Abstract #0739

IL-6 knockout reduces doxorubicin-induced neurotoxicity

Jonas Yeung^1,2, Rosanna Weksberg³, Sharon L Guger⁴, Russell Schachar⁵, Shinya Ito⁶, and Brian Nieman^1,2

¹Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada, ²Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada, ³Departments of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada, ⁴Psychology Department, The Hospital for Sick Children, Toronto, ON, Canada, ⁵Department of Psychiatry, The Hospital for Sick Children, Toronto, ON, Canada, ⁶Division of Clinical Pharmacology & Toxicology, The Hospital for Sick Children, Toronto, ON, Canada

Synopsis

Keywords: Neuroinflammation, Cancer, chemotherapy, treatment, late effects, pediatric, development

Motivation: Doxorubicin (DXR) is a widely used chemotherapy agent associated with inflammation and neurocognitive impairment in cancer survivors. Given that DXR has limited access to the brain, indirect mechanisms, such as the generation of systemic pro-inflammatory cytokines, are proposed to induce neurotoxicity and neuroinflammation.

Goal(s): This study aims to probe this hypothesized pro-inflammatory pathway of DXR-induced neurotoxicity.

Approach: We identified an elevation of the pro-inflammatory cytokine IL-6 in DXR-treated mice. Consequently, we utilized MRI to assess neuroanatomical changes after DXR treatment in wildtype and Il-6 knockout mice.

Results: Our findings revealed that Il-6 knockout partially mitigated the neurotoxic effects induced by DXR.

Impact: DXR leads to cognitive impairment that diminishes quality of life for cancer survivors. We demonstrated the involvement of IL-6 in the neurotoxic mechanism of DXR, suggesting a strategy for targeting IL-6 to limit neurotoxicity of cancer treatments.

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