Increase of sodium channels in demyelinated lesions of multiple sclerosis

doi:10.1016/0006-8993(91)90321-L

Brain Research

Volume 556, Issue 2, 16 August 1991, Pages 311-316

https://doi.org/10.1016/0006-8993(91)90321-L Get rights and content

Abstract

Redistribution of sodium channels along demyelinated pathways in multiple sclerosis (MS) could be an important event in restoring conduction prior to other reparative mechanisms such as remyelination. Sodium channels in human multiple sclerosis lesions were identified by quantitative light microscopic autoradiography using tritiated saxitoxin (STX), a highly specific sodium channel ligand. Demyelinated areas in various central nervous system regions containing denuded but vital axons exhibited a high increase of STX-binding sites by up to a factor of 4 as compared to normal human white matter. This important finding could be explain aspects of fast clinical remissions and ‘silent’ MS lesions on functional and morphological properties. Demyelinated axons may functionally reorganize their membranes and adapt properties similar to those of slow conducting unmyelinated nerve fibres which have a higher amount and a more diffuse distribution of STX binding sites. This report is the first description of an altered distribution of voltage-sensitive sodium channels in human multiple sclerosis lesions.

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(1976)

Cited by (114)

Acquired channelopathies as contributors to development and progression of multiple sclerosis
2014, Experimental Neurology
Citation Excerpt :
Interestingly, EAE severity in this mouse model is reduced and associated with decreased neuronal degeneration and axonal loss (O'Malley et al., 2009). From a conceptual point of view, it is widely believed that the diffuse expression of Nav channels after demyelination helps to keep up normal conduction of action potentials (Moll et al., 1991). While this is highly beneficial in phases of acute injury, the spreading of Nav channels might as well be counterproductive by contributing to excitotoxicity during chronic disease.
Multiple sclerosis (MS), the most frequent inflammatory disease of the central nervous system (CNS), affects about two and a half million individuals worldwide and causes major burdens to the patients, which develop the disease usually at the age of 20 to 40. MS is likely referable to a breakdown of immune cell tolerance to CNS self-antigens resulting in focal immune cell infiltration, activation of microglia and astrocytes, demyelination and axonal and neuronal loss. Here we discuss how altered expression patterns and dysregulated functions of ion channels contribute on a molecular level to nearly all pathophysiological steps of the disease. In particular the detrimental redistribution of ion channels along axons, as well as neuronal excitotoxicity with regard to imbalanced glutamate homeostasis during chronic CNS inflammation will be discussed in detail. Together, we describe which ion channels in the immune and nervous system commend as attractive future drugable targets in MS treatment.
Molecular mechanisms linking neuroinflammation and neurodegeneration in MS
2014, Experimental Neurology
Citation Excerpt :
Demyelination of axons disturbs the salutatory conduction of nerves. Sodium channels that are primarily expressed at the nodes of Ranvier (and nerve terminals) are upregulated in formerly myelinated axonal sections to restore nerve conduction in MS patients (Moll et al., 1991; Waxman, 2006). This redistribution of sodium channels causes an increased energy (ATP) demand to reduce increasing sodium levels via the Na+/K+ ATPase (Craner et al., 2004; Dutta et al., 2006).
Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disorder of the central nervous system (CNS) and one of the leading causes of neurological deficits and disability in young adults in western countries. Current medical treatment mainly influences disease progression via immunomodulatory or immunosuppressive actions. Indeed, MS research has been foremost focused on inflammation in the CNS, but more recent evidence suggests that chronic disability in MS is caused by neurodegeneration. Imaging studies show an early involvement of neurodegeneration as brain atrophy and gray matter lesions can be observed at disease onset. Thus, neuroprotective treatment strategies and the elucidation of the molecular mechanisms underlying neurodegeneration in MS have attracted the attention of the scientific community. Experimental autoimmune encephalomyelitis (EAE; the most commonly used animal model for MS), novel in-vivo imaging techniques such as two-photon microscopy and recently discovered molecular changes have offered new insights into the pathogenesis of neuroinflammation as well as neurodegeneration in MS. This review focuses on the interaction between components of the immune system and the neuronal compartment, as well as describing the most important molecular mechanisms that lead to axonal and neuronal degeneration in MS and EAE.
Demyelination in multiple sclerosis
2014, Handbook of Clinical Neurology
Citation Excerpt :
Paranodal and juxtaparanodal axonal proteins are also profoundly modified. A redistribution of Nav channels along the naked axon has been reported in experimental models of demyelination and in MS lesions both by autoradiography and by immunohistochemistry (Moll et al., 1991; Noebels et al., 1991; Craner et al., 2004a, b; Coman et al., 2006). It remains unknown whether this change is due to a Nav channel synthesis or to a redistribution of Nav channels from nearby nodes into the demyelinated (previously internodal) membrane.
