Inhibition of rho family functions by lovastatin promotes myelin repair in ameliorating experimental autoimmune encephalomyelitis.
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. In addition, 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 (chondroitin sulfate proteoglycan-NG2(+) and late oligodendrocyte progenitor marker(+)), and terminal-differentiation (myelin basic protein(+)) of OPs was significantly increased in association with induction of a promyelinating milieu by lovastatin in mixed glial cultures stimulated with proinflammatory cytokines. Lovastatin-induced effects were reversed by cotreatment 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 (geranylgeranyl transferase inhibitor-298) and downstream effectors {i.e., Rho-family functions (C3-exoenzyme) and Rho kinase [Y27632 (N-(4-pyridyl)-4-(1-aminoethyl)cyclohexanecarboxamide dihydrochloride)]} but not by an inhibitor of farnesyl-transferase (farnesyl transferase inhibitor-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. Together, these data provide unprecedented evidence that-like immune cells-geranylgeranyl-pyrophosphate depletion and thus inhibition of Rho family functions in glial cells by lovastatin promotes myelin repair in ameliorating EAE.
Paintlia
Ajaib Singh
AS
Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA. singhi@musc.edu
Paintlia
Manjeet Kaur
MK
Singh
Avtar Kaur
AK
Singh
Inderjit
I
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007249:Inflammation; D008148:Lovastatin / Q000494:pharmacology* / Q000627:therapeutic use*; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology*; D009414:Nerve Growth Factors / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*; D018631:ras Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors*
D001549:Benzamides; C102521:GGTI 298; C096898:L 744832; D009414:Nerve Growth Factors; D011106:Polyisoprenyl Phosphates; D002784:Cholesterol; D008148:Lovastatin; D008715:Methionine; D006903:Hydroxymethylglutaryl CoA Reductases; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid