NEUROFUNCTIONAL IMPACT OF HYPER-CVAD REGIMEN IN JUVENILE MICE AND EVALUATION OF THERAPEUTIC INTERVENTIONS

Chemotherapy-induced cognitive impairment (CICI) is a frequent and debilitating complication of cancer treatment, particularly affecting pediatric and adolescent patients during critical periods of brain development. Hyper-CVAD, a widely used multi-agent chemotherapy regimen for hematological malignancies, has been increasingly associated with persistent cognitive dysfunction; however, its underlying neurobiological mechanisms and potential therapeutic strategies remain poorly understood.

In this study, we established a juvenile mouse model of Hyper-CVAD–induced neurofunctional impairment to investigate cognitive consequences during adolescent brain maturation. Behavioral assessments were combined with histological and molecular analyses to characterize chemotherapy-associated deficits. Hyper-CVAD treatment resulted in pronounced cognitive impairments accompanied by alterations in white matter integrity, enhanced neuroinflammatory responses, increased oxidative stress, and dysregulation of synaptic plasticity–related signaling pathways.

To explore potential interventions, we evaluated the therapeutic effects of environmental enrichment using a Marlau cage, as well as pharmacological treatment with methylphenidate, in Hyper-CVAD–treated mice. Both interventions were assessed for their ability to alleviate cognitive deficits and modulate neuroimmune and neuroplasticity-related mechanisms, including BDNF–TrkB signaling.

Together, these findings demonstrate that Hyper-CVAD induces robust neurofunctional and neuroimmune alterations during juvenile development and that both environmental and pharmacological interventions can partially restore cognitive function. This work provides mechanistic insight into CICI and supports the development of targeted therapeutic strategies to mitigate chemotherapy-related cognitive impairment in pediatric oncology.