Treatment of prion infection in vitro and in vivo
Alzheimer's & Dementia: The Journal of the Alzheimer's Association(2010)
Abstract
Prion diseases are transmissible neurodegenerative disorders characterized by the conversion of cellular prion protein, PrPC, into the infectious scrapie isoform, PrPSc. There are no existing treatments, leading investigators to pursue drug therapies such as quinacrine which successfully clears prion infection in vitro but has poor results in vivo. The structurally similar fluphenazine and trimipramine have potential to clear prion infection like quinacrine, but have never been tested.. A library of styryl-based compounds originally synthesized to image amyloid deposits in vivo has applications in prion disease by possibly recognizing the β-sheet-rich PrPSc and blocking the PrPSc to PrPC interaction. None of these compounds have previously been used in prion therapeutics. All compounds were screened for therapeutic efficacy in our N2a/22L tissue culture model of prion infection, as well as the inhibition of PrP peptide fibril formation in vitro. Compounds were applied over a range of concentrations for 72 hrs. Based on therapeutic efficacy, two styryl-based imaging compounds, 23I and 59 (out of a library of 90 agents), along with fluphenazine and trimipramine were chosen for in vivo testing. After a week of in vivo treatment to ensure non-toxicity, 15 mice per group were inoculated with 139a prion strain and treated within hours and subsequently five times a week until sacrifice. At 60 dpi where CNS presence of PrPSc is not expected, 2 animals per group were sacrificed and their spleens analyzed for lymphatic PrPSc. Beginning around 100 dpi, animals underwent a test of ataxia and will be sacrificed after scoring positive three consecutive weeks. Brain and spleen tissue will be analyzed for evidence of disease, including spongiform changes and presence of PrPSc In tissue culture studies, fluphenazine and trimipramine showed a 99% and 87.6% PrPSc reduction at 1.6 μM, with an IC50 of 0.15 μM and 0.66 μM, respectively. The two imaging agents, 23I and 59, reduce PrPSc by 25% and 20% at 5 μM, respectively. Animals are currently undergoing treatment following 139a prion inoculation. We demonstrate the utility of four compounds to significantly inhibit PrPSc infection in a N2a/22L tissue culture system. We are in the progress of testing these in vivo.
MoreTranslated text
Key words
prion infection,vitro,treatment
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined