title: KU32 prevents 5-fluorouracil induced cognitive impairment.
abstract: 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.
authors.affiliation: Department of Applied Behavioral Science, University of Kansas, 4041 Dole Developmental Center, 1000 Sunnyside Ave., Lawrence, KS 66045, USA. Electronic address: sofis@ku.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sofis
authors.affiliation: Department of Applied Behavioral Science, University of Kansas, 4041 Dole Developmental Center, 1000 Sunnyside Ave., Lawrence, KS 66045, USA. Electronic address: dpj@ku.edu.
authors.forename: David P
authors.initials: DP
authors.lastname: Jarmolowicz
authors.affiliation: Department of Chemistry, University of Kansas, 2919 Malott Hall, 1251 Wescoe Hall Dr., Lawrence, KS 66045, USA.
authors.forename: Sam V
authors.initials: SV
authors.lastname: Kaplan
authors.affiliation: Department of Chemistry, University of Kansas, 2919 Malott Hall, 1251 Wescoe Hall Dr., Lawrence, KS 66045, USA.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Gehringer
authors.affiliation: Department of Applied Behavioral Science, University of Kansas, 4041 Dole Developmental Center, 1000 Sunnyside Ave., Lawrence, KS 66045, USA.
authors.forename: Shea M
authors.initials: SM
authors.lastname: Lemley
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, 4070 Malott Hall, 1251 Wescoe Hall Dr., Lawrence, KS 66045, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Garg
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, 4070 Malott Hall, 1251 Wescoe Hall Dr., Lawrence, KS 66045, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Blagg
authors.affiliation: Department of Chemistry, University of Kansas, 2919 Malott Hall, 1251 Wescoe Hall Dr., Lawrence, KS 66045, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Johnson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced* / Q000517:prevention & control*; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000633:toxicity*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009675:Novobiocin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; C581040:KU-32 compound; D018696:Neuroprotective Agents; D009675:Novobiocin; D005472:Fluorouracil
keywords: Chemobrain; Cognitive impairment; Inhibition; KU32; Temporal discrimination; Timing