Abstract
Oxidative stress plays a crucial role in many neurodegenerative conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s as well as Huntington’s disease. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis (MS). Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic-progressive MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Here, fumaric acid esters (FAE) are a new, orally available treatment option which had already been tested in phase II/III MS trials demonstrating beneficial effects on relapse rates and magnetic resonance imaging markers. In vitro, application of dimethylfumarate (DMF) leads to stabilization of Nrf2, activation of Nrf2-dependent transcriptional activity and abundant synthesis of detoxifying proteins. Furthermore, application of FAE involves direct modification of the inhibitor of Nrf2, Kelch-like ECH-associated protein 1. On cellular levels, the application of FAE enhances neuronal survival and protects astrocytes against oxidative stress. Increased levels of Nrf2 are detected in the central nervous system of DMF treated mice suffering from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In EAE, DMF ameliorates the disease course and improves preservation of myelin, axons and neurons. Finally, Nrf2 is also up-regulated in the spinal cord of autopsy specimens from untreated patients with MS, probably as part of a naturally occurring anti-oxidative response. In summary, oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapies like FAE.
Highlights
IntroductionIn almost every chronic neurologic disease, spanning from inflammatory backgrounds to underlying primary degenerative processes, oxidative stress may play a major functional role in pathogenesis of disease initiation and progression
Oxidative Stress in Neurologic DiseasesIn almost every chronic neurologic disease, spanning from inflammatory backgrounds to underlying primary degenerative processes, oxidative stress may play a major functional role in pathogenesis of disease initiation and progression.In general, oxidative stress is generated by the inability to detoxify or to repair the resulting damage caused by the generation of reactive oxygen species (ROS) like superoxide (O2−), hydrogen peroxide (H2O2) or hydroxyl radicals (·OH)
Oxidative stress is generated by the inability to detoxify or to repair the resulting damage caused by the generation of reactive oxygen species (ROS) like superoxide (O2−), hydrogen peroxide (H2O2) or hydroxyl radicals (·OH)
Summary
In almost every chronic neurologic disease, spanning from inflammatory backgrounds to underlying primary degenerative processes, oxidative stress may play a major functional role in pathogenesis of disease initiation and progression. Oxidative stress is generated by the inability to detoxify or to repair the resulting damage caused by the generation of reactive oxygen species (ROS) like superoxide (O2−), hydrogen peroxide (H2O2) or hydroxyl radicals (·OH). In concert, these molecules may eventually lead to oxidation or nitrosylation resulting in cellular damage, associated with cell death and subsequent organ dysfunction. Evidence indicates that oxidative stress, glutamate excitotoxicity and inflammation are major contributors to the resulting neuropathology, as for example shown in thiamine deficiency. In this condition, increased production of ROS is observed in the brain [1]. Stress in thiamine deficiency, further changes include an increased expression of heme oxygenase (HO)-1 and intercellular adhesion molecule (ICAM)-1 as well as microglia activation [2,3]
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