Thymol nanoparticles ameliorate oxaliplatin-induced cognitive impairment via modulation of Nrf2/HO-1, endoplasmic reticulum stress, and NLRP3 inflammasome signaling in rats

Abstract

Chemobrain was delineated as a severe, debilitating neurological problem with a high prevalence rate in cancer survivors. Platinum-based chemotherapeutic agents, such as oxaliplatin (OXA), are effective in the treatment of colorectal cancer. Deleteriously, OXA cancer cells' killing ability is associated with the development of cognitive deficits; yet, the exact mechanism of this process is not fully decoded. This study aimed to investigate the neuromodulatory effect of thymol (THY) in a rat model of OXA-induced chemobrain, as well as to contemplate the possible underlying mechanisms. THY nanoparticles were prepared exploiting the nanoemulsion technique. Rats were divided into six groups: control, OXP (4 mg/kg, i.p), THY (30 mg/kg, oral), THY (60 mg/kg, oral), THY nanoemulsion (10 mg/kg, oral), and THY nanoemulsion (10 mg/kg, intranasal). Several behavioral, histopathological and biochemical parameters were evaluated. Results displayed that THY abated OXA-induced impairment in cognitive function. THY corrected the histological alterations induced by OXA. THY averted the increased activity of acetylcholinesterase and butyrylcholinesterase enzymes caused by OXA treatment. Conjunctly, THY mitigated oxidative stress and endoplasmic reticulum stress as evident from its effect on Nrf2/HO-1 and GRP78/ATF6/CHOP axes. The substantial impact of THY on modulating neuroinflammation cues was also evident by its effect on the NLR family pyrin domain-containing 3 (NLRP3) inflammasome pathway. Finally, the cytotoxic ability of OXA was not impeded by THY treatment on HCT-116 and Caco-2 cells. These findings imply the neuroprotective potential of THY against OXA-induced memory problems and unveil novel intersecting nodes between oxidative stress, unfolded-protein response, and neuroinflammation.