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.

Dynamic Balance of Microglia and Astrocytes Involved in the Remyelinating Effect of Ginkgolide B

“…Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), accompanied by the following pathological manifestations, such as immune cell invasion, demyelination and axonal degeneration (Reich et al, 2018). Although the exact cause of oligodendrocyte damage and loss is not fully elucidated, several hypotheses have been proposed and are being tested, including oxidative stress, mitochondrial dysfunction, neuroinflammation, protein misfolding (Dendrou et al, 2015;Stone and Lin, 2015;Ibitoye et al, 2016;Rajda et al, 2017).…”

Strategies for Neuroprotection in Multiple Sclerosis and the Role of Calcium

“…As described above, excitotoxicity is known to occur under pathological conditions and has been associated with both experimental autoimmune encephalomyelitis (EAE) and MS [164]. AMPA and KA receptors are involved in the pathological pathway of excitotoxicity, and an inhibition of these receptors can decrease EAE severity [24].…”

Novel Approaches of Oxidative Stress Mechanisms in the Multiple Sclerosis Pathophysiology and Therapy

“…In this reaction, the greatest amount of harmful ROS and RNS is formed. In the case of the disturbed mitochondrial antioxidant production, the following are observed: decreased adenosine triphosphate synthesis, impaired Ca 2+ , and elevated ROS and RNS (16,19). Mitochondrial dysfunction plays a particular role in inflammatory processes.…”

“…They possess their own DNA and are genetically independent organelles. Moreover, they are involved in apoptosis and metabolism of fatty acids (16)(17)(18)). An oxidative energy metabolism is required for the lifespan of neurons while the large amount of adenosine triphosphate is produced during oxidative phosphorylation.…”