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

Abstract

Scientific background: Neurodegeneration following inflammatory injury is considered to be a pathological correlate of irreversible disability in patients with multiple sclerosis (MS). The presence of amyloid precursor protein in active lesions, oxidative injury of mitochondrial DNA, dis/inactivation of mitochondrial enzymes, loss of axonal density in normal appearing white matter, reduction of N-acetylaspartate (NAA)/creatinin ratio in magnetic resonance spectroscopy (MRS) and the correlation between reduced NAA levels and disability have been determined as evidences of neurodegeneration in MS. In the disease immunopathogenesis some biological indicators of axonal transsection as NAA, actin, tubulin, L-neurofilaments, anti-axolemma IgG, antigangliozide antibodies, 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 disability has been made in the very early times when the first histopathologic signs of multiple sclerosis were discovered. Although it has a long past, the role of neurodegenerative mechanisms in the axonal transsection has been recently described. Genetic factors, excitotoxicity, apoptosis, 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 component 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 receptors increased on postsynaptic membrane and apoptotic cellular death occur because of prolonged activation of these receptors. Proinflammatory 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 deficits 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 exchange, leading to further Ca entry. Energy failure will also promote Ca release from intracellular stores. Also, after demyelination a new organisation of different types of sodium channels has been shown to appear on axons and inflammatory cells. In this manuscript the role of voltage-gated sodium channels and glutamate excitotoxicity, and interactions of glutamate with receptors and cytokines on the immunopathogenesis of multiple sclerosis are reviewed and discussed.