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The 3‐hydroxy‐3‐methylglutaryl co‐enzyme A reductase inhibitor pravastatin enhances neurite outgrowth in hippocampal neurons
Author(s) -
Pooler Amy M.,
Xi Shijun C.,
Wurtman Richard J.
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.03763.x
Subject(s) - pravastatin , neurite , prenylation , rhoa , endocrinology , biology , medicine , pharmacology , chemistry , microbiology and biotechnology , biochemistry , cholesterol , signal transduction , enzyme , in vitro
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.