Abstract Because of major advancements in cancer treatment especially chemotherapy, 85% of children with cancer are predicted to survive for 5 years or more. However, chemotherapy can cause long-term health problems when childhood cancer survivors enter adulthood (late effects). The neurocognitive features of these late effects (chemobrain) include trouble in concentrating, memorizing, decreased processing speed, slower development over time, etc. To gain a better understanding of the mechanism underlying pediatric chemotherapy-induced cognitive impairments, we developed a pre-clinical model using carboplatin (commonly used to treat pediatric CNS tumors, ovarian and lung cancer) in juvenile mice to study long-term neurological defects. The puzzle box test was used to evaluate mouse executive function. Immunohistochemistry (IHC) and single nuclear RNA sequencing (snRNAseq) were performed to identify cellular and molecular contributors, followed by assays that evaluate mitochondrial function. Our result demonstrated dose-dependent deficits in executive function 7-9 weeks after carboplatin administration in mice of both sexes. IHC performed in hippocampus, the critical region involved in executive function, revealed astrocyte atrophy after carboplatin treatment. Further snRNAseq analysis in hippocampus revealed changes in the expression of genes associated with mitochondrial function in astrocytes, but not neurons, yet seahorse assay performed in brain synaptosomes revealed neuronal mitochondria function deficits following carboplatin treatment. The preliminary rescue data showed a trend towards the reversal of carboplatin-induced deficits in executive function by Urolithin A, an mitophagy inducer. As astrocytes can supply healthy mitochondria to neurons, we hypothesize that carboplatin-induced mitochondrial deficits in astrocytes may inhibit astrocyte-to-neuron mitochondria supply, and that promoting clearance of dysfunctional mitochondria accelerates neuronal recovery. This study established a preclinical model that can be leveraged to mechanistically understand the long-term neurotoxicity of chemotherapy among children. Further studies will aim to pinpoint the underlying mechanisms and therapeutic targets.
Singh et al. (Fri,) studied this question.