Suppression of ER Stress Underlies Montelukast's Neuroprotective Actions in D-Gal/AlCl3-Induced Alzheimer's Disease in Rats.

Abstract

Alzheimer's disease (AD) is a neurodegenerative ailment characterized by neuronal and cognitive dysfunctions. Notably, cysteinyl leukotriene receptor 1 (CysLT1R) overexpression was detected in various AD models. It was closely associated with other hallmarks of AD, including increased oxidative stress, neuroinflammation, amyloid beta (Aβ) deposition, and endoplasmic reticulum (ER) stress. Montelukast (MTK), a CysLT1R antagonist, is an anti-asthmatic drug possessing antioxidant and anti-inflammatory properties. Consequently, this study aimed to mechanistically investigate MTK's neuroprotective potential on D-galactose/Aluminum Chloride (D-gal/AlCl3)-induced AD in rats. This was accomplished by allocating thirty-six adult male Wistar rats into four equal groups as follows: Group I served as the control group, and Group II was orally treated daily with MTK (10 mg/kg) for eight weeks. At the same time, groups III and IV were administered D-gal (65 mg/kg/day, SC) and AlCl3 (200 mg/kg/day, p.o.), starting from week 3 until the end of the experiment, for the remaining six consecutive weeks, to induce AD. Group IV received MTK orally daily for eight weeks. The findings showed that dampening CysLT1R expression by MTK ameliorated D-gal/AlCl3-induced amyloidopathy. MTK rectified the behavioral outcomes, as evidenced by the improved parameters in the novel object recognition, Y-maze, and Morris water maze tests. MTK hampered oxidative stress (MDA and GSH), inflammatory (NF-κB and TNF-α), glial activation (GFAP and Iba1), apoptotic (Caspase-3), ER stress, and Aβ biomarkers. Additionally, MTK, as a CysLT1R antagonist, exerted these favorable actions via adjustment of PERK/IRE1-α/CHOP, NF-κB, mTOR, and apoptotic axes. In conclusion, this study underscored the use of MTK as a promising neuroprotective approach for mitigating AD via modulation of ER stress, neuroinflammatory, and apoptotic trajectories.