Redistribution Of Sodium Channels Research Articles

What can sodium MRI reveal about sodium accumulation in the brain: implications for multiple sclerosis

Multiple sclerosis: needs for biomarkers of neuronal injury Multiple sclerosis (MS) is a chronic disease of the CNS, representing the leading cause of neuro­ logical disability in young adults. Focal inflam­ matory and demyelinating lesions disseminated in the cerebral white matter have been considered for several decades to be the main feature of MS. However, recent histological studies have also demonstrated the presence of diffuse and progressive damage in cerebral white and gray matter, leading to neuronal injury [1–3]. While neuronal injury is known to occur progressively from the onset of MS and is thought to be a significant cause of increasing clinical disability, the mechanisms underlying neuronal injury are still poorly understood. Furthermore, the conventional MRI metrics lack the specificity required to depict this pathological process, so noninvasive and in vivo biomarkers of neuronal injury are needed. Recently, several experimental studies have highlighted the potential key role of sodium accumulation leading to the pathogenesis of neuronal injury [4–7]. It appears that occurrence of demyelination is followed by upregulation and redistribution of sodium channels along the entire demyelinated axolemna [4,8,9]. The increased number of sodium channels enhances the amount of energy required from the Na/K ATPase. Concomitantly, soluble mediators of inflammation disturb the functional integrity of mitochondria, resulting in decreased ATP production [5,10]. All of these mechanisms driven by mitochondrial energy failure result in axonal sodium accumulation, which leads to reversed activity of the Na/Ca exchanger and axonal calcium import. This calcium overload stimulates a variety of toxic calcium­dependent enzymes, causing structural and functional axonal injury [6,10]. Brain sodium MRI: a unique noninvasive tool to depict accumulation of sodium in MS Sodium (Na) MRI appears to be the unique noninvasive way to detect and quantify in vivo the sodium concentration in the brain based on the magnetic properties of the Na nucleus [11–13]. In the human brain, sodium is distributed in two compartments; the intracellular and the extracellular compartments. The concentration gradient between the two compartments is kept constant through the effect of the sodium–potassium pump. The total sodium concentration measured by sodium MRI is the average sodium concentration between the two compartments. Sodium MRI is a promising diagnostic tool since pathological processes can alter this ion gradient. This technique has already been used to investigate strokes and brain tumors [14]. However, sodium MRI remains a challenging technique due to several limitations. A major problem of sodium MRI is related to the very short transverse relaxation time (T 2 ) of Na (<2 ms) that requires the use of imaging sequences with very short echo times (<200 μs), generally not provided by the manufacturers to detect the MR signal. The second major limitation of sodium MRI is related to its very low in vivo sensitivity, 20,000­times lower, compared with proton and leading to poor signal­to­noise ratio [15]. To date, only two studies have been per­ formed in MS that examine the total sodium concentration accumulation in lesions and normal appearing brain tissue [16,17]. Both studies demonstrated significant accumulation of total sodium concentration inside white matter lesions, normal appearing white matter and gray matter compartments. In patients with early stage relapsing–remitting MS, Zaaraoui et al. found that sodium MRI revealed abnormally high concentrations of sodium in specific brain

Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis

Mitochondrial content within axons increases following demyelination in the central nervous system, presumably as a response to the changes in energy needs of axons imposed by redistribution of sodium channels. Myelin sheaths can be restored in demyelinated axons and remyelination in some multiple sclerosis lesions is extensive, while in others it is incomplete or absent. The effects of remyelination on axonal mitochondrial content in multiple sclerosis, particularly whether remyelination completely reverses the mitochondrial changes that follow demyelination, are currently unknown. In this study, we analysed axonal mitochondria within demyelinated, remyelinated and myelinated axons in post-mortem tissue from patients with multiple sclerosis and controls, as well as in experimental models of demyelination and remyelination, in vivo and in vitro. Immunofluorescent labelling of mitochondria (porin, a voltage-dependent anion channel expressed on all mitochondria) and axons (neurofilament), and ultrastructural imaging showed that in both multiple sclerosis and experimental demyelination, mitochondrial content within remyelinated axons was significantly less than in acutely and chronically demyelinated axons but more numerous than in myelinated axons. The greater mitochondrial content within remyelinated, compared with myelinated, axons was due to an increase in density of porin elements whereas increase in size accounted for the change observed in demyelinated axons. The increase in mitochondrial content in remyelinated axons was associated with an increase in mitochondrial respiratory chain complex IV activity. In vitro studies showed a significant increase in the number of stationary mitochondria in remyelinated compared with myelinated and demyelinated axons. The number of mobile mitochondria in remyelinated axons did not significantly differ from myelinated axons, although significantly greater than in demyelinated axons. Our neuropathological data and findings in experimental demyelination and remyelination in vivo and in vitro are consistent with a partial amelioration of the supposed increase in energy demand of demyelinated axons by remyelination.

