Attenuation of doxorubicin-induced oxidative damage in rat brain by regulating amino acid homeostasis with Astragali Radix

The nervous system disorders caused by doxorubicin (DOX) are among the severe adverse effects that dramatically reduce the quality of life of cancer survivors. Astragali Radix (AR), a popular herbal drug and dietary supplement, is believed to help treat brain diseases by reducing oxidative stress and maintaining metabolic homeostasis. Here we show the protective effects of AR against DOX-induced oxidative damage in rat brain via regulating amino acid homeostasis. By constructing a clinically relevant low-dose DOX-induced toxicity rat model, we first performed an untargeted metabolomics analysis to discover specific metabolic features in the brain after DOX treatment and AR co-treatment. It was found that the amino acid (AA) metabolism pathways altered most significantly. To accurately characterize the brain AA profile, we established a sensitive, fast, and reproducible hydrophilic interaction chromatography–tandem mass spectrometry method for the simultaneous quantification of 22 AAs. The targeted analysis further confirmed the changes of AAs between different groups of rat brain. Specifically, the levels of six AAs, including glutamate, glycine, serine, alanine, citrulline, and ornithine, correlated (Pearson |r| > 0.47, p < 0.05) with the brain oxidative damage that was caused by DOX and rescued by AR. These findings present that AAs are among the regulatory targets of DOX-induced brain toxicity, and AR is a promising therapeutic agent for it.