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

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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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