Potential Targets of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor for Multiple Sclerosis Therapy

Abstract

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins are newly identified immunomodulators. In vivo treatment of SJL/J mice with lovastatin reduced the duration and clinical severity of active and passive experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Lovastatin induced the expression of GATA3 and the phosphorylation of STAT6, whereas it inhibited tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT4. Inhibition of the Janus kinase-STAT4 pathway by lovastatin modulated T0 to Th1 differentiation and reduced cytokine (IFN-γ and TNF-α) production, thus inducing Th2 cytokines (IL-4, IL-5, and IL-10). It inhibited T-bet (T box transcription factor) and NF-κB in activated T cells and significantly reduced infiltration of CD4- and MHC class II-positive cells to CNS. Further, it stabilized IL-4 production and GATA-3 expression in differentiated Th2 cells, whereas in differentiated Th1 cells it inhibited the expression of T-bet and reduced the production of IFN-γ. Moreover, lovastatin-exposed macrophage and BV2 (microglia) in allogeneic MLRs induced the production of the anti-inflammatory cytokine IL-10. These observations indicate that the anti-inflammatory effects of lovastatin are mediated via T cells as well as APCs, because it modulates the polarization patterns of naive T cell activation in an APC-independent system. Together, these findings reveal that lovastatin may have possible therapeutic value involving new targets (in both APCs and T cells) for the treatment of multiple sclerosis and other inflammatory diseases.

3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate β-Amyloid-Induced Microglial Inflammatory Responses

“…Delbosc et al, 2002;Zelvyte et al, 2002) in both vascular and myeloid-lineage cells. The efficacy of this class of drugs as antiinflammatory agents in the CNS has been convincingly demonstrated in a murine model of experimental allergic encephalitis (Youssef et al, 2002;Nath et al, 2004). Statins have also been shown to protect neurons from excitotoxic injury (Zacco et al, 2003).…”

“…Statins also exhibit robust anti-inflammatory effects (Pahan et al, 1997;Bellosta et al, 1998;Ortego et al, 1999;Grip et al, 2000Grip et al, , 2002Wong et al, 2001;Delbosc et al, 2002;Youssef et al, 2002;Zelvyte et al, 2002;Nath et al, 2004). Many of the antiinflammatory actions of statins are postulated to arise from a reduction of isoprenoid intermediates in the cholesterol biosynthetic pathway (Liao and Laufs, 2004).…”

Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair

“…However, recent clinical and experimental studies have documented a variety of statins' pleiotropic effects, such as anti-inflammatory, antiproliferative, antithrombotic and antioxidant activities in various pathological conditions [7][8][9][10][11][12][13][14][15][16][17].…”

“…In addition to their cholesterol-lowering effects, more recent studies have reported on their previously unrecognized immunomodulatory effects [4,5]. In order to discuss statins' pleiotropic mechanisms of action, which have therapeutic potential in treating CNS inflammatory diseases [6][7][8][9], we will outline statins' mechanisms of action that target specific steps in the pathogenesis of MS.…”

“…Recent observations of statin-mediated protection of neuroprogenitor cells from inflammatory insult and the resulting enhanced remyelination during experimental allergic encephalomyelitis (EAE), an animal model of MS, suggest that, in addition to immunomodulatory activity [8,9], statins mediate neuroprotection and possibly neuroregeneration [10]. They affect BBB integrity and inhibit the infiltration of inflammatory cells into the CNS [7].…”