Different 2-aminothiazole therapeutics produce distinct patterns of scrapie prion neuropathology in mouse brains

Giles, Kurt, Berry, David B., Condello, Carlo, Hawley, Ronald C., Gallardo-Godoy, Alejandra, Bryant, Clifford, Oehler, Abby, Elepano, Manuel, Bhardwaj, Sumita, Patel, Smita, Silber, B. Michael, Guan, Shenheng, DeArmond, Stephen J., Renslo, Adam R. and Prusiner, Stanley B. (2015) Different 2-aminothiazole therapeutics produce distinct patterns of scrapie prion neuropathology in mouse brains. Journal of Pharmacology and Experimental Therapeutics, 355 1: 2-12. doi:10.1124/jpet.115.224659

Author Giles, Kurt
Berry, David B.
Condello, Carlo
Hawley, Ronald C.
Gallardo-Godoy, Alejandra
Bryant, Clifford
Oehler, Abby
Elepano, Manuel
Bhardwaj, Sumita
Patel, Smita
Silber, B. Michael
Guan, Shenheng
DeArmond, Stephen J.
Renslo, Adam R.
Prusiner, Stanley B.
Title Different 2-aminothiazole therapeutics produce distinct patterns of scrapie prion neuropathology in mouse brains
Journal name Journal of Pharmacology and Experimental Therapeutics   Check publisher's open access policy
ISSN 1521-0103
Publication date 2015-10-01
Year available 2015
Sub-type Article (original research)
DOI 10.1124/jpet.115.224659
Open Access Status Not Open Access
Volume 355
Issue 1
Start page 2
End page 12
Total pages 11
Place of publication Bethesda, MD United States
Publisher American Society for Pharmacology and Experimental Therapy
Collection year 2016
Language eng
Formatted abstract
Because no drug exists that halts or even slows any neurodegenerative disease, developing effective therapeutics for any prion disorder is urgent. We recently reported two compounds (IND24 and IND81) with the 2-aminothiazole (2-AMT) chemical scaffold that almost doubled the incubation times in scrapie prion-infected, wild-type (wt) FVB mice when given in a liquid diet. Remarkably, oral prophylactic treatment with IND24 beginning 14 days prior to intracerebral prion inoculation extended survival from ∼120 days to over 450 days. In addition to IND24, we evaluated the pharmacokinetics and efficacy of five additional 2-AMTs; one was not followed further because its brain penetration was poor. Of the remaining four new 2-AMTs, IND114338 doubled and IND125 tripled the incubation times of RML-inoculated wt and Tg4053 mice overexpressing wt mouse prion protein (PrP), respectively. Neuropathological examination of the brains from untreated controls showed a widespread deposition of self-propagating, β-sheet-rich “scrapie” isoform (PrPSc) prions accompanied by a profound astrocytic gliosis. In contrast, mice treated with 2-AMTs had lower levels of PrPSc and associated astrocytic gliosis, with each compound resulting in a distinct pattern of deposition. Notably, IND125 prevented both PrPSc accumulation and astrocytic gliosis in the cerebrum. Progressive central nervous system dysfunction in the IND125-treated mice was presumably due to the PrPSc that accumulated in their brainstems. Disappointingly, none of the four new 2-AMTs prolonged the lives of mice expressing a chimeric human/mouse PrP transgene inoculated with Creutzfeldt-Jakob disease prions.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
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