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.