Orally Administered Amyloidophilic Compound Is Effective in Prolonging the Incubation Periods of Animals Cerebrally Infected with Prion Diseases in a Prion Strain-Dependent Manner

Abstract

The establishment of effective therapeutic interventions for prion diseases is necessary. We report on a newly developed amyloidophilic compound that displays therapeutic efficacy when administered orally. This compound inhibited abnormal prion protein formation in prion-infected neuroblastoma cells in a prion straindependent manner: effectively for RML prion and marginally for 22L prion and Fukuoka-1 prion. When the highest dose (0.2% [wt/wt] in feed) was given orally to cerebrally RML prion-inoculated mice from inoculation until the terminal stage of disease, it extended the incubation periods by 2.3 times compared to the control. The compound exerted therapeutic efficacy in a prion strain-dependent manner such as that observed in the cell culture study: most effective for RML prion, less effective for 22L prion or Fukuoka-1 prion, and marginally effective for 263K prion. Its effectiveness depended on an earlier start of administration. The glycoform pattern of the abnormal prion protein in the treated mice was modified and showed predominance of the diglycosylated form, which resembled that of 263K prion, suggesting that diglycosylated forms of abnormal prion protein might be least sensitive or resistant to the compound. The mechanism of the prion strain-dependent effectiveness needs to be elucidated and managed. Nevertheless, the identification of an orally available amyloidophilic chemical encourages the pursuit of chemotherapy for prion diseases.

Drug resistance confounding prion therapeutics

“…4H) and quinacrine (Fig. 4J), consistent with previous reports (11,15). Compound B treatment up to 10 μM was ineffective against the IND24-resistant strain (Fig.…”

“…Unlike quinacrine, treatment with Compound B or anle138b substantially extended the survival of prion-infected mice (15)(16)(17). Prions from the brains of mice treated with Compound B showed different ratios of mono-to diglycosylated PrP Sc compared with the inoculum (15), and had a different conformational stability (17), but it was not determined whether the resulting prions were resistant to further treatment with Compound B.…”

“…Prions from the brains of mice treated with Compound B showed different ratios of mono-to diglycosylated PrP Sc compared with the inoculum (15), and had a different conformational stability (17), but it was not determined whether the resulting prions were resistant to further treatment with Compound B. Importantly, Compound B contains a hydrazone functionality likely under physiologic conditions to produce an aryl hydrazine, a toxic metabolite and carcinogen (18), limiting its utility as a therapeutic (17).…”

A γ-secretase inhibitor and quinacrine reduce prions and prevent dendritic degeneration in murine brains

“…Interestingly, the use of pentosan polysulfate (PPS) combined with iron(III) meso-tetra(4-sulfonatophenyl)porphine (FeTAP) produced a synergistic prolongation of incubation times in prion-infected mice (8). Although the combination of PPS and FeTAP had to be administered intracerebrally to effect a prolongation of the incubation period, the oral administration of 4-pyridinecarboxaldehyde-2-[4-(5-oxazolyl)phenyl]hydrazone (cpd-B) produced a doubling of the incubation time in RML-infected Tga20 mice when started midway through the incubation period (41).…”

“…Cpd-B was the most effective in prolonging the incubation times of RML-infected mice but had little effect on the incubation times of either Syrian hamsters or Tg(SHaPrP)7 mice inoculated intracerebrally with 263K prions (41). Combining cpd-B with a GSI will be of interest in the continuing search for an effective therapeutic regimen for CJD.…”