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Il-6 knockout reduces doxorubicin-induced toxicity in the developing mouse brain.
Jonas Yeung1, Henry Quach2, Amy P Wong2
1Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Brain, Behavior, and Immunity
|June 30, 2025
Summary
Doxorubicin (DXR) chemotherapy causes brain volume loss in mice, partly by increasing IL-6. Targeting IL-6 may reduce DXR
Area of Science:
- Neuroscience
- Oncology
- Immunology
Background:
- Doxorubicin (DXR) chemotherapy is associated with cognitive impairments in cancer patients, particularly pediatric survivors.
- DXR's limited blood-brain barrier penetration suggests indirect systemic mechanisms mediate its neurotoxicity.
- Pro-inflammatory cytokines are implicated as potential mediators of DXR-induced neurotoxicity.
Purpose of the Study:
- To investigate cytokine level changes following DXR treatment in a pediatric cancer mouse model.
- To evaluate the impact of DXR on brain toxicity, focusing on the role of IL-6.
- To assess DXR's effects on brain volume and neuroinflammation using genetic knockout approaches.
Main Methods:
- Mice received DXR at a childhood-equivalent age (P17, P19) and were analyzed at P20.
- Cytokine levels (IL-6) were measured in plasma and brain tissue.
- Longitudinal in vivo MRI tracked brain volume changes; histological analysis examined neuroinflammation (CD68).
Main Results:
- DXR treatment significantly elevated IL-6 levels in plasma and brain tissue.
- Widespread brain volume reductions were observed post-DXR treatment.
- IL-6 knockout mice showed partial rescue of brain volume loss and reduced microglial activation (CD68).
Conclusions:
- IL-6 plays a significant role in DXR-induced brain toxicity, potentially mediating neurotoxicity despite limited blood-brain barrier penetration.
- Targeting IL-6 may offer a strategy to mitigate chemotherapy-induced structural brain changes and associated cognitive deficits in cancer survivors.
- This study highlights IL-6 as a therapeutic target for managing neurotoxic side effects of DXR chemotherapy.
