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

Abstract

Statins as inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase are widely used as cholesterol-lowering drugs. Recent studies provide evidence that the anti-inflammatory activity of statins, which is independent of their cholesterol-lowering effects, may have potential therapeutic implications for neuroinflammatory diseases such as multiple sclerosis (MS), Alzheimer's disease and brain tumors, as well as traumatic spinal cord and brain injuries. Studies with animal models of MS suggest that, in addition to immunomodulatory activities similar to the ones observed with approved MS medications, statin treatment also protects the BBB, protects against neurodegeneration and may also promote neurorepair. Although the initial human studies on statin treatment for MS are encouraging, prospective randomized clinical studies will be required to evaluate their efficacy in the larger patient population. Keywordsblood-brain barrier; immunomodulation; inflammation; multiple sclerosis; neurodegeneration; neuroinflammatory diseases; neurorepair; pleotropic effects; statins Multiple sclerosis (MS) is a chronic CNS disease with a chronic inflammatory response directed against the myelin antigens [1,2]. Immunological studies indicate that autoreactive CD4 + and CD8 + lymphocytes migrate into the CNS following antigen recognition in the peripheral circulation. Once in the CNS, T cells undergo reactivation by abundant myelin antigens and perpetuate an inflammatory response that leads to demyelination and axonal loss †Author for correspondence

Immunomodulatory Effects of IFN-β and Lovastatin on Immunophenotype of Monocyte-Derived Dendritic Cells in Multiple Sclerosis

“…Current MS treatment is only partially effective, however, and it is important to identify existing or novel classes of drugs that may benefit MS therapy. Recent studies have demonstrated that oral cholesterol-lowering HMG-CoA reductase inhibitors (known as statins) have immunomodulatory properties (Ghittoni et al 2006;Markovic-Plese et al 2008). In experimental autoimmune encephalomyelitis (EAE), a model of MS, and in vitro, statins have been shown to promote the differentiation and expansion of myelin protein-reactive regulatory Th2 cells and to suppress the upregulation of MHC class II and co-stimulatory molecules on APCs (Neuhaus et al 2002;Youssef et al 2002).…”

Simvastatin Inhibits IFN Regulatory Factor 4 Expression and Th17 Cell Differentiation in CD4+ T Cells Derived from Patients with Multiple Sclerosis

“…Statins are orally administered competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid (MA) (8). As effective cholesterol-lowering agents, statins have been extensively used for prevention of cardiovascular disease.…”

Effects of atorvastatin on experimental spinal cord ischemia-reperfusion injury in rabbits

“…These oxygen radicals further aggravate tissue damage (10,24,42). Glutamate-mediated calcium toxicity induced mitochondrial dysfunction and the associated loss of energy supply together with formation of free oxygen radicals are important targets of spinal cord injury studies (36). These radicals react with the cellular lipids and mitochondrial membranes and produce lipid peroxides.…”

“…They are used for treatment of dyslipidemias and prevention of cardiovascular diseases (15,45). On last two decades, extensive research has focused on these agents, revealing their neuroprotective and immunomodulatory effects (15,29,36,45,50).…”

“…Although the neuroprotective effects of statins are partially understood; correcting blood flow, reducing coagulation, reducing oxidative damage and immune regulatory effects seem to be the probable mechanisms (15,29,36,45,50).…”