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

Abstract

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.