Styryl-based and tricyclic compounds as potential anti-prion agents

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Prion diseases are fatal neurodegenerative disorders caused by misfolded prion proteins (PrPSc).
• Current therapies for prion diseases are ineffective, necessitating the development of new treatments.
• A mouse neuroblastoma cell culture model (N2a/22L) is utilized to screen for anti-prion compounds.

Purpose of the Study:

• To screen a library of styryl-based imaging agents for anti-prion activity.
• To evaluate the anti-prion efficacy of trimipramine and fluphenazine in a cell culture model.
• To assess the therapeutic potential of promising compounds in a mouse model of prion disease.

Main Methods:

• Screening of styryl-based compounds and existing drugs (trimipramine, fluphenazine) in N2a/22L prion-infected cells.
• Assessment of compound toxicity in cell culture and in vitro amyloid disaggregation.
• In vivo evaluation in CD-1 mice infected with 139A PrPSc, monitoring incubation period and brain pathology.

Main Results:

• Two imaging agents (23I and 59) demonstrated anti-prion activity without toxicity in cell culture.
• Trimipramine and fluphenazine also showed anti-prion effects in the cell culture model.
• All four tested compounds significantly prolonged the asymptomatic incubation period and reduced prion disease markers in mice.

Conclusions:

• Compounds 23I, 59, trimipramine, and fluphenazine show therapeutic potential for prion diseases.
• These agents warrant further investigation and development as potential treatments for prion infections.
• The study highlights the utility of cell-based screening and in vivo validation for identifying prion disease therapeutics.