A model of methotrexate encephalopathy: neurotransmitter and pathologic abnormalities

Methotrexate may cause seizures, dementia, and leukoencephalopathy when given in toxic doses to children with leukemia or solid tumors. Even in therapeutic doses, treatment with this drug is associated with an increased incidence of seizures in children with leukemia. To study mechanisms of injury, juvenile rats were given multiple intraventricular injections of methotrexate and the brains were analyzed for histopathology and biogenic amine metabolites of dopamine and serotonin. Disruption of monoamine metabolism has been proposed as a cause of brain dysfunction from this chemotherapy. Multiple injections (1 or 2 mg/kg) produced convulsions in an increasingly larger percentage of animals at higher cumulative doses, and five doses produced the neuropathological changes seen in human leukoencephalopathy. A single dose reduced the concentration of brain metabolites of dopamine, but not serotonin, six hours later. The effect was less pronounced after five doses. This rodent model should be useful for studying the metabolic basis of methotrexate encephalopathy.