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Methotrexate Neurotoxicity: In Vitro Studies Using Cerebellar Explants from Rats¹

Departments of Neurology [M. R. G., B. L. H.] and Oncology [S. A. G.], The Johns Hopkins Hospital, Baltimore, Maryland 21205

The mechanism of methotrexate (MTX)-induced neurotoxicity was investigated using cerebellar explant cultures from fetal rats. After 3 weeks of growth, myelinated cultures were treated with MTX at 1 µM, lysolecithin at 1 mg/dl, or unaltered nutrient medium. Myelin sheaths devoid of axons were observed by histological and electron microscopic preparations after 2 weeks of MTX exposure. After 5 weeks, cultures were almost entirely devoid of myelin sheaths. Myelin basic protein in the media removed from the cultures showed an increase in concentration after 3 weeks of MTX exposure and was significantly greater than control after 5 weeks of exposure. 2',3'-Cyclic nucleotide 3'-phosphohydrolase activity, a measure of oligodendroglial function, was not significantly different in the MTX group compared to controls. Lysolecithin-treated cultures showed widespread destruction and an early increase in myelin basic protein release into the medium. These data indicate that, in the cerebellar explant cultures, MTX is primarily a neuronal toxin, and the demyelination is a consequence of axonal loss and is not related to a change in oligodendroglial cell function. These findings provide new insight into the pathogenesis of MTX-induced neurotoxicity.

¹ Supported by grants from the Center for Alternatives to Animal Testing, Baltimore, MD, the Keck Foundation, and the American Cancer Society.

² To whom requests for reprints should be addressed, at Department of Neurology, Johns Hopkins Hospital, Meyer 1-130, 600 N. Wolfe St., Baltimore, MD 21205.

Received 8/15/88. Revised 12/12/88. Accepted 2/ 1/89.