The notion of analyzing the role of the mevalonate pathway in the regulation of inducible nitric oxide synthase and pro-inflammatory cytokines originated in the fact intermediates of this biochemical pathway are isoprenoids, which are recognized to play a crucial role in causing small G proteins like Ras and Rac as described above. The truth is, this milestone finding has Imatinib clinical trial changed statin research. In these days, statin drugs are being widely considered as possible therapeutic agents against various neuroinflammatory and neuro-degenerative disorders. Because lovastatin checks HMG-COA reductase, both mevalonate and farnesyl pyrophosphate are capable of reversing the inhibitory influence of lovastatin on the activation of NF?B and the expression of iNOS. Nevertheless, addition of cholesterol and ubiquinone to astrocytes does not prevent the inhibitory effect of lovastatin. These results claim that depletion of FPP, rather than end products of the mevalonate pathway, is responsible for the observed inhibitory influence of lovastatin on the expression of iNOS. Elimination of LPS induced activation of NF?B and expression of iNOS in glial cells by farnesyltransferase inhibitors indicates a crucial role for the farnesylation response in the regulation of the iNOS gene. Consistent with a role of farnesylation in the activation Infectious causes of cancer of p21Ras, a dominant negative mutant of p21Ras also attenuated activation of NF?B and expression of iNOS in rat and human primary astrocytes. Statins also prevent interferon inducible and constitutive transcription of the major histocompatibility complex class II transactivator, which regulates almost all MHC class II gene expression. Lately, Landreth and Cordle have indicated that statins inhibit fibrillar AB induced expression of iNOS in mouse BV 2 microglial cells by inhibiting isoprenylation of Rac. Taken together, these studies suggest that mevalonate metabolites control the expression of iNOS in glial cells via modulating isoprenylation of small G proteins. Stimulation of endothelial NOS In individuals with atherosclerosis and hypercholesterolemia, endothelial function is well known to be impaired small molecule Hedgehog antagonists due to decreased activity of endothelium derived NO. In general walls, NO is produced from endothelial nitric oxide synthase. These drugs have been found to induce eNOS derived NO production, while statins prevent the expression of iNOS. This beneficial effect of statins is located to be independent of cholesterol lowering. Change of this effect by geranylgeranyl pyrophosphate but not FPP suggests that Rac/Rho but not Ras play a role in down regulation of eNOS. In addition, Akt has been proven to phosphorylate eNOS and increase the production of NO. Mevalonate, an intermediate of the cholesterol biosynthetic pathway, inhibits phosphatidylinositol 3 kinase and thereby attenuates the activation of protein kinase B, on the other hand. Furthermore, according to Feron et al., atorvastatin raises NO production by decreasing the expression of caveolin 1, a negative regulator of eNOS.