Reduction of Cholesterol Synthesis by Methylxanthines in Cultured Glial Cells

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Abstract
Summary: Methylxanthines are shown in this study to decrease cholesterol synthesis in cultured C-6 glial cells. Aminophylline (10−3M) produced a rapid decline in cholesterol synthesis so that by 6 hr, synthesis in treated cells was less than 20% of that in untreated cells, and by 24 hr, less than 10%. Aminophylline induced parallel changes in 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity, the rate-limiting enzyme in cholesterol synthesis. Theophylline and caffeine produced similar effects. Thus, methyxanthines caused a specific, enzyme-mediated reduction in cholesterol synthesis in C-6 glia. In an attempt to relate the methylxanthines' effect on cultured glial cells to the developing nervous system, cholesterol synthesis was studied in the presence of 10−4M aminophylline. This represents a theophylline concentration in the culture medium that is of the same order of magnitude as that produced in whole brain of animals administered therapeutic doses of aminophylline. Under these conditions, cholesterol synthesis was reduced to approximately 60% of control after 48 and 72 hr. Speculation: Cholesterol is the major lipid constituent of myelin and other cell membranes and reduction in synthesis of this lipid could have deleterious effects. C-6 glia are models of the glial stem cell found in developing brain before myelination, e.g., human brain in the perinatal period. This study raises the question whether serious reductions in brain cholesterol synthesis occur in vivo during the treatment of neonatal apnea.