Implications for Therapy

Consideration of the preceding mechanism reveals several potential avenues by which axons might be protected from degeneration in inflammatory disorders such as MS. First, NO could be scavenged, or inflammatory NO production could be suppressed. These are attractive goals, but they are not only difficult to achieve in patients with currently available drugs; they are also potentially dangerous. Effective NO scavenging would lead to unacceptable increases in blood pressure, and experiments with iNOS inhibitors in EAE have revealed that such therapies can have lethal results (Willenborg et al., 1999), probably as a result of the release from NO-mediated suppression of peripheral immune events. Second, the sodium-calcium exchanger could be suppressed to avoid the damaging entry of calcium ions. The potential value of this avenue has already been demonstrated in a laboratory model of NO-induced axonal injury (Smith et al., 2001b; Kapoor et al., 2003), and we are currently examining its utility in animals with EAE. However, there are significant questions with regard to whether this will ever be an acceptable therapy for chronic use in patients. Finally, it should be possible to protect axons from degeneration by limiting the rise in intra-axonal sodium by partial blockade of their sodium channels. Such drugs are commonly used in neurological practice as anti-convulsants, and they are acceptable and safe for chronic administration. The potential efficacy in MS of this approach is suggested by the successful axonal protection that has recently been achieved using sodium channel-blocking agents in some simplified laboratory models (Kapoor et al., 1998, 2003; Smith et al., 2001b; Garthwaite et al., 2002) and in animal models of MS, namely phenytoin in progressive EAE (Lo et al., 2002, 2003) and flecainide in chronic relapsing EAE (Fig. 7) (Bechtold et al., 2004). The good results with flecainide have now been reproduced with lamotrigine, and to a lesser extent with phenytoin, in chronic relapsing EAE (DA Bechtold, KJ Smith, unpublished observations). Carbamazepine was not found to be effective in axonal protection in this study, but this result, and the limited protection produced by phenytoin, are

Figure 6 Two series of averaged compound action potentials recorded in parallel, in an anesthetized rat, over a 12-hour period from two separate dorsal roots using the arrangement indicated (inset). The data are shown in three-dimensional perspective, as in Figure 1. In the left plot, the root was stimulated at 1 Hz throughout, but in the right the stimulation was a 100 Hz for the first 6 hours, followed by 1 Hz for the remaining 6 hours. On both sides the records were relatively stable for the first 2.5 hours, but conduction block was imposed on nearly all the axons by a 2-hour exposure to NO. This block was released upon removal of the NO. In the left plot all the axons continued to conduct for the remaining 7.5 hours of the experiment. In contrast, in the right plot it is clear that exposure to the same concentration of NO, but experienced in conjunction with 100 Hz impulse activity, resulted in only a transient recovery of function, followed by persistent conduction block, despite the later reduction of the stimulus frequency to only 1 Hz. Histological examination of the roots at the end of the experiment revealed that whereas the root stimulated at only 1 Hz during the period of NO exposure was quite normal in appearance, all the axons exposed to NO in conjunction with stimulation of 100 Hz had undergone degeneration. (Redrawn from Smith et al., 2001a.)

Figure 6 Two series of averaged compound action potentials recorded in parallel, in an anesthetized rat, over a 12-hour period from two separate dorsal roots using the arrangement indicated (inset). The data are shown in three-dimensional perspective, as in Figure 1. In the left plot, the root was stimulated at 1 Hz throughout, but in the right the stimulation was a 100 Hz for the first 6 hours, followed by 1 Hz for the remaining 6 hours. On both sides the records were relatively stable for the first 2.5 hours, but conduction block was imposed on nearly all the axons by a 2-hour exposure to NO. This block was released upon removal of the NO. In the left plot all the axons continued to conduct for the remaining 7.5 hours of the experiment. In contrast, in the right plot it is clear that exposure to the same concentration of NO, but experienced in conjunction with 100 Hz impulse activity, resulted in only a transient recovery of function, followed by persistent conduction block, despite the later reduction of the stimulus frequency to only 1 Hz. Histological examination of the roots at the end of the experiment revealed that whereas the root stimulated at only 1 Hz during the period of NO exposure was quite normal in appearance, all the axons exposed to NO in conjunction with stimulation of 100 Hz had undergone degeneration. (Redrawn from Smith et al., 2001a.)

Control

Control

Figure 7 Four series of records obtained using the same protocol as in Figure 6. In the upper two plots the combination of impulse activity and NO exposure resulted in persistent conduction block in almost all of the axons, as in Figure 6. Despite experiencing exactly the same protocol, however, conduction in the adjacent roots (lower two plots) was restored, showing that almost all the axons survived. In these roots, the sodium channel-blocking agent flecainide was included with the NO donor, although in a sufficiently low dose that conduction persisted despite the presence of the drug. The inclusion of flecainide protected the axons from degeneration. (Modified from Kapoor et al., 2003.)

Figure 7 Four series of records obtained using the same protocol as in Figure 6. In the upper two plots the combination of impulse activity and NO exposure resulted in persistent conduction block in almost all of the axons, as in Figure 6. Despite experiencing exactly the same protocol, however, conduction in the adjacent roots (lower two plots) was restored, showing that almost all the axons survived. In these roots, the sodium channel-blocking agent flecainide was included with the NO donor, although in a sufficiently low dose that conduction persisted despite the presence of the drug. The inclusion of flecainide protected the axons from degeneration. (Modified from Kapoor et al., 2003.)

likely due to the short plasma half-life of these drugs in the rat, as monitoring of circulating levels revealed the presence of only subclinical concentrations during part of the day. In view of these findings, clinical trials are planned to examine the value of lamotrigine and phenytoin in patients with MS.

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