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 intracranial glioblastoma growth. To elucidate the mechanism of action of these molecules in vivo, we have investigated their effect on the cholesterol biosynthesis in the injured brain. In a bilateral lesion model, injection of liposomes containing 7 beta-hydroxy-cholesterol decreased [3H]acetate incorporation into neutral lipids and cholesterol by 30% and 40%, respectively. Structural analogues were tested using a unilateral lesion model. The injury did not significantly affect cholesterogenesis; injection of 7 beta-hydroxycholesterol or 7 beta-hydroxycholesteryl-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 cholesterol and by-products of the cholesterol pathway play a key role in cell division, we have assessed the effect of oxysterols on reactive astrocyte proliferation. The incorporation of bromodeoxyuridine showed that up to 46% of astrocytes were proliferating 24 h after the injury. Injection of 12 nmol of 7 beta-hydroxycholesterol or 7 beta-hydroxycholesteryl-3-oleate reduced the labelling index to 26%, whereas the labelling index in the 7-keto-cholesteryl-3-oleate-treated cortex was 37%. These findings demonstrate that oxysterols are potent inhibitors of the endogenous cholesterol biosynthesis in brain and show a correlation between cholesterogenesis and reactive astrocyte proliferation.
Bochelen
D
D
CNRS UPR 416, Laboratoire de Neurobiologie Moléculaire des Interactions Cellulaires, Strasbourg, France.
Mersel
M
M
Behr
P
P
Lutz
P
P
Kupferberg
A
A
D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002540:Cerebral Cortex / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000096:biosynthesis*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006888:Hydroxycholesterols / Q000494:pharmacology*; D007150:Immunohistochemistry; D007653:Ketocholesterols / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D005904:Glial Fibrillary Acidic Protein; D006888:Hydroxycholesterols; D007653:Ketocholesterols; C085947:7-hydroxycholesteryl-3-oleate; C096407:7-ketocholesteryl-3-oleate; C011724:cholest-5-en-3 beta,7 alpha-diol; D002784:Cholesterol; D001973:Bromodeoxyuridine