Axonal degeneration in multiple sclerosis: Is it time for neuroprotective strategies?

Multiple sclerosis is a chronic neurological disorder characterized by inflammatory demyelination in the central nervous system (CNS), coupled with degeneration of central axons. Although most patients begin with a relapsing-remitting course, the majority will eventually enter a chronic progressive phase with progressive clinical disabilities. It is the loss of axons that is suspected to be the underlying process responsible for irreversible clinical dysfunction; axonopathy seems to begin early in the course of the disease well before the progressive phase sets in and even involves nonlesional “normal-appearing” white matter. Although axonal pathology in MS has been recognized for over a hundred years, with morphological features including axonal spheroid formation and ultimately transection, very little is known about the underlying molecular mechanisms. This is in contrast with the large amounts of data obtained over the years pertaining to immunological mechanisms, which paved the way for the development of moderately effective disease-modifying agents in routine clinical use. As effective as these agents are at reducing relapse rates and lesion formation, perhaps more importantly, it is still unclear what the effects are on progression of long-term disability. In this issue of the Annals, Smith and colleagues describe how flecainide, a “use-dependent” Na channel blocking antiarrhythmic compound, was able to reduce morbidity and mortality in a rat model of chronic relapsing experimental allergic encephalomyelitis (CREAE). Although all animal models attempting to mirror human disease have inherent limitations, chronic EAE exhibits axonal pathology very similar to that found in MS and therefore represents a reasonable model in which to study axonal degeneration and test neuroprotective treatments. These authors report that daily administration of flecainide significantly reduced neurological disability, preserved axon counts, improved conduction, and even reduced myelin loss in the spinal cord. Together, these outcome measures provide strong evidence for a beneficial effect of Na channel blocking agents in EAE, consistent with recent reports using the Na channel blocking anticonvulsant phenytoin. However, as the authors discuss in their current article, markers of inflammation were not studied to rule out the possibility that Na channel blockers somehow modulate the immune assault on the CNS. Flecainide also reduced mortality compared with vehicle controls, and consequently, improved clinical scores. Part of the observed reduction in mortality could be attributed to a direct cardioprotective effect of this drug; moribund animals could be expected to suffer adverse cardiac events, and the antiarrhythmic actions of flecainide may partially mitigate cardiac morbidity. These issues notwithstanding, the electrophysiological and histochemical data clearly and convincingly show a sparing of structure and function in spinal cord white matter by flecainide in rats with CR-EAE. On the surface, blocking Na channels in already compromised and demyelinated axons is counterintuitive, so why would a Na channel inhibitor be expected to improve outcome in EAE or MS? Although immunological mechanisms in these disorders have been extensively studied, in contrast, we know very little about the causes of tissue (particularly axonal) degeneration in MS or EAE, even though such changes have been observed pathologically for a great many years. In the last decade, studies in models of ischemia and neurotrauma have provided considerable information about the fundamental cellular and molecular mechanisms of white matter injury (for a review, see Stys). A summary of the various interdependent events is illustrated in Figure 1. Ischemia leads to ATP depletion, failure of Na-Kand Ca-ATPases (see Fig 1:1a,b), inward Na leak through Na channels that fail to completely inactivate (see Fig 1:3a), and K efflux (see Fig 1:3b). This, in turn, depolarizes axons and increases axonal [Na], which will release Ca from “axoplasmic reticulum” (“AR”; see Fig 1:2a,b); admit Ca via reverse Na-Ca exchange (see Fig 1:4) and voltage-gated Ca channels (see Fig 1:2a, 10); and release glutamate by reverse Nadependent glutamate transport (see Fig 1:8), with subsequent activation of various ionotropic and metabotropic glutamate receptors (see Fig 1:9). A catastrophic increase in intracellular [Ca] (see Fig 1:5) is the “final common pathway” which then overloads mitochondria (see Fig 1:6) and drives a variety of Ca-dependent enzyme systems (see Fig 1:7) to damage cells. This cascade was largely derived from hypoxic/ischemic models, but recent observations suggest that it has relevance to inflammatory CNS disorders as well. The connection becomes even more convincing if we consider this scheme in the context of a mismatch between supply of cellular energy and demand, rather than an isolated supply deficit which occurs during an ischemic episode for instance. Concerning the supply side of the equation, it is known that nitric oxide (NO) is generated in substantial quantities in inflammatory lesions; this molecule, among many other effects, impairs mitochondrial electron transport and therefore oxidative phosphorylation. Indeed, exposing central white matter to NO causes ATP depletion and irreversible injury. Moreover, very recent studies show reEDITORIALS