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MS-8209, a water-soluble amphotericin B derivative, affects both scrapie agent replication and PrPres accumulation in
Abstract:
Amphotericin B (AmB) has been shown to delay hamster scrapie. Infectivity studies have been performed previously using AmB in order to understand the relationship between the accumulation of an abnormal isoform (PrPres) of the prion protein and 263K scrapie agent replication in the brain. The first study reported that AmB had no effect upon agent replication, although it delayed the development of both clinical signs and PrPres accumulation. However, subsequent experiments using the same model showed a significant effect both on agent replication and PrPres accumulation early in infection. This fundamental discrepancy was assumed to be linked to differences in experimental protocols. In order to unravel the issue, a new experiment has been performed encompassing different protocols and using an AmB derivative, MS-8209, that can be used at higher doses because of its lower toxicity. The findings of this study exclude the suspected differences in the protocols as the reason for previous conflicting results, and suggest strongly that these discrepancies were due to a low dose of AmB causing a 'threshold effect'. Overall, this study indicates that, in this model, PrPres cannot be dissociated from infectivity by polyene antibiotics.
Insights
Amphotericin B (AmB) may not fully stop prion disease replication. Studies suggest a dose-dependent effect, indicating AmB
Area of Science:
- Neuroscience
- Infectious Diseases
- Biochemistry
Background:
- Amphotericin B (AmB) has demonstrated potential in delaying hamster scrapie progression.
- Previous studies yielded conflicting results regarding AmB's effect on prion protein (PrPres) accumulation and 263K scrapie agent replication.
- Discrepancies were hypothesized to stem from variations in experimental protocols.
Purpose of the Study:
- To investigate the discrepancy in previous findings on Amphotericin B's effect on scrapie.
- To evaluate the impact of different experimental protocols and a novel AmB derivative (MS-8209) on prion disease.
- To clarify the relationship between PrPres accumulation, agent replication, and infectivity.
Main Methods:
- Conducted infectivity studies using Amphotericin B and its derivative MS-8209 in a hamster scrapie model.
- Employed varied experimental protocols to address previous discrepancies.
- Assessed agent replication, PrPres accumulation, clinical signs, and infectivity.
Main Results:
- The study's findings excluded protocol differences as the cause of previous conflicting results.
- Evidence strongly suggests that a low dose of Amphotericin B created a 'threshold effect', explaining earlier discrepancies.
- In this model, polyene antibiotics like AmB could not dissociate abnormal prion protein (PrPres) from infectivity.
Conclusions:
- Conflicting results in prior Amphotericin B studies are attributed to a dose-dependent 'threshold effect', not protocol variations.
- Amphotericin B's efficacy in delaying scrapie symptoms is not linked to a complete inhibition of prion replication.
- Polyene antibiotics, including Amphotericin B, do not fully separate prion infectivity from the accumulation of abnormal prion protein (PrPres).