High-dose leucovorin reverses acute high-dose methotrexate neurotoxicity in the rat

Authors

  • Dr. Peter C. Phillips MD,

    Corresponding author
    1. Department of Neurology Memorial Sloan-kettering Cancer Center, New York, NY
    2. Department of Pediatrics Memorial Sloan-kettering Cancer Center, New York, NY
    • Department of Neurology, The Johns Hopkins Hospital, 600 North Wolfe St, Baltimore, MD 21205
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  • H. Tzvi Thaler PhD,

    1. Department of Biostatistics Laboratory, Memorial Sloan-kettering Cancer Center, New York, NY
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  • Jeffrey C. Allen MD,

    1. Department of Neurology Memorial Sloan-kettering Cancer Center, New York, NY
    2. Department of Pediatrics Memorial Sloan-kettering Cancer Center, New York, NY
    Current affiliation:
    1. New York University Medical Center, 550 1st Ave, New York, NY 10016
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  • David A. Rottenberg MD

    1. Department of Neurology Memorial Sloan-kettering Cancer Center, New York, NY
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Abstract

Intravenous high-dose methotrexate (HD-MTX) reduces cerebral glucose metabolism and produces behavioral abnormalities and electroencephalographic slowing in an animal model of acute HD-MTX neurotoxicity and in cancer patients undergoing HD-MTX chemotherapy. We used our model of HD-MTX neurotoxicity in the rat to determine if leucovorin (5-formyltetrahydrofolate) reduces this neurotoxicity, and extended our characterization of this model to identify regional as well as global HD-MTX treatment effects and to investigate HD-MTX-induced alterations in regional brain pH. Intravenous high-dose leucovorin reversed the HD-MTX-induced decrease in cerebral glucose metabolism and associated behavioral and electroencephalographic abnormalities in the rat, but low-dose leucovorin was ineffective. The major effect of HD-MTX on cerebral glucose metabolism was a global reduction; however, smaller region-specific treatment effects were identified in auditory, thalamic, and white matter structures. HD-MTX did not alter regiona brain pH. These findings suggest a potential clinical role for high-dose leucovorin in severe or prolonged acute HD-MTX neurotoxicity and provide an important justification for the role of positron emission tomography in the early detection of clinical HD-MTX neurotoxicity.

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