Format

Send to

Choose Destination
J Pharmacol Exp Ther. 2015 Oct;355(1):2-12. doi: 10.1124/jpet.115.224659. Epub 2015 Jul 29.

Different 2-Aminothiazole Therapeutics Produce Distinct Patterns of Scrapie Prion Neuropathology in Mouse Brains.

Author information

1
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
2
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco stanley.prusiner@ucsf.edu.

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 (PrP(Sc)) prions accompanied by a profound astrocytic gliosis. In contrast, mice treated with 2-AMTs had lower levels of PrP(Sc) and associated astrocytic gliosis, with each compound resulting in a distinct pattern of deposition. Notably, IND125 prevented both PrP(Sc) accumulation and astrocytic gliosis in the cerebrum. Progressive central nervous system dysfunction in the IND125-treated mice was presumably due to the PrP(Sc) 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.

PMID:
26224882
PMCID:
PMC4576665
DOI:
10.1124/jpet.115.224659
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center