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

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.

Hypoxia and the Kynurenine Pathway: Implications and Therapeutic Prospects in Alzheimer’s Disease

“…The kynurenine pathway involves the breakdown of tryptophan to nicotinamide adenine dinucleotide (NAD + ) and other active metabolites. Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are the main enzymes involved in this pathway; they catalyze the rate-limiting step, which is the conversion of tryptophan to N-formylkynurenine ( Figure 3 ) [ 82 ]. The cytosolic enzyme IDO is an endocellular, monomeric hemoprotein with a molecular mass of 45 kDa.…”

“…Besides, in experiments using a standard AD model, triple-transgenic AD (3xTg-AD) mice show high levels of INF- γ and IDO in their cerebrum [ 82 ]. The impairment caused by these high levels of INF- γ and IDO includes oxidative stress, increased levels of tau phosphorylation, impairment in the immune system, and increased A β 42 levels.…”

Metabolic determinants of leukocyte pathogenicity in neurological diseases

“…Quinolinic acid is the final product of tryptophan degradation via the kynurenine pathway (KP), which is activated in the CNS, in particular in microglial cells, during AD and promotes neuronal degeneration and death (Cervenka, Agudelo, & Ruas, 2017;Zádori, Veres, Szalárdy, Klivényi, & Vécsei, 2018). Targeting the KP ameliorated AD pathogenesis in animal models, and this beneficial effect might be because of reduced production of neurotoxic quinolinic acid in the CNS (Fertan et al, 2019;Sorgdrager, Naudé, Kema, Nollen, & Deyn, 2019;Yu et al, 2015). However, data by Busse and colleagues suggest that the KP is up-regulated in peripheral immune cells during AD, suggesting that KP blockade may also reduce quinolinic acid production from CNS-infiltrating peripheral immune cells (Busse et al, 2018;Sorgdrager et al, 2019).…”

A Series of 2‐((1‐Phenyl‐1H‐imidazol‐5‐yl)methyl)‐1H‐indoles as Indoleamine 2,3‐Dioxygenase 1 (IDO1) Inhibitors

“…The most potent compound, 12 f, displayed the best LE value (0.4), which is comparable to the mean LE value (0.45) for most approved drugs administered orally. [45] The 'GBVI/WSA dG' docking scores [46a] for our compounds are given in Table 1 and 2 to estimate the binding affinity of each ligand in the active site of IDO1. We can see that most of the active compounds, including 9d and 12 f, have low GBVI/WSA binding free energy.…”

“…[46b-d] There are several potential applications for a brain penetrant IDO1 inhibitor. [16,45,47] To evaluate our compounds for their ability to penetrate the brain, we used two assessment tools, one called the Brain Exposure Efficiency (BEE) score, and the other called the Blood Brain Barrier (BBB) score; both developed by our group. [48,49] The BBB score estimates passive diffusion across the BBB, whereas the BEE score predicts active transport across the BBB as a function of efflux and influx transporters.…”