CNSC-13. UNDERSTANDING LONG-TERM COGNITIVE SIDE EFFECTS OF PEDIATRIC BRAIN TUMOR CHEMOTHERAPY AND THERAPEUTIC MITIGATION VIA ENHANCED MITOPHAGY

Abstract Advances in cancer treatment have raised the survival rate of children with brain tumors to 75.5%. However, treatments can lead to long-term side effects, including chemotherapy-induced cognitive impairments (CICI). The mechanisms behind pediatric brain tumor-associated CICI are poorly understood, and no FDA-approved treatments exist to prevent or reverse them. We developed a preclinical model by administering carboplatin to 3-week-old juvenile mice. Cognitive function was assessed using the puzzle box test (PBT, executive function) and novel object place recognition test (NOPRT, working memory/attention). For cellular and molecular mechanisms, we conducted single-nucleus RNA sequencing, immunohistochemistry, and Seahorse assay. Two months after cessation of juvenile carboplatin exposure, mice exhibited deficits in PBT and NOPRT, indicating enduring cognitive impairments. We noted a reduction in astrocyte density and morphological complexity in the hippocampus of these mice, while the densities of microglia and oligodendroglia remained unchanged. Further transcriptomic analyses revealed that juvenile exposure to carboplatin disrupts mitochondrial pathways in hippocampal astrocytes but not in neurons. Supporting the in vivo findings, carboplatin decreased the number of human hippocampal astrocytes and lowered their mitochondrial oxygen consumption rate in vitro. Given that astrocytes can exchange mitochondria with neurons to support synaptic communication, we isolated synaptosomes to evaluate mitochondrial function. The results indicate that juvenile carboplatin exposure also compromises synaptic mitochondrial function. To counteract the mitochondrial deficits in both astrocytes and neurons, we administered urolithin A, a mitophagy-inducing compound, to juvenile carboplatin-exposed mice in adulthood. Urolithin A alleviated the cognitive and mitochondrial deficits caused by carboplatin. Additionally, urolithin A exhibited an inhibitory effect on the growth of medulloblastoma cells in vitro, suggesting a potential strategy for alleviating CICI in medulloblastoma survivors. Our findings reveal that juvenile carboplatin exposure impairs hippocampal astrocyte mitochondria and cognitive function, which can be alleviated by administering a mitophagy enhancer.