Orally administered indomethacin acutely reduces cellular prion protein in the small intestine and modestly increases survival of mice exposed to infectious prions

Abstract

Objective. The oral uptake of infectious prions represents a common way to acquire a prion disease; thus, host factors, such as gut inflammation and intestinal “leakiness”, have the potential to influence infectivity. For example, the ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) is known to induce intestinal inflammation and increase intestinal permeability. Previously, we reported that normal cellular prion protein (PrP^C) expression was increased in experimental colitis, and since the level of PrP^C expressed is a determinant of prion disease propagation, we hypothesized that NSAID administration prior to the oral inoculation of mice with infectious prions would increase intestinal PrP^C expression and accelerate the onset of neurological disease. Materials and methods. In the long-term experiments, one group of mice was gavaged with indomethacin, followed by a second gavage with brain homogenate containing mouse-adapted scrapie (ME7). Control mice received ME7 brain homogenate alone. Brain and splenic tissues were harvested at several time points for immunoblotting, including at the onset of clinical signs of disease. In a second series of experiments, mice were gavaged with indomethacin to assess the acute effects of this treatment on intestinal PrP^C expression. Results. Acutely, NSAID treatment reduced intestinal PrP^C expression, and chronically, there was a modest delay in the onset of neurological disease. Conclusion. In contrast to our hypothesis, brief exposure to an NSAID decreased intestinal PrP^C expression and led to a modest survival advantage following oral ingestion of infectious prions.

Key Words:

• cellular prion protein
• cyclooxygenase
• inflammation
• inflammatory bowel disease
• nonsteroidal anti-inflammatory drugs

Acknowledgments

The authors would like to acknowledge the Prion Core Facility at the University of Calgary and thank Sampson Law for technical assistance throughout the study. Funding: This study was supported by a grant from the Alberta Prion Research Institute, Alberta Innovates – Bio Solutions (to KAS and FRJ). FRJ was supported by a Canada Research Chair award. KAS holds the Crohn’s and Colitis Foundation of Canada Chair in Inflammatory Bowel Disease Research at the University of Calgary.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.