Montelukast (MTK) is a cysteinyl leukotriene receptor antagonist widely used to suppress the inflammatory response in asthma and allergic rhinitis. Despite being suggested as a potential therapeutic strategy for neuroinflammatory disorders, such as Alzheimer’s Disease, the number of reported adverse drug reactions (ADRs) have been increasing, especially neuropsychiatric ADRs. With a poorly understood metabolism and no mechanism known for its ADRs, our goal was to elucidate the metabolism of MTK, as well as its influence on the metabolome and proteome using a multiomics approach. Test mice were treated with 1 mg/kg MTK by oral gavage once a day for one week, and selected tissues and fluids were collected for metabolite and protein extraction. Samples were analysed by ultra-performance liquid chromatography coupled to high-resolution electrospray ionization tandem mass spectrometry (UPLC-ESI-HRMS/MS), followed by a bioinformatics-driven data treatment approach using XCMS and MaxQuant. Brain metabolomics indicated that pathways involved in energy management and in the turnover of biomolecular building blocks (e.g., amino acids and nucleosides) are the pathways most affected by MTK. An increased corticosterone level suggests a hyper-activated neuroendocrine system, which is involved in stress response, mood changes, and emotion. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is supported by alterations in the levels of neurosteroids and neurotransmitters such as dopamine, serotonin, histamine, and GABA. Species involved in redox maintenance were also unbalanced. A decrease in the GSH/GSSG ratio coupled to decreased L-γ-glutamylcysteine and dihydrolipoate levels point to an overall increased oxidative status. This could be implicated in some brain disorders, and is consistent with data obtained from metabolism studies, where a non-enzymatic MTK-GSH conjugate was identified. Moreover, proteomics data are also consistent with HPA hyper-activation, with consequent dysregulation of neurotransmitters and their signalling pathways. To conclude, an integrative omics approach suggests that neuropsychiatric ADRs are caused by an imbalance of the HPA axis. Moreover, the brain maturation stage could be the key to explain children's susceptibility to neuropsychiatric ADRs when compared to adults.

Montelukast neurotoxicity unveiled by MS multiomics – HPA axis and redoxome dysregulation

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.