Behavioral profiling of hyperbaric oxygen as an intervention for chemotherapy-related functional impairments in male and female mice

Chemobrain or chemotherapy-related cognitive impairment (CRCI) affects up to 75% of cancer patients and survivors following chemotherapy treatments. Chemotherapy typically affects multiple domains including learning, memory, attention, executive function, and mood regulation, persisting for decades after treatment cessation and significantly diminishing cancer survivors quality of life. Despite its prevalence and long-term impact, effective interventions for CRCI remain limited. This study investigated the behavioral effects of HBO on mice exposed to chemotherapy drugs methotrexate (MTX) and 5-fluorouracil (5-FU). Adult male and female C57BL/6 mice received intraperitoneal injections of either saline or chemotherapy (Low-dose: MTX 37.5 mg/kg and 5-FU 50 mg/kg; High-dose: MTX 70 mg/kg and 5-FU 100 mg/kg) once a week for three weeks. Concurrently, subsets of mice underwent daily HBO (2.4 ATA, 90 minutes) five days a week for three weeks. Animals health was evaluated weekly, and behavioral assessment of cognitive, motor, and affective functions was conducted post-treatment. Our results showed that chemotherapy, especially at high-dose, impaired spatial memory and navigation, avoidance learning, fear discrimination, and anxiety regulation differently between males and females. HBO significantly alleviated chemotherapy-induced avoidance learning impairment in both sexes and improved coordinated running capacity in high-dose treated males. However, chemotherapy-HBO cotreatment increased spatial memory deficit in males and increased anxiety-like behaviors in females. In conclusion, even though HBO had some nuanced effects on the various domains, some reversal of CRCI effects were observed. Therefore, HBO should be further studied and considered as a potential treatment for chemobrain.