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.

Radiation-induced gray matter atrophy in patients with nasopharyngeal carcinoma after intensity modulated radiotherapy: a MRI magnetic resonance imaging voxel-based morphometry study

“…In addition, the influence of chemotherapy cannot be excluded in extensive GM deficits. According to one previous study, platinum-based chemotherapy exposure reduced dendritic branching and spine volume, and induced apoptosis of neurons and NSC within the hippocampal formation (24). The alteration of GM volume was observed in breast cancer because some cytotoxic agents, mainly including 5-FU, thiotepa and cyclophosphamide, can cross over the blood brain barrier, and disrupt cell division in the brain regions that are critical for memory and learning (25).…”

Platinum‐induced peripheral neurotoxicity: From pathogenesis to treatment

“…Approximately 60% (range 26‐90%) children receiving cisplatin develop irreversible bilateral hearing loss, which may have a deleterious effect in their speech, language, and social skills . Cisplatin exposure has also been associated with cognitive dysfunction, the so‐called “chemo‐brain”, which is beyond the scope of this review …”

Doxorubicin-Induced Cognitive Impairment: The Mechanistic Insights

“…the brain, and several clinical studies reported that patients of all ages treated with doxorubicin exhibited impaired ability in cognitive assessments (10)(11)(12)(13).…”

“…In addition, doxorubicin causes the production of invasive systemic reactive oxygen species (ROS) ( 9 ). Notably, despite its limited passage through the blood-brain barrier (BBB), doxorubicin can still cause severe neurotoxicity in the brain, and several clinical studies reported that patients of all ages treated with doxorubicin exhibited impaired ability in cognitive assessments ( 10 – 13 ).…”