Kurt R. Stover, Paul M. Stafford, Andreea C. Damian, Jagadeesh P. Pasangulapati, Jake Goodwin-Tindall, Lucía M. López Vásquez, Sanghyun Lee, Seung-Pil Yang, Mark A. Reed, Christopher J. Barden and Donald F. Weaver* Pages 705 - 714 ( 10 )
<p>Background: Indoleamine 2,3-dioxygenase (IDO1) inhibition is a promising target as an Alzheimer’s disease (AD) Disease-modifying therapy capable of downregulating immunopathic neuroinflammatory processes. <p> Methods: To aid in the development of IDO inhibitors as potential AD therapeutics, we optimized a lipopolysaccharide (LPS) based mouse model of brain IDO1 inhibition by examining the dosedependent and time-course of the brain kynurenine:tryptophan (K:T) ratio to LPS via intraperitoneal dosing. <p> Results: We determined the optimal LPS dose to increase IDO1 activity in the brain, and the ideal time point to quantify the brain K:T ratio after LPS administration. We then used a brain penetrant tool compound, EOS200271, to validate the model, determine the optimal dosing profile and found that a complete rescue of the K:T ratio was possible with the tool compound. <p> Conclusion: This LPS-based model of IDO1 target engagement is a useful tool that can be used in the development of brain penetrant IDO1 inhibitors for AD. A limitation of the present study is the lack of quantification of potential clinically relevant biomarkers in this model, which could be addressed in future studies.</p>
Alzheimer’s disease, indoleamine 2,3-dioxygenase, lipopolysaccharide, pharmacology, kynurenine, tryptophan.