The PI3K-AKT-VEGF Signaling Pathway Contributes to Doxorubicin-induced Chemotherapy-related Cognitive Impairment

INTRODUCTION: Chemotherapy-related cognitive impairment (CRCI) has been identified as one of the primary adverse effects of chemotherapy. Doxorubicin (DOX) is an anthracycline chemotherapeutic agent recognized as a fundamental component of chemotherapy. Nevertheless, limited research has been conducted to elucidate the neurotoxic mechanisms of DOX-mediated CRCI. We investigated the neurotoxic mechanisms of DOX by utilizing network toxicology and transcriptomic methods. METHODS: DOX-induced CRCI animal models were successfully established. Spatial learning and memory were assessed using the Morris water maze (MWM) test. The levels of neuronal and synapserelated proteins in the cortex and hippocampus were detected. To elucidate the molecular mechanisms underlying DOX-induced neurotoxicity, an integrated approach combining network toxicology with transcriptomic profiling was employed. Lastly, the neurotherapeutic potential of LY294002 in relieving DOX-induced BBB disruption, neuronal cell loss, and cognitive impairment was evaluated. RESULTS: Our findings demonstrate that DOX induces spatial learning and memory deficits and promotes neuronal cell loss, primarily by disrupting the blood-brain barrier (BBB) via the PI3K-AKT signaling pathway. Notably, we identified a significant upregulation of vascular endothelial growth factor (VEGF) within astrocytes in mice following DOX exposure. DISCUSSION: Pharmacological inhibition of PI3K with LY294002 significantly reduced VEGF expression, mitigated BBB disruption and neuronal loss, and consequently alleviated DOX-associated cognitive impairment. CONCLUSION: DOX exerts neurotoxic effects by promoting VEGF oversecretion through the upregulation of the PI3K-AKT pathway. Inhibition of the PI3K-AKT pathway effectively mitigates these effects, thereby alleviating DOX-induced BBB disruption, neuronal cell loss, and cognitive impairment.