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Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters.

Lee DH, Gold R, Linker RA - Int J Mol Sci (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Erlangen; Schwabachanlage 6, Erlangen 91054, Germany; E-Mail: ralf.linker@uk-erlangen.de.

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.

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Mechanisms of oxidative injury and cytoprotection in a demyelinating Central Nervous System (CNS) lesion. Free radicals comprise nitric oxide (NO) and reactive oxygen as well as nitrogen species (Reactive Oxygen Species (ROS) or Reactive Nitrogen Species (RNS), respectively) which are mainly produced by macrophages, microglia and astrocytes. ROS and RNS lead to damage of neurons, axons, myelin and oliogdendrocytes (indicated by arrows). This process also may involve mitochondrial damage. Black squares indicate mitochondria which accumulate in injured axons. The cytoptrotective transcription factor Nrf2 is present in neurons, oligodendrocytes and astrocytes as part of the cellular anti-oxidative response. Abbreviations: OL, oligodendrocyte; MP, myeloperoxidase.
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f2-ijms-13-11783: Mechanisms of oxidative injury and cytoprotection in a demyelinating Central Nervous System (CNS) lesion. Free radicals comprise nitric oxide (NO) and reactive oxygen as well as nitrogen species (Reactive Oxygen Species (ROS) or Reactive Nitrogen Species (RNS), respectively) which are mainly produced by macrophages, microglia and astrocytes. ROS and RNS lead to damage of neurons, axons, myelin and oliogdendrocytes (indicated by arrows). This process also may involve mitochondrial damage. Black squares indicate mitochondria which accumulate in injured axons. The cytoptrotective transcription factor Nrf2 is present in neurons, oligodendrocytes and astrocytes as part of the cellular anti-oxidative response. Abbreviations: OL, oligodendrocyte; MP, myeloperoxidase.

Mentions: Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS affecting both white and grey matter. Histopathologically, MS is characterized by focal demyelinating lesions throughout the white matter, which frequently coincide with cortical demyelination and which may be preceded by apoptotic destruction of oligodendrocytes [74,75]. Additionally, axonal damage is a key feature of MS pathogenesis that best correlates with permanent neurological deficits in patients. In general, axonal damage is observed in early as well as chronically demyelinating lesions and, in acute stages, is associated with the number of infiltrating immune cells. Inflammatory processes with infiltrating leukocytes play a crucial role in the pathology of the MS lesion mediated by the production of inflammatory mediators which also involve reactive oxygen species. Yet, also non-inflammatory mechanisms such as mitochondrial dysfunction may contribute to neurodegeneration in MS [76]. Excessive release of free radicals may play an important role in MS pathogenesis and promote transendothelial leukocyte migration as well as contribute to oligodendrocyte damage and as axonal degeneration [77–80]. Thus, oxidative stress stemming from different cell types and targeting several cellular components of the CNS to a variable extent is involved in this detrimental concert (Figure 2).


Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters.

Lee DH, Gold R, Linker RA - Int J Mol Sci (2012)

Mechanisms of oxidative injury and cytoprotection in a demyelinating Central Nervous System (CNS) lesion. Free radicals comprise nitric oxide (NO) and reactive oxygen as well as nitrogen species (Reactive Oxygen Species (ROS) or Reactive Nitrogen Species (RNS), respectively) which are mainly produced by macrophages, microglia and astrocytes. ROS and RNS lead to damage of neurons, axons, myelin and oliogdendrocytes (indicated by arrows). This process also may involve mitochondrial damage. Black squares indicate mitochondria which accumulate in injured axons. The cytoptrotective transcription factor Nrf2 is present in neurons, oligodendrocytes and astrocytes as part of the cellular anti-oxidative response. Abbreviations: OL, oligodendrocyte; MP, myeloperoxidase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472775&req=5

f2-ijms-13-11783: Mechanisms of oxidative injury and cytoprotection in a demyelinating Central Nervous System (CNS) lesion. Free radicals comprise nitric oxide (NO) and reactive oxygen as well as nitrogen species (Reactive Oxygen Species (ROS) or Reactive Nitrogen Species (RNS), respectively) which are mainly produced by macrophages, microglia and astrocytes. ROS and RNS lead to damage of neurons, axons, myelin and oliogdendrocytes (indicated by arrows). This process also may involve mitochondrial damage. Black squares indicate mitochondria which accumulate in injured axons. The cytoptrotective transcription factor Nrf2 is present in neurons, oligodendrocytes and astrocytes as part of the cellular anti-oxidative response. Abbreviations: OL, oligodendrocyte; MP, myeloperoxidase.
Mentions: Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS affecting both white and grey matter. Histopathologically, MS is characterized by focal demyelinating lesions throughout the white matter, which frequently coincide with cortical demyelination and which may be preceded by apoptotic destruction of oligodendrocytes [74,75]. Additionally, axonal damage is a key feature of MS pathogenesis that best correlates with permanent neurological deficits in patients. In general, axonal damage is observed in early as well as chronically demyelinating lesions and, in acute stages, is associated with the number of infiltrating immune cells. Inflammatory processes with infiltrating leukocytes play a crucial role in the pathology of the MS lesion mediated by the production of inflammatory mediators which also involve reactive oxygen species. Yet, also non-inflammatory mechanisms such as mitochondrial dysfunction may contribute to neurodegeneration in MS [76]. Excessive release of free radicals may play an important role in MS pathogenesis and promote transendothelial leukocyte migration as well as contribute to oligodendrocyte damage and as axonal degeneration [77–80]. Thus, oxidative stress stemming from different cell types and targeting several cellular components of the CNS to a variable extent is involved in this detrimental concert (Figure 2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Erlangen; Schwabachanlage 6, Erlangen 91054, Germany; E-Mail: ralf.linker@uk-erlangen.de.

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.

Show MeSH
Related in: MedlinePlus