Methotrexate neurotoxicity: in vitro studies using cerebellar explants from rats.
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 microM, 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.
Gilbert
M R
MR
Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland 21205.
Harding
B L
BL
Grossman
S A
SA
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000032:analysis; D000818:Animals; D002531:Cerebellum / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D046508:Culture Techniques; D008727:Methotrexate / Q000633:toxicity*; D004676:Myelin Basic Protein / Q000032:analysis; D009474:Neurons / Q000187:drug effects; D010727:Phosphoric Diester Hydrolases; D051381:Rats
D004676:Myelin Basic Protein; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D010727:Phosphoric Diester Hydrolases; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; C571339:Cnp protein, rat; D008727:Methotrexate