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Current Alzheimer Research

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

Development and Optimization of a Target Engagement Model of Brain IDO Inhibition for Alzheimer’s Disease

Author(s): 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*

Volume 20, Issue 10, 2023

Published on: 26 January, 2024

Page: [705 - 714] Pages: 10

DOI: 10.2174/0115672050283199240111111801

Price: $65

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Abstract

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.

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.

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.

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.

Keywords: Alzheimer’s disease, indoleamine 2, 3-dioxygenase, lipopolysaccharide, pharmacology, kynurenine, tryptophan.

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