KU32 prevents 5-fluorouracil induced cognitive impairment

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Chemotherapy induced cognitive impairment (i.e. chemobrain) involves acute and long-term deficits in memory, executive function, and processing speed. Animal studies investigating these cognitive deficits have had mixed results, potentially due to variability in the complexity of behavioral tasks across experiments. Further, common chemotherapy treatments such as 5-fluorouracil (5-FU) break down myelin integrity corresponding to hippocampal neurodegenerative deficits and mitochondrial dysfunction. There is little evidence, however, of pharmacological treatments that may target mitochondrial dysfunction. Using a differential reinforcement of low rates (DRL) task combining spatial and temporal components, the current study evaluated the preventative effects of the pharmacological agent KU32 on the behavior of rats treated with 5-FU (5-FU + Saline vs. 5FU + KU32). DRL performance was analyzed the day after the first set of injections (D1), the day after the second set of injections (D7) and the last day of the experiment (D14). The 5FU + KU32 group earned significantly more reinforcers on the DRL task at D7 and D14 than the 5FU + Saline group. Further, the 5FU + KU32 group showed significantly better temporal discrimination. The 5FU + KU32 showed within-group improvement in temporal discrimination from D7 to D14. No significant differences were observed in spatial discrimination, however, those in the 5FU + Saline group responded more frequently on T3 compared to the 5FU + KU32 group, highlighting temporal discrimination differences between groups. The current data suggest that KU32 shows promise in the prevention of chemotherapy induced impairments in temporal discrimination.HIGHLIGHTSEffects of 5FU chemobrain were tested using a novel spatial DRL paradigm.Preventative effects of KU32 with 5FU were compared to 5FU with Saline.Temporal discrimination was worse in rats receiving 5FU + Saline than 5FU + KU32.The 5FU + KU32 group showed within-group improvement in temporal discrimination.Spatial discrimination differences were not observed between the groups.

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