EFFECT OF OXYSTEROL TREATMENT ON CHOLESTEROL-BIOSYNTHESIS AND REACTIVE ASTROCYTE PROLIFERATION IN INJURED RAT-BRAIN CORTEX

We have reported previously that oxysterols inhibit astrogliosis and i ntracranial glioblastoma growth. To elucidate the mechanism of action of these molecules in vivo, we have investigated their effect on the c holesterol biosynthesis in the injured brain. In a bilateral lesion mo del, injection of liposomes containing 7 beta-hydroxycholesterol decre ased [H-3]acetate incorporation into neutral lipids and cholesterol by 30% and 40%, respectively. Structural analogues were tested using a u nilateral lesion model. The injury did not significantly affect choles terogenesis; injection of 7 beta-hydroxycholesterol or 7 beta-hydroxyc holesteryl-3-oleate reduced acetate incorporation into cholesterol by 47% and 43%, respectively. Both 7-ketocholesteryl-3-oleate and 7 alpha -hydroxycholesteryl-3-oleate inhibited cholesterogenesis by 32%. As ch olesterol and by-products of the cholesterol pathway play a key role i n cell division, we have assessed the effect of oxysterols on reactive astrocyte proliferation. The incorporation of bromodeoxyuridine showe d that up to 46% of astrocytes were proliferating 24 h after the injur y. Injection of 12 nmol of 7 beta-hydroxycholesterol or 7 beta-hydroxy cholesteryl-3-oleate reduced the labelling index to 26%, whereas the l abelling index in the 7-ketocholesteryl-3-oleate-treated cortex was 37 %. These findings demonstrate that oxysterols are potent inhibitors of the endogenous cholesterol biosynthesis in brain and show a correlati on between cholesterogenesis and reactive astrocyte proliferation.