Introduction
Montelukast (MTK,
1-([(1(R )-(3-(2-(7-chloro-2-quinolinyl)-(E )-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio]methyl)
cyclopropylacetic acid) is an antagonist of the cysteinyl leukotrienes
receptor 1 (CysLTR1), widely used by patients with
asthma and allergic rhinitis to manage their symptoms. In addition to
CysLTR1 inhibition, MTK has been identified as an
inhibitor of new targets, including 5-lipoxygenase (5-LOX) (Ramireset al. , 2004), as well as of the CysLTR2,
P2Y12 (Trinh et al. , 2019), and GPR17
(Marschallinger et al. , 2015) receptors, suggesting that MTK can
be exploited in other pathologies. In fact, MTK has been proposed for
repurposing in a number of other diseases, particularly
neurodegenerative disorders,
including Alzheimer’s disease
(AD) (Lai et al. , 2014a; Lai et al. , 2014b; Marschallingeret al. , 2015), Parkinson’s disease (Jang et al. , 2017;
Mansour et al. , 2018; Nagarajan and Marathe, 2018; Wallin and
Svenningsson, 2021; Zhang et al. , 2014) and Huntington’s disease
(Kalonia et al. , 2010). Recent studies have identified MTK as
being able to improve cognitive and neurological functions due to its
modulation role in the inflammatory and apoptotic cascades involved in
neurodegenerative features, particularly those where TNF‑α, NF-κB,
caspase-3, Bcl-2, MAPK, and IL-1β participate. Moreover, MTK appears to
lead to a decrease in α‑synuclein load and in Aβ1‑42induced neurotoxicity, as well as to modulate the oxidative stress
associated with a dysregulation of the GSH/GSSG balance or of superoxide
dismutase activity - two key factors in the maintenance of redox
homeostasis (Grinde et al. , 2021; Jang et al. , 2017;
Kalonia et al. , 2010; Lai et al. , 2014a; Lai et
al. , 2014b; Mansour et al. , 2018; Marschallinger et al. ,
2020; Marschallinger et al. , 2015; Michael et al. , 2021;
Nagarajan and Marathe, 2018; Zhang et al. , 2016).
Clinical trials are ongoing to assess the effects of MTK in
neurodegenerative disorders, including Alzheimer’s disease. However, the
mechanisms responsible for such effects are still poorly explored.
This work aims to interrogate proteomics data in order to identify
biological pathways affected by montelukast that may support its
repurposing for AD management. Toward this end, a reinterpretation
strategy based on proteomics datasets originated form our previous work
(Marques et al. , 2022d) and deposited in public repositories
(Marques et al. , 2022a; Marques et al. , 2022b) was
followed. Thus, raw mass spectrometry-based proteomics data from mice
and from chicken neuron cultures treated with MTK were reinterpreted in
order to identify potential mechanisms supporting MTK’s repurposing for
neurodegenerative diseases. One of the major features of omics studies
consists of the generation of big data sets; however, the huge
information contained in these data is systematically under-analysed. A
data-reinterpretation strategy not only allows extracting further
information from the same data sets, but also favours data dissemination
among the scientific community, reducing the costs associated with
research projects, as well as the laboratory resources and waste.
Besides, this strategy also contributes to the 3Rs principles of animal
research (Russell and Burch, 1959) since no additional animals were
employed.