Axonal protection in models of neuroinflammatory disease.

Axonal degeneration is a major cause of permanent neurological deficit in inflammatory demyelinating diseases such as multiple sclerosis (MS), but the events that lead to the degeneration remain unclear. It has been shown that axons degenerate when exposed to the inflammatory mediator nitric oxide, especially if they are electrically active during exposure, and that partial blockade of sodium channels can protect axons from such degeneration. The studies presented in this thesis whether sodium channel blocking agents, such as flecainide and lamotrigine, can reduce axonal degeneration in models of inflammatory demyelinating disease. Chronic relapsing experimental autoimmune encephalomyelitis (CR-EAE) and experimental autoimmune neuritis (EAN) provide well-established models of MS and Guillain-Barré Syndrome (GBS), respectively. Over a number of independent trials, flecainide significantly lowered disease severity and significantly reduced axonal degeneration in CR-EAE, regardless of whether treatment was initiated prior to inoculation or close to disease onset (7 days post-inoculation). The available data suggest that flecainide achieves axonal protection by: (i) reducing the magnitude of spinal cord inflammation during CR-EAE, thereby lessening possible inflammatory insults responsible for axonal degeneration; and (ii) limiting deleterious sodium accumulation within CNS axons which are exposed to severe inflammation. Lamotrigine also significantly reduces axonal degeneration in rats with CR-EAE. With regard to EAN, flecainide administration at the onset of disease again significantly reduced the neurological deficit and provided significant protection against axonal degeneration. These findings may suggest a novel avenue for axonal protection in MS, GBS and other neuroinflammatory disorders.