INHIBITION OF P42 P44 MITOGEN-ACTIVATED PROTEIN-KINASE BY OXYSTEROLS IN RAT ASTROCYTE PRIMARY CULTURES AND C6 GLIOMA CELL-LINES/

We previously demonstrated that oxysterols inhibit the growth of exper imental glioblastoma induced in the rat brain cortex, Mechanism of act ion of these compounds remains obscure. In this study, we investigated the effect of 7 beta-hydroxycholesterol (7 beta-OHCH) and 7ketocholes terol (7k-CH) on the growth and MAP kinase activity in three in vitro biological models: rat astrocyte primary cultures, primary cultures tr eated by dibutyryl-cAMP (reactive cells), and the C6 glioma cell line. The oxysterols are not lethal to primary astrocytes, even if MAP kina se activity is decreased, particularly when cells were treated with 7k -CH, Both oxysterols are toxic to reactive astrocytes, and as compared with untreated primary cultures, they amplified the MAP kinase activi ty decrease. However, the mechanism of action of oxysterols on reactiv e astrocytes seems not to be linked to the MAP kinase pathway, In high ly proliferating C6 cell lines, only 7 beta-OHCH has an antiproliferat ive effect and is cytotoxic. The inhibition of MAP kinase activity is a function of 7 beta-OHCH concentration. PD098059, a MAP kinase pathwa y inhibitor, has only a time-limited antiproliferative effect on C6 ce ll growth. We conclude that in C6 cells, the MAP kinase activity decre ase is correlated with the toxic effect of 7 beta-OHCH and occurs at f irst stages of 7 beta-OHCH action. J, Neurosci, Res. 53:38-50, 1998, ( C) 1998 Wiley-Liss, Inc.