Statins with a closed-ring structure (
mevastatin,
lovastatin, and
simvastatin) and with an open-ring structure (
pravastatin and
fluvastatin) are widely used in the human population to manage
hypercholesterolemia. These
statins may have neuroprotective or neurotoxic effects, but these effects remain controversial. We have utilized
adenosine 3',5'-cyclic monophosphate-induced terminally differentiated murine
neuroblastoma (NB) cells in culture as an experimental model to study the effect of
statins. Results showed that
mevastatin induced degenerative changes and reduced the viability of differentiated NB cells by inhibiting
proteasome activity.
Lactacystin, an established inhibitor of
proteasome, also produced similar degenerative changes in these cells. In contrast,
pravastatin neither affected the degeneration and viability of differentiated NB cells nor the
proteasome activity. High-performance liquid chromatography (HPLC) analysis of the extract obtained from
mevastatin-treated growth medium and differentiated cells revealed that about 50% of
mevastatin is converted to an open-ring structure in the growth medium; however, differentiated cells did not convert any portion of
mevastatin into an open-ring structure and accumulated only
mevastatin with a closed-ring structure.
Mevalonic acid lactone by itself did not affect the viability of differentiated NB cells or the
proteasome activity, but it completely prevented
mevastatin-induced degeneration and decreased viability by reducing the uptake of
mevastatin and by blocking its action on
proteasome activity.
Mevalonic acid failed to prevent
lactacystin-induced degeneration and inhibition of
proteasome activity. Our results suggest that
mevastatin could act as a neurotoxic agent or
neuroprotective agent, depending upon the extent of its hydrolysis to an open-ring structure and the level of
mevalonic acid.