Simvastatin promotes neurite outgrowth in the presence of inhibitory molecules found in central nervous system injury.
Statins (3-hydroxy-3-methylglutaryl-CoA [HMG-CoA] reductase inhibitors) inhibit the rate-limiting step in the mevalonate pathway, conversion of HMG-CoA to mevalonate, by competitive inhibition with the enzyme HMG-CoA reductase. Statins not only lower cholesterol levels, but are also thought to exert neuroprotective and neurogenic effects that may be beneficial in treating brain and spinal cord injuries. Data presented here illustrate that simvastatin enables neurite outgrowth in the presence of growth-inhibitory molecules commonly found at central nervous system (CNS) injury sites. To assess the effect of simvastatin on neurite outgrowth in the presence of inhibitory molecules present at CNS injury sites, rat embryonic cortex explants or postnatal spinal cord explants were grown on membrane filters prepared with alternating stripes of laminin and myelin/laminin. Immunostaining indicated that myelin stripes contain myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), and Nogo, but do not contain chondroitin sulfate proteoglycan (CSPG). When control explants were grown in the presence of alternating stripes, neurite outgrowth preferentially extended in regions containing laminin only. In contrast, neurite outgrowth from explants grown in the presence of simvastatin was significantly less selective for laminin regions and was able to extend into regions containing myelin (p < 0.01). Simvastatin-induced effects were reversed by addition of mevalonate. Isoprenyl transferase inhibitors GGTI-286 and FTI-277, inhibitors of biochemical steps subsequent to HMG-CoA conversion to mevalonate, mimicked simvastatin- induced effects. These data suggest that simvastatin counteracts myelin-associated neurite outgrowth inhibition signals via mevalonate pathway inhibition, and may be beneficial in promoting axon regeneration in brain and spinal cord injury.
Holmberg
Eric
E
Spinal Cord Society Research Center, Fort Collins, Colorado 80526-1826, USA.
Nordstrom
Tuija
T
Gross
Mica
M
Kluge
Bridget
B
Zhang
Shu-Xin
SX
Doolen
Suzanne
S
D000818:Animals; D018929:Cell Culture Techniques; D002540:Cerebral Cortex / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007797:Laminin / Q000502:physiology*; D009186:Myelin Sheath / Q000502:physiology*; D016501:Neurites / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D019821:Simvastatin / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects / Q000254:growth & development / Q000473:pathology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007797:Laminin; D019821:Simvastatin