Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis

Lu, Fengmin; Selak, Mary; O’Connor, John; Croul, Sidney; Lorenzana, Carlos; Butunoi, Catalin; Kálmán, Bernadette

doi:10.1016/s0022-510x(00)00343-9

Cited by 300 publications

(244 citation statements)

References 43 publications

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“…Several studies have analyzed radical mediated tissue injury in MS lesions biochemically and through the immunocytochemical identification of oxidized nucleotides, proteins or lipids [104]. The results suggested increased oxidative injury in MS brains, although not all studies were able to show significant differences between MS and control tissue [4,10,24,69,71,88,105,107]. Furthermore, on a cellular basis oxidized epitopes were mainly seen in macrophages and astrocytes, cells which are not the prime target of destruction within the lesions [69,24,105].…”

Section: Oxidative Damage In Ms Lesionsmentioning

confidence: 99%

The molecular basis of neurodegeneration in multiple sclerosis

2011

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a b s t r a c tStudies aimed to elucidate the pathogenesis of the disease and to find new therapeutic options for multiple sclerosis (MS) patients heavily rely on experimental autoimmune encephalomyelitis (EAE) as a suitable experimental model. This strategy has been highly successful for the inflammatory component of the disease, but had so far little success in the development of neuroprotective therapies, which are also effective in the progressive stage of the disease. Here we discuss opportunities and limitations of EAE models for MS research and provide an overview on the complex mechanisms leading to demyelination and neurodegeneration in this disease. We suggest that the underlying mechanisms involve adaptive and innate immunity. However, mitochondrial injury, resulting in energy failure, is a key element of neurodegeneration in MS and is apparently driven by radical production in activated microglia.

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Section: Oxidative Damage In Ms Lesionsmentioning

confidence: 99%

The molecular basis of neurodegeneration in multiple sclerosis

2011

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“…In order to compensate for the impulse conduction at demyelinated regions along the axon, mitochondria migrate into the sites of axonal damage to provide ATP (65). However, with time, mitochondrial function is affected because of mitochondrial DNA damage mediated by free radicals generated from activated immune cells, a common feature of chronic-MS plaques (66). Thus, mitochondria play a central role in the function and survival of the neuron.…”

Section: Discussionmentioning

confidence: 99%

A Novel Unbiased Proteomic Approach to Detect the Reactivity of Cerebrospinal Fluid in Neurological Diseases

Menon

Steer

Short

et al. 2011

Molecular & Cellular Proteomics

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Neurodegenerative diseases, such as multiple sclerosis represent global health issues. Accordingly, there is an urgent need to understand the pathogenesis of this and other central nervous system disorders, so that more effective therapeutics can be developed. Cerebrospinal fluid is a potential source of important reporter molecules released from various cell types as a result of central nervous system pathology. Here, we report the development of an unbiased approach for the detection of reactive cerebrospinal fluid molecules and target brain proteins from patients with multiple sclerosis. To help identify molecules that may serve as clinical biomarkers for multiple sclerosis, we have biotinylated proteins present in the cerebrospinal fluid and tested their reactivity against brain homogenate as well as myelin and myelin-axolemmal complexes. Proteins were separated by two-dimensional gel electrophoresis, blotted onto membranes and probed separately with biotinylated unprocessed cerebrospinal fluid samples. Protein spots that reacted to two or more multiple sclerosis-cerebrospinal fluids were further analyzed by matrix assisted laser desorption ionization-time-of-flight time-of-flight mass spectrometry. In addition to previously reported proteins found in multiple sclerosis cerebrospinal fluid, such as ␣␤ crystallin, enolase, and 14 -3-3-protein, we have identified several additional molecules involved in mitochondrial and energy metabolism, myelin gene expression and/or cytoskeletal organization. These include aspartate aminotransferase, cyclophilin-A, quaking protein, collapsin response mediator protein-2, ubiquitin carboxy-terminal hydrolase L1, and cofilin. To further validate these findings, the cellular expression pattern of collapsin response mediator protein-2 and ubiquitin carboxy-terminal hydrolase L1 were investigated in human chronic-active MS lesions by immunohistochemistry. The observation that in multiple sclerosis lesions phosphorylated collapsin response mediator protein-2 was increased, whereas Ubiquitin carboxy-terminal hydrolase L1 was down-regulated, not only highlights the importance of these molecules in the pathology of this disease, but also illustrates the use of our approach in attempting to decipher the complex pathological processes leading to multiple sclerosis and other neurodegenerative diseases.

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“…Excessive NO and ROS production in the brain are believed to contribute to neurodegenerative processes [24][25][26]. Various dietary-derived polyphenolic compounds that inhibit the LPSinduced NO production may have neuroprotective potential [15,20,27].…”

Section: Discussionmentioning

confidence: 99%

Protective effect of 1,2,4-benzenetriol on LPS-induced NO production by BV2 microglial cells

Hou

Chen

et al. 2005

J Biomed Sci

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SummaryHydroxyhydroquinone or 1,2,4-benzenetriol (BT) detected in the beverages has a structure that coincides with the water-soluble form of a sesame lignan, sesamol. We previously showed that sesame antioxidants had neuroprotective abilities due to their antioxidant properties and/or inducible nitric oxide synthase (iNOS) inhibition. However, studies show that BT can induce DNA damage through the generation of reactive oxygen species (ROS). Therefore, we were interested to investigate the neuroprotective effect of BT in vitro and in vivo. The results showed that instead of enhancing free radical generation, BT dosedependently (10-100 lM) attenuated nitrite production, iNOS mRNA and protein expression in lipopolysaccharide (LPS)-stimulated murine BV-2 microglia. BT significantly reduced LPS-induced NF-jB and p38 MAPK activation. It also significantly reduced the generation of ROS in H 2 O 2 -induced BV-2 cells and in H 2 O 2 -cellfree conditions. The neuroprotective effect of BT was further demonstrated in the focal cerebral ischemia model of Sprague-Dawley rat. Taken together, the inhibition of LPS-induced nitrite production might be due to the suppression of NF-jB, p38 MAPK signal pathway and the ROS scavenging effect. These effects might help to protect neurons from the ischemic injury.

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Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis

Cited by 300 publications

References 43 publications

The molecular basis of neurodegeneration in multiple sclerosis

The molecular basis of neurodegeneration in multiple sclerosis

A Novel Unbiased Proteomic Approach to Detect the Reactivity of Cerebrospinal Fluid in Neurological Diseases

Protective effect of 1,2,4-benzenetriol on LPS-induced NO production by BV2 microglial cells

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