Choroid plexus-CSF-targeted antioxidant therapy protects the brain from toxicity of cancer chemotherapy

Neuron. 2022 Oct 19;110(20):3288-3301.e8. doi: 10.1016/j.neuron.2022.08.009. Epub 2022 Sep 6.


For many cancer patients, chemotherapy produces untreatable life-long neurologic effects termed chemotherapy-related cognitive impairment (CRCI). We discovered that the chemotherapy methotrexate (MTX) adversely affects oxidative metabolism of non-cancerous choroid plexus (ChP) cells and the cerebrospinal fluid (CSF). We used a ChP-targeted adeno-associated viral (AAV) vector approach in mice to augment CSF levels of the secreted antioxidant SOD3. AAV-SOD3 gene therapy increased oxidative defense capacity of the CSF and prevented MTX-induced lipid peroxidation in the hippocampus. Furthermore, this gene therapy prevented anxiety and deficits in short-term learning and memory caused by MTX. MTX-induced oxidative damage to cultured human cortical neurons and analyses of CSF samples from MTX-treated lymphoma patients demonstrated that MTX diminishes antioxidant capacity of patient CSF. Collectively, our findings motivate the advancement of ChP- and CSF-targeted anti-oxidative prophylactic measures to relieve CRCI.

Keywords: CSF; CSF metabolomics; SOD3; antioxidants; chemotherapy-induced cognitive impairment; choroid plexus; metabolite profiling; methotrexate; neurotoxicity; oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants* / pharmacology
  • Antioxidants* / therapeutic use
  • Choroid Plexus
  • Hippocampus
  • Humans
  • Methotrexate / toxicity
  • Mice
  • Neoplasms* / chemically induced
  • Oxidative Stress


  • Antioxidants
  • Methotrexate