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Identification of region-specific amino acid signatures for doxorubicin-induced chemo brain
Peijia Liu1, Linling Guo2, Xinyue Yu2
1Department of Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150001, China.
Abstract:
Doxorubicin (DOX) is a cornerstone of chemotherapy for solid tumors and leukemias. DOX-induced cognitive impairment, termed chemo brain, has been reported in cancer survivors, whereas its mechanism remains poorly understood. Here we initially evaluated the cognitive impairments of mice treated with clinically relevant, long-term, low-dosage of DOX. Using HILIC-MS/MS-based targeted metabolomics, we presented the changes of 21 amino acids across six anatomical brain regions of mice with DOX-induced chemo brain. By mapping the altered amino acids to the human metabolic network, we constructed an amino acid-based network module for each brain region. We identified phenylalanine, tyrosine, methionine, and γ-aminobutyric acid as putative signatures of three regions (hippocampus, prefrontal cortex, and neocortex) highly associated with cognition. Relying on the reported mouse brain metabolome atlas, we found that DOX might perturb the amino acid homeostasis in multiple brain regions, similar to the changes in the aging brain. Correlation analysis suggested the possible indirect neurotoxicity of DOX that altered the brain levels of phenylalanine, tyrosine, and methionine by causing metabolic disorders in the liver and kidney. In summary, we revealed the region-specific amino acid signatures as actionable targets for DOX-induced chemo brain, which might provide safer treatment and improve the quality of life among cancer survivors.
Insights
Doxorubicin chemotherapy can cause cognitive impairment ("chemo brain"). This study identified specific amino acid changes in mouse brain regions, revealing potential targets for mitigating this side effect in cancer survivors.
Area of Science:
- Neuroscience
- Metabolomics
- Oncology
Background:
- Doxorubicin (DOX) is a vital chemotherapy drug for various cancers.
- DOX-induced cognitive impairment, or "chemo brain," is a concern for cancer survivors, but its mechanisms are unclear.
- Understanding DOX's neurotoxic effects is crucial for improving patient quality of life.
Purpose of the Study:
- To investigate the cognitive effects of long-term, low-dose DOX treatment in mice.
- To identify specific metabolic changes in the brain associated with DOX-induced cognitive impairment.
- To explore the relationship between DOX treatment, brain amino acid profiles, and potential organ-specific metabolic disruptions.
Main Methods:
- Mice were treated with clinically relevant, long-term, low-dose DOX.
- Targeted metabolomics using HILIC-MS/MS was employed to analyze amino acid levels in six brain regions.
- Altered amino acid data were mapped to metabolic networks and compared with existing brain metabolome atlases.
Main Results:
- DOX treatment induced cognitive impairments in mice.
- Significant alterations in 21 amino acids were observed across different brain regions.
- Phenylalanine, tyrosine, methionine, and gamma-aminobutyric acid were identified as key signatures in cognition-associated brain regions.
- DOX treatment appeared to disrupt amino acid homeostasis in the brain, mirroring changes seen in aging.
- Correlation analysis suggested indirect neurotoxicity mediated by liver and kidney metabolic disturbances.
Conclusions:
- Region-specific amino acid signatures were identified as potential biomarkers for DOX-induced chemo brain.
- These findings offer actionable targets for developing safer chemotherapy strategies.
- Mitigating DOX's metabolic effects could improve cognitive function and quality of life for cancer survivors.
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