Vincristine-induced brain toxicity is reduced with prevention of peripheral axon degeneration in Sarm1 knockout mice

Vincristine is an essential chemotherapy agent administered for various pediatric cancers including acute lymphoblastic leukemia (ALL). While multi-agent chemotherapy for pediatric ALL is highly curative, with survival approaching 95%, it carries the risk of irreversible neurocognitive late effects. Vincristine is known to cause peripheral neuropathy, but its relationship to brain toxicity remains understudied. We investigated vincristine-mediated brain toxicity in young mice lacking Sarm1, a gene whose deletion protects against vincristine-induced peripheral neuropathy. Littermate wildtype and knockout mice were randomly assigned to saline or vincristine groups. In vivo MRI was performed from childhood to early adulthood to measure brain structure volumes, followed by ex vivo diffusion tensor imaging (DTI) to assess microstructural changes. In a separate cohort, electron microscopy (EM) quantified axon morphology in the sciatic nerve and corpus callosum. Vincristine induced significant volume reduction across the brain, while Sarm1 knockout reduced loss in both grey and white matter. Several regions, including the amygdala and dentate gyrus, showed near-complete recovery in knockouts. DTI revealed limited changes with no genotype differences. EM demonstrated vincristine-induced axon morphology alterations in wildtype mice in both the sciatic nerve and corpus callosum. Sarm1 knockout rescued sciatic nerve morphology but not corpus callosum axons. These findings suggest that SARM1-mediated peripheral axon damage may contribute to vincristine-induced brain volume deficits, whereas brain axons may be affected through distinct, SARM1-independent mechanisms. These results suggest a link between vincristine-induced peripheral axon damage and alterations in brain development, with implications for neurocognitive deficits experienced by ALL survivors. Our results suggest that mitigating vincristine-induced peripheral neuropathy may also help reduce neurocognitive deficits in pediatric patients undergoing vincristine treatment.