UC Irvine

Chemotherapy-related cognitive impairments (CRCI) are commonly reported during and after completion of chemotherapy treatment. CRCI includes changes across various cognitive domains such as working memory, executive function, attention, and processing speed. While up to 75% of cancer patients experience cognitive impairments during chemotherapy treatment, up to 34% of survivors experience long-term CRCI years after treatment completion. Clinical studies have found structural brain changes, including hippocampal atrophy, and reduction in gray and white matter density, which correlate with impaired cognitive function in the affected brain regions in cancer survivors following chemotherapy treatment. Earlier studies from our lab have examined the effects of cisplatin chemotherapy on cultured hippocampal neurons and neural stem/progenitor cells (NSCs) and found that at doses lower than those required to kill cancer cells, cisplatin induces severe hippocampal dendritic spine damage and neural cell death, suggesting that neural injury/death including a loss of excitatory synapses may underlie the cellular basis of cisplatin-induced CRCI.

Here we provide evidence for mitochondrial dysfunction as a candidate mechanism for cisplatin-induced CRCI, and the therapeutic potential of the antioxidant N-acetylcysteine to prevent cisplatin-induced neural damage and cognitive impairments in an adult rat model. Since cisplatin is used to treat pediatric as well as adult malignancies, and the risk and extent of cisplatin-induced CRCI on the developing brain have not been well characterized, we also developed two pediatric rat models of CRCI to examine the long-term effects of systemic cisplatin administration on cognitive function when administered during infancy or adolescence. We employed clinically relevant doses of cisplatin to develop our rat models of cisplatin-induced CRCI and used hippocampus-dependent behavioral tasks to assess neurocognitive function. Lastly, we developed an ovarian cancer xenograft rat model, in which we determined that delayed NAC administration could prevent cisplatin-induced CRCI without interfering with its anti-cancer efficacy.