Chemotherapy-induced cognitive impairment, referred to as "chemobrain", is widely acknowledged as a significant adverse effect of cancer therapy. Paclitaxel, a chemotherapeutic drug, has been reported to cause cognitive impairment clinically and in animal models. However, the precise mechanisms are not fully understood. The current study explored the potential neuroprotective effect of lycopene in paclitaxel-induced cognitive impairment in mice and its potential underlying mechanisms. Mice were randomly allocated into six groups: control, paclitaxel-treated (10 mg/kg), lycopene-treated (5, 10, and 20 mg/kg) + paclitaxel, and lycopene alone-treated (20 mg/kg) groups. The effect of lycopene treatment on behavioral function and histological examination was assessed. Lycopene (20 mg/kg) was selected for additional investigation into the underlying mechanisms. Lycopene treatment counteracted paclitaxel-induced oxidative stress by reducing lipid peroxidation and enhancing catalase levels. Additionally, lycopene-treated mice demonstrated a significant elevation in nuclear factor erythroid 2-related factor 2 with no significant effect on hemeoxygenase-1. Moreover, paclitaxel administration elevated endoplasmic reticulum stress markers
glucose-regulated protein78, activating Transcription Factor 6, C/EBP homologous protein, and apoptosis marker annexin V which were significantly reduced by lycopene treatment. Furthermore, lycopene mitigated paclitaxel-induced neuroinflammation through the reduction of the levels of the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome axis markers
nuclear factor-κB, NLRP3, caspase-1, interleukin-1β, and interleukin-18. Our study findings may provide new evidence that lycopene mitigates paclitaxel-induced cognitive impairment in mice by reversing oxidative stress, endoplasmic reticulum stress, and inflammatory mechanisms.