Statins and the blood–brain barrier: Plugging the holes

Many advances in modern medicine have come about by coincidence. This is certainly true of some of the currently approved pharmacotherapies for multiple sclerosis (MS). One rationale for testing interferonin MS clinical trials was its antiviral properties. Yet there have been no data presented to date that would support viral inhibition as a mechanism of action of interferonin MS. Glatiramer acetate was designed to induce central nervous system autoimmune disease in rodents. Three decades later, glatiramer acetate was approved as an immunoregulatory treatment for MS. The story of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, is quite different and presents one of the earliest examples of rational drug design. Konrad Emil Bloch and Feodor Lynen are widely credited with discovering the regulation of cholesterol and fatty-acid metabolism. Eventually, the identification of 3-hydroxy-3-methylglutaryl coenzyme A reductase led to the discovery of mevastatin (formerly known as compactin), a microbial metabolite that suppressed this rate-limiting enzyme of the cholesterol pathway and de novo cholesterol synthesis. Since then, numerous statins have been approved for the treatment of hypercholesterolemia, and the clinical benefits have been widely reported in the scientific literature. Immunoregulatory properties of statins were discovered much later: Statin treatment significantly improved the long-term survival of heart transplant recipients compared with placebo, independent of its cholesterol-lowering effects. This observation led to the investigation of molecular and cellular mechanisms of action of statins. A significant amount of this work was conducted in neuroimmunology, and specifically in experimental autoimmune encephalomyelitis, an animal model of MS (Fig). In this issue of Annals of Neurology, Ifergan and colleagues present yet another mechanism of action of statins that may be relevant to MS. Specifically, they tested the hypothesis that statins exert biological effects on endothelial cells of the blood–brain barrier (BBB). The BBB is different morphologically from other endothelia. Specifically, the endothelial cells that constitute the BBB are interconnected by complex tight junctions, which severely limit any cellular transmigration and paracellular transport. Thus, the brain has long been considered relatively immune privileged. Consequently, a compromise of the BBB has been equated with MS disease activity. Ifergan and colleagues elegantly designed an in vitro biological barrier that resembles the BBB: Human brain microvascular endothelial cells were plated in the upper compartment of a Boyden chamber and grown to confluency. The integrity of this biological membrane was assessed by the diffusion of fluorescent-labeled bovine serum albumin from the upper to the lower compartment by force of gravity. The authors make several important observations. First, lovastatin and simvastatin stabilize the integrity of their BBB model in a dose-dependent manner by interfering with isoprenylation events. That both agents are equipotent in their effect on the BBB is surprising, given that simvastatin is more potent in lowering blood low-density lipoprotein cholesterol on a dose-by-dose comparison. Second, the statin doses used in this in vitro model of the BBB are similar to plasma levels achieved with therapeutic doses of simvastatin in patients with hypercholesterolemia. Third, statins reduced the secretion of the chemokines CCL2 and CXCL10 by human brain microvascular endothelial cells and decreased the migration of leukocytes from patients with a clinically isolated syndrome or MS across biological membranes. Perhaps not surprisingly, the migration of cells from healthy donors was unaffected. A likely explanation for this observation is that leukocytes in noninflammatory states lack chemokine receptor expression. As neuroimmunologists, we have come to view the presence of leukocytes within the central nervous system as something undesirable. However, the primary role of T and B cells in the brain and spinal cord is immunosurveillance. It is therefore encouraging that statins, at least in vitro, do not have an effect on cell migration across biological barriers in healthy individuals. The data that Ifergan and colleagues presented, together with the previously published work by other investigators, are compelling and present a rationale for the use of statins in MS. Two small, open-label, clinical studies confirmed the safety of statin therapy in MS. Trials to tests the efficacy of statins as monotherapy, or in combination with approved agents, are in the planning stage or ongoing. Should statins prove effective in MS therapy, it would not be a coincidence.