Received for publication December 11, 2007.
Revised January 31, 2008.
Accepted for publication January 31, 2008.

Inhibition of Rho Family Functions by Lovastatin Promotes Myelin Repair in Ameliorating Experimental Autoimmune Encephalomyelitis

Abstract

Impaired remyelination is critical to neuroinflammation in multiple sclerosis (MS), which causes chronic and relapsing neurological impairments. Recent studies revealed that immunomodulatory activity of statins in an experimental autoimmune encephalomyelitis (EAE) model of MS are via depletion of isoprenoids (farnesyl-pyrophosphate and geranylgeranyl-pyrophosphate) rather than cholesterol in immune cells. Additionally, we previously documented that lovastatin impedes demyelination and promotes myelin repair in treated EAE animals. To this end, we revealed the underlying mechanism of lovastatin-induced myelin repair in EAE using in vitro and in vivo approaches. Survival, proliferation (NG2⁺ and O4⁺) and terminal-differentiation (MBP⁺) of OPs was significantly increased in association with induction of a promyelinating milieu by lovastatin in mixed glial cultures stimulated with pro-inflammatory cytokines. Lovastatin-induced effects were reversed by co-treatment with mevalonolactone or geranylgeranyl-pyrophosphate, but not by farnesyl-pyrophosphate or cholesterol, suggesting that depletion of geranygeranyl-pyrophosphate is more critical than farnesyl-pyrophosphate in glial cells. These effects of lovastatin were mimicked by inhibitors of geranylgeranyl-transferase (GGTI-298) and down-stream effectors i.e., Rho-family functions (C3-exoenzyme) and Rho kinase (Y27632), but not by an inhibitor of farnesyl-transferase (FTI-277). Moreover, activities of Rho/Ras family GTPases were reduced by lovastatin in glial cells. Corresponding with these findings, EAE animals exhibiting demyelination (on peak clinical day; clinical scores 3.0) when treated with lovastatin and aforementioned agents validated these in vitro findings. Taken together, these data provide unprecedented evidence that--like immune cells--geranylgeranyl-pyrophosphate depletion thus inhibition of Rho family functions in glial cells by lovastatin promotes myelin repair in ameliorating EAE.

Key words: PDGF, Interleukins, Tumor necrosis factor, Ras, Cdc42, rho, rac, other small G proteins, Immunocytochemistry, Regulation of gene expression, Excitotoxicity, neurodegeneration