An in vitro study of the effects of lovastatin on human fetal brain cells

We used various cultures of embryonic brain cells and a line of immortal astrocytes as in vitro model systems to study the direct effects of the hypolipidemic drug lovastatin on developing human CNS cells. Our data showed that pharmacological concentrations of the drug significantly affected growth and development of neuronal and astroglial cells in serum- and lipid-free media. Lovastatin at concentrations of 0.01-1000 ng/ml effectively inhibited intracellular cholesterol synthesis in primary and immortal astrocytes as well as in glial-neuronal reaggregated cultures. Primary astrocytes were more sensitive to minimal concentrations of the drug than their immortal counterparts and glial-neuronal aggregates. A concentration of 100 ng/ml of lovastatin significantly increased activity of LDL receptors both in primary and immortal astrocytes by about 100% and 50%, respectively (p < 0.001 and p < 0.01, respectively). Proliferation of immortal astrocytes in serum-free medium was entirely inhibited by 100 ng/ml of lovastatin. By contrast, a concentration of 5 ng/ml of lovastatin had no significant effect on cell proliferation. Long-term exposure of human brain explants to 100 ng/ml of lovastatin resulted in detrimental ultrastructural changes in neuronal and glial cells and led to cell death. Our data suggest that lovastatin is neurotoxic to developing brain cells and we propose that its in vivo adverse effects on the CNS may be attributed, at least in part, to its direct influence on human neurons and astrocytes as observed in vitro.