This review, focused on demyelination in multiple sclerosis, is divided in two parts. The first part addresses the many and not exclusive mechanisms leading to demyelination in the central nervous system. Although the hypothesis that a primary oligodendrocyte or myelin injury induces a secondary immune response in the central nervous system is still a matter of debate, most recent advances underline the influence of a primary immune response against myelin antigen(s), with a diversity of potential targets. Whereas multiple sclerosis was long considered as a T cell-mediated disease, the role of B lymphocytes is now increasingly recognized, and the influence of antibodies on tissue damage actively investigated. The second part of the review describes the axonal consequences of demyelination. Segmental demyelination results in conduction block or slowing of conduction through adaptative responses, notably related to modifications in the distribution of voltage gated sodium channels along the denuded axon. If demyelination persists, these changes, as well as the loss of trophic and metabolic support, will lead to irreversible axonal damage and loss. In this respect, favouring early myelin repair, during a window of time when axonal damage is still reversible, might pave the way for neuroprotection.
Clinical neurophysiology of multiple sclerosis
2014, Handbook of Clinical Neurology
Citation Excerpt :
Moreover, abnormalities on multimodal EPs may be predictive of future development of disability (Kallmann et al., 2006; Leocani et al., 2006; Jung et al., 2008), especially in the early stages of the disease (Kallmann et al., 2006; Jung et al., 2008), suggesting that EPs could be useful in the identification of patients with initial, subclinical involvement of eloquent pathways, which are important in determining the development of disability. After unilateral optic neuritis, VEPs detected improving nervous conduction over more than 3 years (Niklas et al., 2009) and 5 years (Brusa et al., 2001), despite little recovery in visual function, possibly related to remyelination (Brück et al., 2003; Patrikios et al., 2006; Patani et al., 2007) or ion channel reorganization in the demyelinated region (Waxman, 1978, 2002; Moll et al., 1991). Subtle worsening of conduction in the fellow asymptomatic eye has been suggested to indicate an insidious demyelinating process which, although accompanied by worsening of contrast sensitivity, would have been undetected by clinical examination alone (Brusa et al., 2001).
The availability of new treatments able to modify the natural course of multiple sclerosis (MS) has generated interest in paraclinical measures to monitor disease evolution. Among these, neurophysiologic measures, mainly evoked potentials (EPs), are used in the functional assessment of central sensorimotor and cognitive networks affected by MS. EP abnormalities may reveal subclinical lesions, objectivate the involvement of sensory and motor pathways in the presence of vague disturbances, and provide indications of the demyelinating nature of the disease process. However, their diagnostic value is much lower than that of magnetic resonance imaging, and is more sensitive to brain and cervical spinal cord lesions. The application of EPs in assessing disease severity and monitoring the evolution of nervous damage is more promising, thanks to their good correlation with disability in cross-sectional and longitudinal studies, and potential use as paraclinical endpoints in clinical trials. Recent evidence indicates that EPs performed early in the disease may help to predict a worse future progression in the long term. If confirmed, these data suggest the possible usefulness of EPs in the early identification of patients who are more likely to develop future disability, thus requiring more frequent monitoring or being potential candidates for more aggressive disease-modifying treatments.
Sodium imaging as a marker of tissue injury in patients with multiple sclerosis
2013, Multiple Sclerosis and Related Disorders
Citation Excerpt :
While the expression of some Na channel isoforms may have an adaptive role restoring conduction, other isoforms may have a maladaptive role contributing to axonal degeneration (Smith and Lassmann, 2002). Immunocytochemical studies using panspecific Na channel antibodies subsequently confirmed the appearance of increased numbers of Na channels in experimentally demyelinated axons and in demyelinated lesions from MS patients (England et al., 1991; Moll et al., 1991). It has been hypothesized that the molecular mechanisms of axonal/neuronal injury in inflammatory demyelinating diseases shares a final common pathway with those in hypoxia (Stys, 2004): under both pathophysiological conditions, a mismatch of the cellular demand and the production of energy can occur with subsequent depletion of adenosine tri-phosphate (ATP).
Recent studies have suggested that intra-axonal sodium accumulation contribute to axonal degeneration in patients with MS. Advances in MRI hardware and software allow acquisition of brain sodium signal in vivo. This review begins with a summary of the experimental evidence for impairment of sodium homeostasis in MS. Then, MRI methods for sodium acquisition are reviewed and the application of the techniques in patients with MS is discussed. Sodium imaging and ultra-high field MRI have the potential to provide tissue-specific markers of neurodegeneration in MS.
Synthesis and evaluation of a <sup>125</sup>I-labeled iminodihydroquinoline-derived tracer for imaging of voltage-gated sodium channels
2013, Bioorganic and Medicinal Chemistry Letters
In vivo imaging of voltage-gated sodium channels (VGSCs) can potentially provide insights into the activation of neuronal pathways and aid the diagnosis of a number of neurological diseases. The iminodihydroquinoline WIN17317-3 is one of the most potent sodium channel blockers reported to date and binds with high affinity to VGSCs throughout the rat brain. We have synthesized a ¹²⁵I-labeled analogue of WIN17317-3 and evaluated the potential of the tracer for imaging of VGSCs with SPECT. Automated patch clamp studies with CHO cells expressing the Na_v1.2 isoform and displacement studies with [³H]BTX yielded comparable results for the non-radioactive iodinated iminodihydroquinoline and WIN17317-3. However, the ¹²⁵I-labeled tracer was rapidly metabolized in vivo, and suffered from low brain uptake and high accumulation of radioactivity in the intestines. The results suggest that iminodihydroquinolines are poorly suited for tracer development.

