despite the absence of preclinical in vivo studies to evaluate efficacy. Quinacrine failed to provide therapeutic benefit. The aim of the study was to investigate possible pharmacokinetic and/or pharmacodynamic explanations for the discrepancy between the proven action of quinacrine in vitro and its lack of clinical efficacy. We conducted in vitro experiments reproducing the culture conditions in which antiprion effects had been previously observed and recalculated the EC(50) by determining the actual extracellular (120 nM) and intracellular (6713 nM) quinacrine neuroblastoma concentrations with the reported quinacrine EC(50) (300 nM). A randomized clinical trial in scrapie-affected ewes confirmed the absence of therapeutic benefit of quinacrine. The in vivo quinacrine exposure was evaluated in a pharmacokinetic investigation in healthy ewes. Cerebrospinal fluid concentrations (<10.6 and 55 nM after administration of therapeutic and toxic quinacrine doses, respectively) were much lower than the quinacrine extracellular neuroblastoma concentrations corresponding to the reported EC(50). The total brain tissue concentrations (3556 nM) obtained after a repeated therapeutic dosage regimen were within the range of the intracellular neuroblastoma quinacrine concentrations. In conclusion, in order to avoid in vivo trials for which failure can be predicted, the measurement in vitro of the antiprion EC(50) in both intra- and extracellular biophases should be determined. It can then be established if these in vitro antiprion concentrations are achievable in vivo.

Algorithms↗

PubMed2002

Aging in the random energy model.

The random energy model (REM) has become a key reference model for glassy systems. In particular, it is expected to provide a prime example of a system whose dynamics shows aging, a universal phenomenon characterizing the dynamics of complex systems. The analysis of its activated dynamics is based on so-called trap models, introduced by Bouchaud, that are also used to mimic the dynamics of more complex disordered systems. In this Letter we report the first results that justify rigorously the trap model predictions in the REM.

Journal Article↗