Pattern of axonal injury in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis: Implications for multiple sclerosis

Axonal damage is a correlate for increasing disability in multiple sclerosis. Animal models such as experimental autoimmune encephalomyelitis (EAE) may help to develop better therapeutical neuroprotective strategies for the human disease. Here we investigate the pattern of axonal injury in murine myelin oligodendrocyte glycoprotein peptide 35–55 (MOG) induced EAE. Inflammatory infiltration, axonal densities and expression of amyloid precursor protein (APP), neurofilaments (SMI31 and 32) as well as expression of sodium channels were quantified in lesions, the perilesional area and normal appearing white matter (NAWM). Quantification of T cells and macrophages revealed a significant reduction of inflammatory infiltration at later disease stages despite an increase of demyelinated areas and persistent clinical disability. In lesions, axonal density was already significantly reduced early and throughout all investigated disease stages. A significant axonal loss was also seen in the grey matter and at later time points in the perilesion as well as NAWM. Numbers of axons characterized by non-phosphorylated neurofilaments and re-distribution of sodium channels 1.2 and 1.6 increased over the course of MOG-EAE whilst APP positive axons peaked at the maximum of disease. Finally, double-labeling experiments revealed a strong colocalization of sodium channels with APP, neurofilaments and the axonal nodal protein Caspr, but not glial and myelin markers in actively demyelinating lesions. In summary, progressive axonal loss distant from lesions is mainly associated with changes in neurofilament phosphorylation, re-distribution of sodium channels and demyelination. This axonal loss is dissociated from acute inflammatory infiltration and markedly correlates with clinical impairment. Consequently, therapeutic intervention may be promising at early stages of EAE focusing on inflammation, or later in disease targeting degenerative mechanisms.

Mitochondrial dysfunction plays a key role in progressive axonal loss in Multiple Sclerosis

Multiple Sclerosis is the most common inflammatory demyelinating disease of the central nervous system and is the leading cause of non traumatic neurological disability in young adults. In recent years it has become increasingly evident that axonal degeneration is a key player in the pathogenesis of disability in MS but the mechanisms that lead to axonal damage are not fully understood. It seems likely that the causes of axonal damage vary at different stages of the disease and several theories have evolved that address the mechanisms leading to axonal loss in the acute stages of demyelination. There has been relatively little attention given to investigation of the mechanisms involved in chronic axonal loss in the progressive stages of MS. We propose a hypothesis that mitochondria play a key role in this chronic axonal loss. Following demyelination there is redistribution of sodium channels along the axon and mitochondria are recruited to the demyelinated regions to meet the increased energy requirements necessary to maintain conduction. The mitochondria present within the chronically demyelinated axons will be functioning at full capacity. The axon may well be able to function for many years due to these adaptive mechanisms but we propose that eventually, despite antioxidant defences, free radical damage will accumulate and mitochondrial function will become compromised. ATP concentration within the axon will decrease and the effect on axonal function will be profound. The actual cause of cell death could be due to a number of mechanisms related to mitochondrial dysfunction including failure of ionic homeostasis, calcium influx, mitochondrial mediated cell death or impaired axonal transport. Whatever the cause of axonal loss our hypothesis is that mitochondria are central to this process. We explore steps to test this hypothesis and discuss the possible therapeutic approaches which target the mitochondrial mechanisms that may contribute to chronic axonal loss.

Increase of sodium channels in demyelinated lesions of multiple sclerosis

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.