Axonal protection in experimental autoimmune neuritis by the sodium channel blocking agent flecainide

Bechtold, David A.; Yue, Xiaodong; Evans, Richard; Davies, Meirion; Gregson, N. A.; Smith, Kenneth J.

doi:10.1093/brain/awh328

Cited by 68 publications

(47 citation statements)

References 78 publications

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“…This hypothesis is supported by our observation that blocking Na + channels of syntaphilin-null demyelinated axons significantly reduced axonal degeneration. This is consistent with previous reports that Na + channel blockers reduced axonal degeneration in the immune-mediated demyelinating mouse models of experimental autoimmune encephalomyelitis and neuritis (38,47,48) and in myelinated peripheral axons treated with NO (37). Given that glutamatemediated excitotoxicity has been implicated in damage of demyelinated axons (49), stationary mitochondria may also have a direct beneficial role to buffer axoplasmic Ca 2+ in demyelinated axons, and this buffering capacity may be compromised in syntaphilindeficient axons.…”

Section: Discussionsupporting

confidence: 92%

“…If reduced mitochondrial density in syntaphilindeficient axons leads to insufficient energy production for axonal survival, blocking Na + -channel activities may be beneficial for the survival of demyelinated syntaphilin-deficient axons. Flecainide is a Na + channel blocker that can reduce axonal loss following NO treatment in vitro and during inflammatory demyelination in vivo (37,38). Indeed, when syntaphilin-deficient slice cultures were treated with flecainide, APP-positive axonal ovoids and transections were significantly decreased in a dose-dependent manner (Fig.…”

Section: Resultsmentioning

confidence: 95%

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Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

Ohno

Hao

Mahad

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

110

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Axonal degeneration is a primary cause of permanent neurological disability in individuals with the CNS demyelinating disease multiple sclerosis. Dysfunction of axonal mitochondria and imbalanced energy demand and supply are implicated in degeneration of chronically demyelinated axons. The purpose of this study was to define the roles of mitochondrial volume and distribution in axonal degeneration following acute CNS demyelination. We show that the axonal mitochondrial volume increase following acute demyelination of WT CNS axons does not occur in demyelinated axons deficient in syntaphilin, an axonal molecule that immobilizes stationary mitochondria to microtubules. These findings were supported by time-lapse imaging of WT and syntaphilin-deficient axons in vitro. When demyelinated, axons deficient in syntaphilin degenerate at a significantly greater rate than WT axons, and this degeneration can be rescued by reducing axonal electrical activity with the Na + channel blocker flecainide. These results support the concept that syntaphilin-mediated immobilization of mitochondria to microtubules is required for the volume increase of axonal mitochondria following acute demyelination and protects against axonal degeneration in the CNS.A xonal loss is the major cause of permanent neurological disability in individuals with primary diseases of myelin (1). Axonal degeneration associated with myelin diseases has been well studied in the immune-mediated CNS demyelinating disease multiple sclerosis. Two mechanisms are responsible for the degeneration of demyelinated axons in multiple sclerosis brains. First, axons are transected in acute multiple sclerosis lesions (2) and axonal injury correlates with the number of infiltrating peripheral immune cells (3, 4). Edema associated with breakdown of the blood-brain barrier and toxic substances secreted by inflammatory immune cells are thought to transect the acutely demyelinated axon (5). Second, chronically demyelinated axons degenerate as a result of loss of trophic support provided by oligodendrocytes and myelin (6, 7). In addition to increasing the speed of nerve transmission, oligodendrocytes and myelin provide axons with trophic support that is essential for their longterm survival (8-10). Although most demyelinated axons compensate for loss of oligodendrocytes/myelin, additional insults to axonal mitochondria impair axonal metabolism, increase axonal Ca 2+ , and promote progressive disruption of mitochondrial function (11,12). Changes in axonal mitochondria have been described in chronically demyelinated axons in postmortem multiple sclerosis tissue, and include decreased expression of nuclear-encoded mitochondrial genes (13), reduced mitochondrial respiration (14), and genetic alterations in mitochondrial DNA (15). A vicious cycle of reduced ATP production and increased axonal Ca 2+ results in degeneration of the chronically demyelinated axon.Myelinated axons contain two populations of mitochondria. Most axonal mitochondria do not appear to translocate and are located at...

