Neuromodulatory effect of troxerutin against doxorubicin and cyclophosphamide-induced cognitive impairment in rats: Potential crosstalk between gut-brain and NLRP3 inflammasome axes

Abstract

"Chemobrain" refers to the cognitive impairment induced by chemotherapy. The doxorubicin and cyclophosphamide cocktail has been used for various cancers, especially breast cancer. However, both have been linked to chemobrain as well as gastrointestinal toxicity. Despite being distinct organs, the gut and the brain have a bidirectional connection between them known as the gut-brain axis. This research aimed to study the neuroprotective effect of troxerutin, a rutin derivative, in chemobrain induced by doxorubicin and cyclophosphamide via a potential impact on the gut-inflammasome-brain axis. Troxerutin was administered at 75, 150, and 300 mg/kg doses. Furthermore, behavioral, histological, and acetylcholinesterase assessments were performed. Accordingly, the highest dose of troxerutin was selected to investigate the potential underlying mechanisms. Troxerutin treatment reversed the chemotherapy-fecal metabolite alterations. Additionally, troxerutin demonstrated positive effects against deterioration of intestinal integrity, permeability, and microbial endotoxins translocation, as evidenced by its effect on tight junction proteins; ZO-1, and claudin-1 expression, and lipopolysaccharide serum levels. Consequently, troxerutin hindered lipopolysaccharide-induced oxidative damage, systemic inflammation, and neuroinflammation. Moreover, troxerutin demonstrated antioxidant effects via its impact on lipid peroxidation, catalase levels, and the Nrf2/HO-1 pathway. Furthermore, chemotherapy-induced inflammation was opposed by troxerutin via downregulation of NLRP3, caspase-1, and the downstream cytokines; IL-18 and IL-1β. Importantly, troxerutin did not abrogate the anticancer activity of doxorubicin and cyclophosphamide in human MCF7 cells. Collectively, our study suggested the potentiality of troxerutin as a therapeutic choice against chemobrain by inhibiting the gut-inflammasome-brain axis and hindering acetylcholinesterase, oxidative stress, and neuroinflammation.

Keywords: Chemobrain; Gut–brain axis; Intestinal integrity; NLRP3 inflammasome; Nrf2/HO-1; Troxerutin.