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: We wish to thank Prof. M. Mumenthaler, Bern, and Dr. J. Kesselring, Valens. This work was generously supported by a grant from The Swiss Multiple Sclerosis Society.

^**: Permanent address: Institute of Pathology, University of Zürich, 8901 Zürich, Switzerland.

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References (27)

Glial and neuronal forms of voltage-dependent sodium channel: characteristics and cell-type distribution

Neuron

Ion channel expression by white matter glia: type-1 astrocyte

Neuron

Regional tritium quenching in quantitative autoradiograpy of the central nervous system

Brain Research

Axonal transport of the voltage-dependent Na⁺ channel protein identified by its tetrodotoxin binding site on rat sciatic nerve

Brain Research

Autoradiographic localization of tetrodotoxin-sensitive Na⁺ channels in rat brain

Neurosci. Lett.

Autoradiographic analysis in rat brain of the post-natal ontogeny of voltage-dependent Na⁺ channels, Ca²⁺-dependent K⁺ channels and slow Ca²⁺ channels identified as receptors for tetrodotoxin, apamin and (−)desmethylxyverapamil

Brain Research

Distribution of voltage-dependent Na⁺ channels identified by high affinity receptors for tetrodotoxin and saxitoxin in rat and human brains: quantitative autoradiographic analysis

Brain Research

Paranodal dysmyelination and increase in tetrodotoxin binding sites in the sciatic nerve of the motor end-plate disease (med/med) mouse during postnatal development

Dev. Biol.

Remyelination of nerve fibers in the transected frog sciatic nerve

Brain Research

Ion channel expression by white matter glia: I. Type 2 astrocytes and oligodendrocytes

Glia

The presence of voltage-gated sodium, potassium and chloride channels in rat cultured astrocytes

Voltage-gated ion channels in rat cultured astrocytes

Continuous conduction in demyelinated mammalian nerve fibres

Nature

Cited by (114)

Acquired channelopathies as contributors to development and progression of multiple sclerosis

Molecular mechanisms linking neuroinflammation and neurodegeneration in MS

Demyelination in multiple sclerosis

Clinical neurophysiology of multiple sclerosis

Sodium imaging as a marker of tissue injury in patients with multiple sclerosis

Synthesis and evaluation of a <sup>125</sup>I-labeled iminodihydroquinoline-derived tracer for imaging of voltage-gated sodium channels