HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

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.
AuthorsKurt Giles, David B Berry, Carlo Condello, Ronald C Hawley, Alejandra Gallardo-Godoy, Clifford Bryant, Abby Oehler, Manuel Elepano, Sumita Bhardwaj, Smita Patel, B Michael Silber, Shenheng Guan, Stephen J DeArmond, Adam R Renslo, Stanley B Prusiner
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 355 Issue 1 Pg. 2-12 (Oct 2015) ISSN: 1521-0103 [Electronic] United States
PMID26224882 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
Chemical References
  • PrPSc Proteins
  • Thiazoles
  • 2-aminothiazole
Topics
  • Animals
  • Brain (drug effects, metabolism, pathology)
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Mice
  • PrPSc Proteins (genetics, metabolism)
  • Scrapie (pathology)
  • Species Specificity
  • Survival Analysis
  • Survival Rate
  • Thiazoles (chemistry, pharmacokinetics, pharmacology, therapeutic use)
  • Transgenes (genetics)
  • Treatment Outcome

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: