The 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor pravastatin enhances neurite outgrowth in hippocampal neurons
Article first published online: 29 MAR 2006
Journal of Neurochemistry
Volume 97, Issue 3, pages 716–723, May 2006
How to Cite
Pooler, A. M., Xi, S. C. and Wurtman, R. J. (2006), The 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor pravastatin enhances neurite outgrowth in hippocampal neurons. Journal of Neurochemistry, 97: 716–723. doi: 10.1111/j.1471-4159.2006.03763.x
- Issue published online: 29 MAR 2006
- Article first published online: 29 MAR 2006
- Received September 29, 2005; revised manuscript received December 19, 2005; accepted December 19, 2005.
- 3-hydroxy-3-methylglutaryl coenzyme A reductase;
Epidemiological studies demonstrate a relationship between statin [3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor] usage and reduced risk of developing Alzheimer's disease. To determine whether statins affect neuronal development, we treated cultured rat hippocampal neurons with pravastatin. After 4–48 h of treatment, pravastatin significantly increased the number of neurites produced by each cell and caused a corresponding increase in levels of the membrane phospholipid phosphatidylcholine. Pravastatin treatment also significantly increased neurite length and branching but did not affect cellular cholesterol levels. Co-incubation with mevalonate, but not cholesterol, abolished the stimulatory effect of pravastatin on neurite outgrowth. Treatment of neurons with isoprenoids also abolished the effect of pravastatin on neurite growth, suggesting that pravastatin may stimulate neuritogenesis by preventing isoprenylation of signaling molecules such as the Rho family of small GTPases. A specific inhibitor of geranylgeranylation, but not farnesylation, mimicked the stimulatory effect of pravastatin on neuritogenesis. Pravastatin treatment significantly decreased levels of membrane-associated RhoA. These data suggest that pravastatin treatment increases neurite outgrowth and may do so via inhibiting the activity of geranylgeranylated proteins such as RhoA.