Hyperbaric Oxygen as Potential Treatment for Chemotherapy-Related Cognitive Impairments

Purpose: “Chemobrain”, characterized by impaired attention, learning and memory retention, is a prevalent condition affecting approximately 75% of patients undergoing cancer treatments. Chemotherapy-related cognitive impairment (CRCI), a subtype of “chemobrain”, can persist for up to 20 years post-treatment, significantly diminishing the daily quality of life for survivors and caretakers. Very few interventions are available to alleviate the effects of chemotherapy on the brain. One potential treatment is hyperbaric oxygen therapy (HBOT), which has shown neuroprotective effects in conditions such as Alzheimer’s disease, traumatic brain injury, and stroke. The current study investigated the effects of HBOT on cognitive impairments induced by commonly used chemotherapeutic agents, and studied the underlying mechanisms with a focus on cellular senescence.

Methods: Four-month-old male and female C57BL/6 mice were injected (i.p.) with saline or chemotherapeutic cocktails (Methotrexate (37.5 mg/kg) + 5-Fluorouracil (50 mg/kg)) once a week for three weeks. Simultaneously, half of the mice underwent daily HBOT session (2.4 ATM for 90 min). Morris water maze was used to measure spatial learning and memory. Hippocampus was evaluated for markers of cellular senescence using western blot analyses.

Results: Chemotherapy exposure impaired spatial learning and memory, which was attenuated by HBOT in male mice only. The exposure was also associated with increased levels of p16INK4a, ɣH2AX, and b-galactosidase (cellular senescence markers), and increased levels of cleaved-Lamin B1 (a surrogate marker of caspase-6 activity relating to apoptosis) in male hippocampus. HBOT seemed to reduce the effects of chemotherapy on ɣH2AX, b-galactosidase, and cleaved-Lamin B1, but not on p16INK4a in males.

Conclusion: HBOT reduced cognitive impairments associated with chemotherapy exposure. Interestingly, females were not impaired by the chosen chemotherapeutic cocktail. Cellular senescence and apoptosis may play a role in the beneficial effects of HBOT.