Effects of the Novel IDO Inhibitor DWG-1036 on the Behavior of Male and Female 3xTg-AD Mice.

Emre Fertan,Donald F Weaver,Elena Diez-Cecilia,Michael G Brant,Kurt R.J Stover,Aimée A Wong,Paul M Stafford,Richard E Brown,Brendan Kelly

doi:10.3389/fphar.2019.01044

Emre Fertan, Donald F Weaver + Show 7 more

Open Access

https://doi.org/10.3389/fphar.2019.01044

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Abstract

The kynurenine pathway metabolizes tryptophan into nicotinamide adenine dinucleotide, producing a number of intermediary metabolites, including 3-hydroxy kynurenine and quinolinic acid, which are involved in the neurodegenerative mechanisms that underlie Alzheimer’s disease (AD). Indolamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of this pathway, is increased in AD, and it has been hypothesized that blocking this enzyme may slow the progression of AD. In this study, we treated male and female 3xTg-AD and wild-type mice with the novel IDO inhibitor DWG-1036 (80 mg/kg) or vehicle (distilled water) from 2 to 6 months of age and then tested them in a battery of behavioral tests that measured spatial learning and memory (Barnes maze), working memory (trace fear conditioning), motor coordination and learning (rotarod), anxiety (elevated plus maze), and depression (tail suspension test). The 3xTg-AD mice treated with DWG-1036 showed better memory in the trace fear conditioning task and significant improvements in learning but poorer spatial memory in the Barnes maze. DWG-1036 treatment also ameliorated the behaviors associated with increased anxiety in the elevated plus maze and depression-like behaviors in the tail suspension test in 3xTg-AD mice. However, the effects of DWG-1036 treatment on the behavioral tasks were variable, and sex differences were apparent. In addition, high doses of DWG-1036 resulted in reduced body weight, particularly in females. Taken together, our results suggest that the kynurenine pathway is a promising target for treating AD, but more work is needed to determine the effective compounds, examine sex differences, and understand the side effects of the compounds.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that results in synaptic dysfunction and cerebral atrophy (Marcello et al, 2012; Pini et al, 2016)
Locomotion The 3xTg-AD mice traveled a less distance on the elevated plus maze (EPM) than WT mice (F(1, 67) = 17.469, p < 0.001), but there were no main effects of treatment (F(1, 67) = 1.679, p > 0.05) nor any significant interactions
There was a significant genotype by sex interaction (F(1, 63) = 9.063, p < 0.01) because the female 3xTg-AD mice had lower frequencies of open arm entry than the female WT mice; the male 3xTg-AD mice had higher frequencies compared to the male WT mice (Figure 4B)

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that results in synaptic dysfunction and cerebral atrophy (Marcello et al, 2012; Pini et al, 2016). IDO Inhibitor on the Behaviour of 3xTg-AD Mice increased Aβ42 in the brain initiates a cascade of neurological deficits that cause the cognitive and behavioral symptoms associated with AD (Hardy and Allsop, 1991; Selkoe, 1991; Selkoe and Hardy, 2016). Immune deficiencies, and glial dysfunction may contribute to the progression of AD (Gella and Durany, 2009; Zhao et al, 2013; Heppner et al, 2015; Jain et al, 2015). The relationship between these proposed disease mechanisms, their temporal pattern of development, and their contributions to specific neurobehavioral deficits remain unclear

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