Simvastatin Promotes Neurite Outgrowth in the Presence of Inhibitory Molecules Found in Central Nervous System Injury

Abstract

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.

Atorvastatin enhances neurite outgrowth in cortical neurons in vitro via up-regulating the Akt/mTOR and Akt/GSK-3β signaling pathways

“…Our findings are consistent with previous reports that statins significantly induce neurite outgrowth in cultured hippocampal neurons [12] , explants of rat embryonic cortex and post-natal spinal cord [13] and PC12 cells [11] . In contrast, statins have also been reported to inhibit neurite outgrowth in cultured cortical neurons, either by reducing cholesterol levels [29] or by inhibition of isoprenylation [30] .…”

“…In addition, the treatment of cells in culture with statins induces a number of striking morphological changes. For example, statin treatment has been reported to promote neurite outgrowth [11][12][13][14] . Furthermore, enhancement of neurite outgrowth by statins treatment is probably mediated by inhibition of Rho isoprenylation, a cholesterol-independent mechanism [12] .…”

RHO GTPase Signaling for Axon Extension: Is Prenylation Important?

“…Decreasing protein prenylation levels with statins promotes neurite outgrowth in some systems [34,[63][64][65][66][67][68][69][70][71] but decreases it in others [62,72,73]. The reasons behind the different results reported in these studies have yet to be fully uncovered but may include (1) the use of different measures of outgrowth, (2) employment of different model systems, (3) assessment of dendrite versus axon outgrowth, or (4) testing of different types of statins.…”

Atorvastatin and simvastatin as analgesic agents in experimental models

“…These agents can reduce formation of the atherosclerotic plaques thereby reducing the morbidity and mortality of cardiovascular events [6] Statins come under the category of HMG Co-A reductase inhibitors, the rate limiting enzyme in cholesterol biosynthesis [7] Atorvastatin is reported to have analgesic properties and also potentiate the action of other analgesics. Barsante, Roffe, Yakora, have summarized that statins have prevented nociception which are observed in inflamed joints and can reserve as better analgesic.…”