Valproic acid treatment results in increased accumulation of prion proteins

Abstract

PrP(Sc), the only identified component of the prion, is an aberrant isoform of PrP(C), a glycoprotein of unknown function. In this study, it was shown that valproic acid, a widely used antiepileptic drug, can cause an increase of several orders of magnitude in the accumulation of PrP(C) in normal neuroblastoma cells (N2a), and of both PrP isoforms in scrapie infected neuroblastoma cells (ScN2a). Although preliminary results indicate that valproic acid administration to hamsters inoculated with prions had no significant effect on disease incubation time, it is suggested that administration of valproic acid to humans at risk of developing Creutzfeldt-Jakob disease should be evaluated with caution.

Effect of transition metals (Mn, Cu, Fe) and deoxycholic acid (DA) on the conversion of PrPCto PrPres

“…DA, which has been implicated in the promotion of colon tumorigenesis and apoptosis (30), contains a carboxyl group which is an oxidized form of a hydroxyl group. A number of other reports suggest that substances with carboxyl acid could have the dual effect of inducing neuronal degeneration and formation or accumulation of fibrils (31)(32)(33)(34). On the basis of the evidence of the elevated Mn levels in affinity-purified PrP Sc from prion-infected brains (9) and high Mn content in sarkosyl supernatants from scrapie brain homogenates compared with low levels in the same type of preparations from control brains (Fig.…”

Screening a library of potential prion therapeutics against cellular prion proteins and insights into their mode of biological activities by surface plasmon resonance

“…Compounds which are known to be both active and inactive were screened. This included nucleic acid derivatives, amino acid and peptide derivatives, antibiotics, dyes and a variety of other compounds such as phenothiazine derivatives, all of which were soluble in either water or DMSO [2,[36][37][38][39][40][41][42][43][44]. For many of the active compounds the mechanism of action is unknown, however, by assessing the ability of active and inactive compounds to bind to huPrP C , as well as to t-huPrP C and moPrP C , it might be possible to begin to understand these mechanisms.…”

“…It has been shown to cause an increase in levels of PrP C and PrP Sc in scrapie infected neuroblastoma cells by several orders of magnitude [38]. Valproic acid is metabolised in vivo into a range of metabolites and it is possible that one of these metabolites is responsible for the effects observed in cell line studies, or that direct binding of valproic acid to huPrP C , as observed in this investigation, could be directly responsible for the increase in PrP Sc levels through an unknown mechanism.…”

Sodium valproate does not augment Prpsc in murine neuroblastoma cells

“…Shaked et al were unable to demonstrate any difference in disease incubation time or prion proteins in the brains of hamsters infected with scrapie strain 263K and administered therapeutically relevant doses of VPA (Shaked et al, 2002). As a consequence, the risk associated with the use of sodium valproate as a possible treatment of CJD symptoms is likely to be small or inexistent.…”

“…Prior to considering valproate as a possible treatment of CJD symptoms, it is important to evaluate effects ofvalproate on prion replication. In 2002, Shaked et al reported the increased accumulation of both pathologic (PrP so) and normal (PrP e) isoforms of prion protein (PrP) in neuroblastoma (N2a) cells infected with the Rocky Mountain Laboratory (RML) scrapie strain (ScN2a) after treatment with the antiepileptic drug, sodium valproate (Shaked et al, 2002). In previous experiments performed at the publication date of this manuscript, no deleterious effect has been observed using neuroblastoma cell line N2a infected with scrapie strain 22L, at concentrations similar to those used by Shaked et al In the present study, these previous experiments were repeated and other experimental conditions, e.g., concentrations and short-term or long-term treatment, were tested using the same experimental cell model.…”