Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). There is increasing evidence that MS is not only characterized by immune mediated inflammatory reactions, but also by neurodegenerative processes. There is cumulating evidence that neurodegenerative processes, for example mitochondrial dysfunction, oxidative stress, and glutamate (Glu) excitotoxicity, seem to play an important role in the pathogenesis of MS. The alteration of mitochondrial homeostasis leads to the formation of excitotoxins and redox disturbances. Mitochondrial dysfunction (energy disposal failure, apoptosis, etc.), redox disturbances (oxidative stress and enhanced reactive oxygen and nitrogen species production), and excitotoxicity (Glu mediated toxicity) may play an important role in the progression of the disease, causing axonal and neuronal damage. This review focuses on the mechanisms of mitochondrial dysfunction (including mitochondrial DNA (mtDNA) defects and mitochondrial structural/functional changes), oxidative stress (including reactive oxygen and nitric species), and excitotoxicity that are involved in MS and also discusses the potential targets and tools for therapeutic approaches in the future.

Keywords: biomarker; excitotoxin; glutamate; mitochondria; multiple sclerosis; neurodegeneration; oxidative stress.

Figure 1

The metabolism of tryptophane: the kynurenine pathway. The red arrows show the direction of the metabolism. KAT: kynurenine–aminotranspherase (adapted from Bohár et al., 2015 [72]).

Figure 2

Therapeutic agents and their target points in EAE. The red frames show the site of the damage, the red arrows the route of excitotoxicity, black arrows indicate the direction of a reaction, and T sign mean blockade. Abbreviation: ODC: oligodendrocyte; R: receptor; GLU: glutamate; mGluIII-R: metabotropic glutamate-receptor; NMDAR: N-methyl-d-aspartate receptor; GLAST: glutamate-aspartate transporter, in human it is called EAAT1 (excitatory amino acid transporter-1); GLT-1: glial transporter-1, in human it is EAAT2; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacide; xc-antiporter: system x_c⁻ cystin/glutamate antiporter; GCPII: Glutamate carboxipeptidase II; NAAG: -acetylaspartylglutamate; CNS: central nervous system.