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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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Scheme depicting the activation of the anti-oxidant transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) including selected target genes presumably involved in anti-oxidant responses.
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f1-ijms-13-11783: Scheme depicting the activation of the anti-oxidant transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) including selected target genes presumably involved in anti-oxidant responses.

Mentions: Over the past decades, several exogenous compounds have been suggested as anti-oxidative treatment approaches, many with ambiguous clinical success. In the recent years, the characterization of endogenous cellular anti-oxidative responses entered the focus of interest, e.g., signaling pathways involving nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Nrf2 is a redox-sensitive basic leucine zipper transcription factor which possesses a domain for interaction with the cytoplasmatic protein kelch like ECH associated protein (Keap-1) [4]. Upon disruption of the keap1 gene, constitutive activation of Nrf2 and its targeted genes causes juvenile lethality due to hyperkeratotic lesions in the esophagus and rodent fore- stomach. In vivo evidence of a functional interaction between Nrf2 and Keap1 has been demonstrated in a setting where the lethality of keap1 deficiency is reversed by the parallel knockout of the nrf2 gene [5]. Under basal conditions, Nrf2 remains in the cytoplasm, associated with the actin cytoskeleton through Keap1 [4]. In the status of homeostasis, Nrf2 is rapidly degraded and displays a half-life between 10 and 40 min [6,7]. In the presence of oxidative stress or electrophilic compounds, the Nrf2-Keap1 interaction is abolished via disruption of distinct cysteine residues in Keap1. Subsequently, Nrf2 translocates into the nucleus, where it dimerizes with small Maf proteins (musculoaponeurotic fibrosarcoma oncogene homologues) to increase the transcription rate of antioxidative response element (ARE)-driven genes (Figure 1). Thus, Nrf2 activation can inhibit or diminish cellular damage in different tissues and organs [8]. Nrf2 associated protective effects depend on the coordinated expression of genes with detoxifying, anti-oxidant capabilities. Here, two enzymatic systems are particularly important for the prevention of oxidative damage in cells of the nervous system: the heme oxygenase system and a group of enzymes involved in glutathione synthesis and utilization.


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)

Scheme depicting the activation of the anti-oxidant transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) including selected target genes presumably involved in anti-oxidant responses.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1-ijms-13-11783: Scheme depicting the activation of the anti-oxidant transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) including selected target genes presumably involved in anti-oxidant responses.
Mentions: Over the past decades, several exogenous compounds have been suggested as anti-oxidative treatment approaches, many with ambiguous clinical success. In the recent years, the characterization of endogenous cellular anti-oxidative responses entered the focus of interest, e.g., signaling pathways involving nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Nrf2 is a redox-sensitive basic leucine zipper transcription factor which possesses a domain for interaction with the cytoplasmatic protein kelch like ECH associated protein (Keap-1) [4]. Upon disruption of the keap1 gene, constitutive activation of Nrf2 and its targeted genes causes juvenile lethality due to hyperkeratotic lesions in the esophagus and rodent fore- stomach. In vivo evidence of a functional interaction between Nrf2 and Keap1 has been demonstrated in a setting where the lethality of keap1 deficiency is reversed by the parallel knockout of the nrf2 gene [5]. Under basal conditions, Nrf2 remains in the cytoplasm, associated with the actin cytoskeleton through Keap1 [4]. In the status of homeostasis, Nrf2 is rapidly degraded and displays a half-life between 10 and 40 min [6,7]. In the presence of oxidative stress or electrophilic compounds, the Nrf2-Keap1 interaction is abolished via disruption of distinct cysteine residues in Keap1. Subsequently, Nrf2 translocates into the nucleus, where it dimerizes with small Maf proteins (musculoaponeurotic fibrosarcoma oncogene homologues) to increase the transcription rate of antioxidative response element (ARE)-driven genes (Figure 1). Thus, Nrf2 activation can inhibit or diminish cellular damage in different tissues and organs [8]. Nrf2 associated protective effects depend on the coordinated expression of genes with detoxifying, anti-oxidant capabilities. Here, two enzymatic systems are particularly important for the prevention of oxidative damage in cells of the nervous system: the heme oxygenase system and a group of enzymes involved in glutathione synthesis and utilization.

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