Domain-specific cognitive impairments following oxaliplatin and 5-fluorouracil treatment in rats: A preclinical study

The FOLFOX chemotherapy regimen, combining oxaliplatin (OXA), 5-fluorouracil (5-FU), and leucovorin (folinic acid), is a global standard of care for colon cancer. However, both clinical and preclinical evidence of the cognitive side effects associated with this treatment remains largely mixed. Therefore, this study aimed to investigate the direct effects of combined OXA and 5-FU treatment on executive function in female Sprague Dawley rats, comparing different dosing protocols. In Experiment 1, rats received three weekly doses of OXA (6 mg/kg, i.p.) and were tested on a delayed non-matching-to-sample (DNMTS) and the novel object recognition (NOR) tasks. OXA did not impair working memory but significantly impaired short-term recognition memory. Experiments 2 and 3 examined the effects of combined OXA and 5-FU treatment using different dosing regimens. Rats treated with two weekly doses of OXA (6 mg/kg, i.p.) and 5-FU (50 mg/kg, i.p.) exhibited significant deficits in set-shifting and spatial working memory but no impairments in reversal learning or recognition memory. Alternative regimens, including a single high-dose group (OXA 8 mg/kg + 5-FU 75 mg/kg) and a low-dose repeated group (OXA 6 mg/kg + 5-FU 50 mg/kg, spaced two weeks apart), produced minimal impairments, although the single-high dose group showed increased perseverative errors during set-shifting. These findings demonstrate that OXA and FOLFOX produce selective, domain-specific cognitive impairments in rats, with set-shifting and working memory particularly vulnerable to combined OXA and 5-FU treatment. These results highlight the need for targeted interventions to mitigate executive dysfunction in colorectal cancer survivors.