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.

Keywords: Chemotherapy-related cognitive impairment (CRCI); Cisplatin (CDDP); Memory; Pediatric.

Fig. 1. Experimental Design

Rats received CDDP (2 mg/kg/day) for five consecutive days at P25–P29 (infancy) or P35–P39 (adolescence). Age-matched controls received 0.9% saline of similar volume. Cognitive testing was completed during adulthood, including novel object recognition (NOR) at P65–P70, context object discrimination (COD) at P75–P78, and fear conditioning (FC) at P93–P94.

Fig. 2. Novel Object Recognition

During NOR testing all groups showed similar total exploration times (A). As expected, control (n = 13) and CDDP-P25 (n = 13) rats explored a novel object (NO) significantly more than a familiar object **p < 0.005 and *p < 0.02; however, exploration between objects for the CDDP-P35 (n = 13) rats was not different (B). Error bars are SEM.

Fig. 3. Context Object Discrimination

During COD testing all groups showed similar total exploration times (A). As expected, control (n = 10) rats explored an out-of-context object significantly more than a familiar object; (***p = 0.001); however, exploration between objects for the CDDP-P25 (n = 10) and CDDP-P35 (n = 10) rats was not different (B). Error bars are SEM.

Fig. 4. Fear Conditioning

Schematic of Fear Conditioning paradigm (A). During context and cued fear conditioning both CDDP-P25 (n = 10) and CDDP-P35 (n = 10) rats showed a trend toward decreasing freezing response during the context test (p = 0.14 and p = 0.17) as compared to controls (n = 7). During the Cue and post-Cue Test, CDDP-P25 rats showed significant decrease in freezing (***p < 0.001). During the Cue Test, CDDP-P35 rats showed significant decreased freezing response (*p < 0.05) which persisted to a lesser degree in the Post–Cue Test (p = 0.06) (B). Error bars are SEM.