Protection against acute inflammatory demyelinating peripheral nerve disease

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DESCRIPTION (provided by applicant): Acute inflammatory demyelinating polyradiculopathy (AIDP) is a common North American and European form of Guillain-Barre' Syndrome (GBS), a disabling inflammatory autoimmune disease of the peripheral nervous system that is characterized by rapid-onset symmetrical paresis with areflexia progressing to neuromuscular paralysis. Considered the leading cause of acute flaccid paralysis in Western countries, GBS occurs with an incidence rate of 0.2-4.0 cases per 100,000. Despite its considerable social impact and economic consequences, studies addressing clinical strategies for the treatment of GBS remain poorly represented. Enhanced infiltration of inflammatory cells into peripheral nerves of GBS patients is strongly suggestive of an immune-mediated pathogenic process. Cellular immunity directed against specific constituents of the peripheral nerve myelin sheath is considered causal in AIDP. The treatment of AIDP/GBS is currently palliative and utilizes non-specific immune-modulating therapies. Advancement of care for GBS patients awaits the development of selective immune-modulating agents or the novel application of existing therapeutic strategies. To address this concern, we recently reported on the application of statins, a group of potent 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, as a novel strategy for the management of experimental autoimmune neuritis (EAN), a well-defined animal model of acute inflammatory peripheral nerve disease. We found that a short-term application of lovastatin was non-toxic and protected against EAN-induced peripheral nerve injury by inhibiting the transendothelial migration of autoreactive leukocytes. How statins affect the migration of autoreactive leukocytes is unclear. In this application, we hypothesize that statins protect against the development of EAN by inhibiting Rho GTPase dependent expression of key cell adhesion molecules on peripheral nerve endothelial cells. We will test this hypothesis using the following Specific Aims: We will determine (1) the dose- and time-dependent effect of lovastatin and simvastatin treatment on Rho-GTPase dependent expression of E-selectin, ICAM-1 and VCAM-1 in primary cultures of rat sciatic nerve endothelial cells and (2) the effect of lovastatin and simvastatin treatment on cell-specific expression of E-selectin, ICAM-1 and VCAM-1 in sciatic nerves harvested from vehicle- or statin-treated Lewis rats with EAN. The overall goal of this application is to define the mechanism by which statins protect against the development of autoimmune inflammatory demyelinating polyradiculopathy. We argue that findings from this study will significantly advance the development of statins as a selective immune-modulating strategy for the treatment of those individuals affected by GBS and related debilitating inflammatory peripheral nerve diseases. PUBLIC HEALTH RELEVANCE Guillain-Barre' Syndrome (GBS) is a potentially highly disabling acquired inflammatory autoimmune disease of the peripheral nervous system that is characterized by a rapid-onset of muscle weakness that in some patients progresses to respiratory failure and paralysis. Subsequent to the virtual eradication of poliomyelitis, GBS is now considered the leading cause of acute flaccid paralysis in Western countries (1) with a reported annual stable incidence rate of 0.2-4.0 cases per 100,000 (2; 3), a rate that is surprisingly similar to that reported for multiple sclerosis (1; 4). In the US, nearly 10,000 GBS cases are reported annually with an overall yearly social and economic burden exceeding $1.8 billion (5). Despite its considerable social impact and economic consequences, studies addressing clinical strategies for the treatment of GBS remain poorly represented. The overall goal of this application is to define the mechanism by which statins protect against the development of autoimmune inflammatory demyelinating polyradiculopathy. We argue that findings from this study will significantly advance the development of statins as a selective immune-modulating strategy for the treatment of those individuals affected by GBS and related debilitating inflammatory peripheral nerve diseases.