Acute high‐dose methotrexate neurotoxicity in the rat

Authors:
  • PPPeter C. Phillips
    Peter C. Phillips
  • HTHoward T. Thaler
    Howard T. Thaler
  • CBClaudia A. Berger
    Claudia A. Berger
  • MFMartin Fleisher
    Martin Fleisher
  • DRDavid A. Rottenberg
    David A. Rottenberg
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Abstract
Intravenous high‐dose methotrexate chemotherapy may produce acute, subacute, or chronic neurotoxicity in patients with cancer. Acute encephalopathies following high‐dose methotrexate treatment are recognized with increasing frequency. This study describes a model of acute high‐dose methotrexate neurotoxicity in the rat characterized by a profound dose‐dependent depression of cerebral glucose metabolism in association with behavioral and electroencephalographc abnormalities. Alterations in the amino acid profile, similar to those described in cancer patients after high‐dose methotrexate treatment, were observed in the absence of biochemical evidence of systemic organ toxicity. This model facilitates the study of the biochemical mechanisms of antifolate neurotoxicity in humans and permits the evaluation of potential therapeutic interventions.

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