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  Steps in Multiple Sclerosis Pathogenesis - II: The Role of Biological Markers, Sodium Channels and Glutamate in Neurodegeneration [Turk J Neurol]
Turk J Neurol. 2006; 12(2): 98-105

Steps in Multiple Sclerosis Pathogenesis - II: The Role of Biological Markers, Sodium Channels and Glutamate in Neurodegeneration

Ömer Faruk Aydın1, Aslı Kurne2, Rana Karabudak2
1Department Of Pediatric Neurology, Ondokuz Mayis University, Faculty Of Medicine, Samsun, Turkey
2Department Of Neurology, Neuroimmunology Unit, Hacettepe University, Faculty Of Medicine, Ankara, Turkey

Scientific background: Neurodegeneration following inflammatory in-
jury is considered to be a pathological correlate of irreversible disability
in patients with multiple sclerosis (MS). The presence of amyloid precur-
sor protein in active lesions, oxidative injury of mitochondrial DNA,
dis/inactivation of mitochondrial enzymes, loss of axonal density in nor-
mal appearing white matter, reduction of N-acetylaspartate (NAA)/cre-
atinin ratio in magnetic resonance spectroscopy (MRS) and the correla-
tion between reduced NAA levels and disability have been determined
as evidences of neurodegeneration in MS. In the disease immunopatho-
genesis some biological indicators of axonal transsection as NAA, ac-
tin, tubulin, L-neurofilaments, anti-axolemma IgG, antigangliozide anti-
bodies, glial fibrillary acid protein, S-100 protein, nitric oxide, neuronal
specific enolase, 14-3-3 protein, apoprotein E have been described and
put in association with the clinicial status.
The description of axonal transsection which is a main cause of disabi-
lity has been made in the very early times when the first histopatholo-
gic signs of multiple sclerosis were discovered. Although it has a long
past, the role of neurodegenerative mechanisms in the axonal transsec-
tion has been recently described. Genetic factors, excitotoxicity, apop-
tosis, depletion of growth factors and energy, inducible demyelination
are the other mechanisms that cause neurodegeneration.
Recent studies have shown that glutamate excitotoxicity may be a com-
ponent in the pathogenesis of MS. Glutamate transporters determine
the levels of extracellular glutamate and are essential to prevent excitotoxicity. In MS, the evident association between insidious and prolonged
microglial activation and glutamate excitotoxicity has been emphasized
and in addition glutamate excitotoxicity is considered to be responsible
due to progressive loss of oligodendrocytes (OLG). Excitotoxicity in OLGs
begins as Ca
+ +
influx via AMPA/kainat receptors. The number of AMPA re-
ceptors increased on postsynaptic membrane and apoptotic cellular death
occur because of prolonged activation of these receptors. Proinflamma-
tory cytokines such as interlukine-1 and tumor necrosis-· as increasing
receptor expression on OLGs cause to be prone to excitotoxic death.
The gradual loss of axons is thought to underlie irreversible clinical defi-
cits in this disease. The precise mechanisms of axonopathy are poorly
understood, but likely involve excess accumulation of Ca ions. In healthy
fibers, ATP-dependent pumps support homeostasis of ionic gradients.
When energy supply is limited, either due to inadequate delivery (e.g.,
ischemia, mitochondrial dysfunction) and/or excessive utilization (e.g.,
conduction along demyelinated axons), ion gradients break down,
unleashing a variety of aberrant cascades, ultimately leading to Ca
overload. During Na pump dysfunction, Na can enter axons through
non-inactivating Na channels, promoting axonal Na overload. This will
gate voltage-sensitive Ca channels and stimulate reverse Na-Ca exchan-
ge, leading to further Ca entry. Energy failure will also promote Ca
release from intracellular stores. Also, after demyelination a new orga-
nisation of different types of sodium channels has been shown to ap-
pear on axons and inflammatory cells.
In this manuscript the role of voltage-gated sodium channels and glu-
tamate excitotoxicity, and interactions of glutamate with receptors and
cytokines on the immunopathogenesis of multiple sclerosis are revie-
wed and discussed.

Keywords: multiple sclerosis, immunopathogenesis, neurodegeneration


Ömer Faruk Aydın, Aslı Kurne, Rana Karabudak. Steps in Multiple Sclerosis Pathogenesis - II: The Role of Biological Markers, Sodium Channels and Glutamate in Neurodegeneration. Turk J Neurol. 2006; 12(2): 98-105

Corresponding Author: Rana Karabudak, Türkiye


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