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 95%

Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

Ohno

Hao

Mahad

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

110

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“…The findings suggest that lamotrigine may provide a novel avenue for axonal protection in MS. Na + /Ca 2+ exchanger, resulting in calcium-mediated axonal degeneration [58]. Intra-axonal sodium accumulation has now been implicated in a number of injury models, including anoxia [36,57], ischemia [26,56], spinal cord injury [13,63], and recently experimental autoimmune encephalomyelitis (EAE) [4,37] and experimental autoimmune neuritis (EAN) [6], a model of Guillain-Barré syndrome. During MS, axons are likely vulnerable to energy depletion and subsequent sodium loading due to the disruption of mitochondrial function by inflammatory mediators, such as nitric oxide (NO) [5].…”

mentioning

confidence: 99%

Axonal protection achieved in a model of multiple sclerosis using lamotrigine

et al. 2006

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Axonal degeneration is a major cause of permanent disability in multiple sclerosis (MS). Recent observations from our and other laboratories suggest that sodium accumulation within compromised axons is a key, early step in the degenerative process, and hence that limiting axonal sodium influx may represent a mechanism for axonal protection in MS. Here we assess whether lamotrigine, a sodium channel-blocking agent, is effective in preventing axonal degeneration in an animal model of MS, namely chronic-relapsing experimental autoimmune encephalomyelitis (CR-EAE). When administered from 7 days post-inoculation, lamotrigine provided a small but significant reduction in the neurological deficit present at the termination of the experiments (averaged over three independent experiments; vehicle: 3.5+/-2.7; lamotrigine: 2.6+/-2.0, P<0.05) and preserved more functional axons in the spinal cord (measured as mean compound action potential area; vehicle: 31.7 microV.ms+/-23.0; lamotrigine: 42.9+/-27.4, P<0.05). Histological examination of the thoracic spinal cord (n=71) revealed that lamotrigine treatment also provided significant protection against axonal degeneration (percentage degeneration in dorsal column; vehicle: 33.5 %+/-38.5; lamotrigine: 10.4 %+/-12.5, P<0.01). The findings suggest that lamotrigine may provide a novel avenue for axonal protection in MS.

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“…[92, [94][95][96][97]. These neuroprotective regimes tested in EAE suggest that one of the major mechanisms involved in axonal degeneration during neuroinflammatory diseases, is the persistent influx of Na + into the axon ultimately leading to neurotoxic levels of Ca 2+ (for review see [86]).…”

Section: Current Ion Channel Theory In Axonal Damagementioning

confidence: 99%

Axonal degeneration in multiple sclerosis: can we predict and prevent permanent disability?

Lee

Taghian

Petratos

2014

Acta Neuropathol Commun

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Axonal degeneration is a major determinant of permanent neurological impairment during multiple sclerosis (MS). Due to the variable course of clinical disease and the heterogeneity of MS lesions, the mechanisms governing axonal degeneration may differ between disease stages. While the etiology of MS remains elusive, there now exist potential prognostic biomarkers that can predict the conversion to clinically definite MS. Specialized imaging techniques identifying axonal injury and drop-out are becoming established in clinical practice as a predictive measure of MS progression, such as optical coherence tomography (OCT) or diffusion tensor imaging (DTI). However, these imaging techniques are still being debated as predictive biomarkers since controversy surrounds their lesion-specific association with expanded disability status scale (EDSS). A more promising diagnostic measure of axonal degeneration has been argued for the detection of reduced N-acetyl aspartate (NAA) and Creatine ratios via magnetic resonance spectroscopic (MRS) imaging, but again fail with its specificity for predicting actual axonal degeneration. Greater accuracy of predictive biomarkers is therefore warranted and may include CSF neurofilament light chain (NF-L) and neurofilament heavy chain (NF-H) levels, for progressive MS. Furthermore, defining the molecular mechanisms that occur during the neurodegenerative changes in the various subgroups of MS may in fact prove vital for the future development of efficacious neuroprotective therapies. The clinical translation of a combined Na + and Ca 2+ channel blocker may lead to the establishment of a bona fide neuroprotective agent for the treatment of progressive MS. However, more specific therapeutic targets to limit axonal damage in MS need investigation and may include such integral axonal proteins such as the collapsin response mediator protein-2 (CRMP-2), a molecule which upon post-translational modification may propagate axonal degeneration in MS. In this review, we discuss the current clinical determinants of axonal damage in MS and consider the cellular and molecular mechanisms that may initiate these neurodegenerative changes. In particular we highlight the therapeutic candidates that may formulate novel therapeutic strategies to limit axonal degeneration and EDSS during progressive MS.

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Axonal protection in experimental autoimmune neuritis by the sodium channel blocking agent flecainide

Cited by 68 publications

References 78 publications

Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

Axonal protection achieved in a model of multiple sclerosis using lamotrigine

Axonal degeneration in multiple sclerosis: can we predict and prevent permanent disability?

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