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 immort al 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 significan tly affected growth and development of neuronal and astroglial cells i n serum- and lipid-free media. Lovastatin at concentrations of 0.01-10 00 ng/ml effectively inhibited intracellular cholesterol synthesis in primary and immortal astrocytes as well as in glial-neuronal reaggrega ted cultures. Primary astrocytes were more sensitive to minimal concen trations of the drug than their immortal counterparts and glial-neuron al aggregates. A concentration of 100 ng/ml of lovastatin significantl y increased activity of LDL receptors both in primary and immortal ast rocytes by about 100% and 50%, respectively (p < 0.001 and p < 0.01, r espectively). Proliferation of immortal astrocytes in serum-free mediu m was entirely inhibited by 100 ng/ml of lovastatin. By contrast, a co ncentration of 5 ng/ml of lovastatin had no significant effect on cell proliferation. Long-term exposure of human brain explants to 100 ng/m l of lovastatin resulted in detrimental ultrastructural changes in neu ronal and glial cells and led to cell death. Our data suggest that lov astatin is neurotoxic to developing brain cells and we propose that it s in vivo adverse effects on the CNS may be attributed, at least in pa rt, to its direct influence on human neurons and astrocytes as observe d in vitro.