Statins As Potential Therapeutic Agents in Multiple Sclerosis Olaf Stüve, MD, PhD, Thomas Prod’homme, PhD, Sawsan Youssef, PhD, Shannon Dunn, PhD, Oliver Neuhaus, MD, Martin Weber, MD, Hans-Peter Hartung, MD, Lawrence Steinman, MD, and Scott S. Zamvil, MD, PhD* Address *Department of Neurology, University of California, San Francisco, 521 Parnassus Avenue, C-440, San Francisco, CA 94143-0114, USA. E-mail: zamvil@ucsf.neuroimmunol.org Current Neurology and Neuroscience Reports 2004, 4:237–244 Current Science Inc. ISSN 1528-4042 Copyright © 2004 by Current Science Inc. Introduction Multiple sclerosis (MS) is an acquired central nervous sys- tem (CNS) demyelinating disease that affects approximately 350,000 individuals in North America alone [1]. Based on the presence of cellular and humoral immune responses [2– 4], and the genetic association with human leukocyte anti- gen (HLA) haplotypes [5], MS is widely considered to be an autoimmune disease [6–9]. Accordingly, currently approved therapies for MS include several interferon beta (IFNβ) prep- arations (Avonex [Biogen Idec, Cambridge, MA], Betaseron [Berlex, Montville, NJ), and Rebif [Serono Group, Geneva, Switzerland]), glatiramer acetate (GA) (Copaxone; Teva, Kansas City, MO), and mitoxantrone (Novantrone; Serono Group, Geneva, Switzerland). All of these agents are only partially effective, are given parenterally, and may have significant side effects [10]. It was recently shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) are effective in ameliorating the clinical course of experimental autoimmune encephalomyelitis (EAE), a model for MS. Statins are cholesterol-lowering drugs that are well tolerated and have an excellent safety record. The inhibition of HMG CoA reductase, the enzyme that catalyzes the conversion of HMG CoA to L-mevalonate, is the mechanism by which statins reduce the blood cholesterol level. L-mevalonate is a key intermediate in cholesterol synthesis. However, several metabolites of L-mevalonate are also involved in post-trans- lational modification of specific proteins involved in cell proliferation and differentiation. These mechanisms, which are independent of the cholesterol-reducing properties of statins, have important pleiotropic biologic consequences. The recently reported anti-inflammatory and immunomo- dulatory properties of statins may also have clinical benefit for patients with MS and other neuroinflammatory diseases of the CNS. This article reviews the current scientific and clin- ical evidence that support a future therapeutic role for statins in EAE and MS. Statins Statins are currently the most potent and best-tolerated agents for the treatment of hypercholesterolemia. Statins reduce total blood cholesterol levels by up to 15% to 40%, low-density lipoprotein (LDL) cholesterol level by 20% to 60%, and triglyceride levels by 10% to 30% [1]. There is convincing evidence that statins significantly decrease car- diovascular-related morbidity and mortality in individuals with and without coronary artery disease [11–19]. Statins are administered orally, and in the majority of clinical tri- als they were tolerated as well as placebo. The competitive inhibition of HMG CoA reductase, the enzyme that cata- lyzes the conversion of HMG CoA to L- mevalonate, leads to a reduction of cholesterol synthesis (Fig. 1). In addition, statins prevent several biologic activities downstream of L- mevalonate [20]. Statins were first discovered in 1973, and lovastatin was approved by the US Food and Drug Administration in 1987 for the treatment of hypercholesterolemia. Since 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reduc- tase inhibitors (ie, statins) are oral cholesterol-lowering drugs. Statins are well tolerated and have an excellent safety record. These agents competitively inhibit HMG CoA reductase, which is the enzyme that catalyzes the conversion of HMG CoA to L-mevalonate. Although L-mevalonate is a key intermediate in cholesterol synthesis, several of its metabolites are involved in post-translational modification of specific proteins involved in cell proliferation and differentiation. Thus, independent of their cholesterol-reducing properties, statins have important pleiotropic biologic effects. Recent reports indicate that statins have anti-inflammatory and neuroprotective properties. Whether statins will be of clinical benefit for patients with multiple sclerosis and other neurodegenerative diseases of the central nervous system will only be known after they are evaluated in prospective randomized clinical trials.