title: Systemic cisplatin exposure during infancy and adolescence causes impaired cognitive function in adulthood.
abstract: Cancer survivors diagnosed during infancy and adolescence may be at risk for chemotherapy-related cognitive impairments (CRCI), however the effects of pediatric chemotherapy treatment on adulthood cognitive function are not well understood. Impairments in memory, attention and executive function affect 15-50% of childhood leukemia survivors related to methotrexate exposure. Systemic cisplatin is used to treat a variety of childhood and adult cancers, yet the risk and extent of cognitive impairment due to platinum-based chemotherapy in pediatric patients is unknown. Systemic cisplatin penetrates the CNS, induces hippocampal synaptic damage, and leads to neuronal and neural stem/progenitor cell (NSC) loss. Survivors of non-leukemic cancers may be at risk for significant cognitive impairment related to cisplatin-driven neurotoxicity. We sought to examine the long-term effects of systemic cisplatin administration on cognitive function when administered during infancy and adolescence in a rat model. We performed cognitive testing in adult rats exposed to systemic cisplatin during either infancy or adolescence. Rats treated as adolescents showed significantly poor retrieval of a novel object as compared to controls. Further, cisplatin-treated infants and adolescents showed poor contextual discrimination as compared to controls, and an impaired response to cued fear conditioning. Ultimately, systemic cisplatin exposure resulted in more profound impairments in cognitive function in rats treated during adolescence than in those treated during infancy. Further, exposure to cisplatin during adolescence affected both hippocampus and amygdala dependent cognitive function, suggesting a more global cognitive dysfunction at this age.
authors.affiliation: University of California, Irvine/CHOC Children's Hospital, 1201W. La Veta Avenue, Orange, CA 92868, USA. Electronic address: tamidjohn@gmail.com.
authors.forename: Tami
authors.initials: T
authors.lastname: John
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: nrlomeli@uci.edu.
authors.forename: Naomi
authors.initials: N
authors.lastname: Lomeli
authors.affiliation: Department of Neurology, Department of Neurological Surgery, Chao Family Comprehensive Cancer Center, University of California, Sprague Hall B200, Irvine, CA, 92697-4775, USA. Electronic address: dbota@uci.edu.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Bota
mesh_terms: D000367:Age Factors; D000375:Aging / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D003072:Cognition Disorders / Q000139:chemically induced*; D003213:Conditioning, Psychological / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin
keywords: Chemotherapy-related cognitive impairment (CRCI); Cisplatin (CDDP); Memory; Pediatric