Wednesday, 27 March 2013

Inhibition of Microglia protects Axons

Morsali D, Bechtold D, Lee W, Chauhdry S, Palchaudhuri U, Hassoon P, Snell DM, Malpass K, Piers T, Pocock J, Roach A, Smith KJ. Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis. Brain. 2013 Mar 20. [Epub ahead of print]

Axonal degeneration is a major cause of permanent disability in the inflammatory demyelinating disease multiple sclerosis, but no therapies are known to be effective in axonal protection. Sodium channel blocking agents can provide effective protection of axons in the white matter in experimental models of multiple sclerosis, but the mechanism of action (directly on axons or indirectly via immune modulation) remains uncertain. Here we have examined the efficacy of two sodium channel blocking agents to protect white matter axons in two forms of experimental autoimmune encephalomyelitis, a common model of multiple sclerosis. Safinamide is currently in phase III development for use in Parkinson's disease based on its inhibition of monoamine oxidase B, but the drug is also a potent state-dependent inhibitor of sodium channels. Safinamide provided significant protection against neurological deficit and axonal degeneration in experimental autoimmune encephalomyelitis, even when administration was delayed until after the onset of neurological deficit. Protection of axons was associated with a significant reduction in the activation of microglia/macrophages within the central nervous system. To clarify which property of safinamide was likely to be involved in the suppression of the innate immune cells, the action of safinamide on microglia/macrophages was compared with that of the classical sodium channel blocking agent, flecainide, which has no recognized monoamine oxidase B activity, and which has previously been shown to protect the white matter in experimental autoimmune encephalomyelitis. Flecainide was also potent in suppressing microglial activation in experimental autoimmune encephalomyelitis. To distinguish whether the suppression of microglia was an indirect consequence of the reduction in axonal damage, or possibly instrumental in the axonal protection, the action of safinamide was examined in separate experiments in vitro. In cultured primary rat microglial cells activated by lipopolysaccharide, safinamide potently suppressed microglial superoxide production and enhanced the production of the anti-oxidant glutathione. The findings show that safinamide is effective in protecting axons from degeneration in experimental autoimmune encephalomyelitis, and that this effect is likely to involve a direct effect on microglia that can result in a less activated phenotype. Together, this work highlights the potential of safinamide as an effective neuroprotective agent in multiple sclerosis, and implicates microglia in the protective mechanism.

Although the original hypothesis used to suggest that sodium channel blockers will be useful in MS was because they block the effects of sodium overload in demyelinated nerves, it was obvious from the very first experiments in 2002 using sodium channel blockers in EAE, that they also had some immunomodulatory effects in mice, that did not have a demyelinated nerve in sight when the drugs were working. It has been shown previously that sodium channel blockers can affect immune function, notably via actions on macrophage/microglia and this study further highlights this. This is good news because we have been searching for inhibitors of microglial function as they could be useful for progressive MS. This study highlights Safinamide, which is a drug used in Parkinsons Disease. It is however a dirty drug as it has many activities on in sodium channel blockage, another is calcium channel blockage, which is also neuroprotective and another is monoamine oxidase . We could add a few more to the list. The question will be how to we show that they work in MS.

We have two trials planned one has started and is investigating effects in optic neuritis and the other is the PROXIMUS trial of sodium channel blockers and the data in this study further suggest our design is a valid approach and that we should treat during the "immunological/inflammatory penumbra". Maybe we will see safinamide on the agenda for MS.


  1. Safinamide as a Na channel blocker seems to have the same mechanism as phenytoin. Also, upregulation of glutathione in microglia would have a beneficial effect on the use of dimethyl fumarate and its role in down regulating oxidative pathways. Might these compounds be used synergistically?

  2. Quite possibly, fumarate is immune modulating and IF it has neuroproection potential two hitting different targets may be beneficial. But that is hypothetical.

    With sodium channel blockers some are better than others


Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.