Nitrotyrosine as a marker for peroxynitrite‐induced neurotoxicity: the beginning or the end of the end of dopamine neurons?

Kuhn, Donald M.; Sakowski, Stacey A.; Sadidi, Mahdieh; Geddes, Timothy J.

doi:10.1111/j.1471-4159.2004.02346.x

Cited by 65 publications

(53 citation statements)

References 88 publications

(154 reference statements)

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“…In the experiments using peroxynitrite or MPTP, tyrosine nitration inactivated TH, which is a rate-limiting enzyme in dopamine synthesis, and is found in ␣-synuclein, a major component of Lewy bodies (Kuhn et al, 2004). Rotenone dose-dependently increased DNA fragmentation, which is a marker of apoptosis induction, in human dopaminergic SH-SY5Y cells, and during this process, the amount of TH was unchanged, as shown previously .…”

Section: Nitration Signal Inhibits and Redistributes Vmat2 937mentioning

confidence: 51%

“…Rotenone is known to cause ROS generation during the process of apoptosis induction. It is also known that nitration of tyrosine residues on intracellular proteins is caused by peroxynitrite, which is formed by intracellular ROS and NO (Koppenol et al, 1992;Kuhn et al, 2004). To investigate the involvement of nitration in rotenone-induced neurotoxicity, we examined nitration of the tyrosine residues of intracellular proteins using anti-nitrotyrosine antibody.…”

Section: Resultsmentioning

confidence: 99%

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Mitochondrial Complex I Inhibitor Rotenone Inhibits and Redistributes Vesicular Monoamine Transporter 2 via Nitration in Human Dopaminergic SH-SY5Y Cells

Watabe¹,

Nakaki²

2008

Mol Pharmacol

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Parkinson's disease is a progressive neurodegenerative disorder characterized by selective degeneration of nigrostriatal dopaminergic neurons. Long-term systemic mitochondrial complex I inhibition by rotenone induces selective degeneration of dopaminergic neurons in rats. We have reported dopamine redistribution from vesicles to the cytosol to play a crucial role in selective dopaminergic cell apoptosis. In the present study, we investigated how rotenone causes dopamine redistribution to the cytosol using an in vitro model of human dopaminergic SH-SY5Y cells. Rotenone stimulated nitration of the tyrosine residues of intracellular proteins. The inhibition of nitric-oxide synthase or reactive oxygen species decreased the amount of nitrotyrosine and attenuated rotenone-induced apoptosis. When we examined the intracellular localization of dopamine immunocytochemically using anti-dopamine/vesicular monoamine transporter 2 (VMAT2) antibodies and quantitatively using high-performance liquid chromatography, inhibiting nitration was found to suppress rotenone-induced dopamine redistribution from vesicles to the cytosol. We demonstrated rotenone to nitrate tyrosine residues of VMAT2 using an immunocytochemical method with anti-nitrotyrosine antibodies and biochemically with immunoprecipitation experiments. Rotenone inhibited the VMAT2 activity responsible for the uptake of dopamine into vesicles, and this inhibition was reversed by inhibiting nitration. Moreover, rotenone induced the accumulation of aggregate-like formations in the stained image of VMAT2, which was reversed by inhibiting nitration. Our findings demonstrate that nitration of the tyrosine residues of VMAT2 by rotenone leads to both functional inhibition and accumulation of aggregate-like formations of VMAT2 and consequently to the redistribution of dopamine to the cytosol and apoptosis of dopaminergic SH-SY5Y cells.

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Section: Nitration Signal Inhibits and Redistributes Vmat2 937mentioning

confidence: 51%

Section: Resultsmentioning

confidence: 99%

Mitochondrial Complex I Inhibitor Rotenone Inhibits and Redistributes Vesicular Monoamine Transporter 2 via Nitration in Human Dopaminergic SH-SY5Y Cells

Watabe¹,

Nakaki²

2008

Mol Pharmacol

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“…Although the nature of ROS was not identified in our studies, superoxide is the primary reactant in the formation of all ROS and reactive nitrogen species, which are also implicated in the etiology of PD (Kuhn et al, 2004). The importance of MPTP-induced ROS production on dopamine neurotoxicity in vivo is underscored in transgenic mice overexpressing copper/zinc superoxide dismutase, a key ROS scavenging enzyme (Przedborski et al, 1992).…”

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confidence: 90%

Uncoupling Protein-2 Is Critical for Nigral Dopamine Cell Survival in a Mouse Model of Parkinson's Disease

Andrews¹,

Horváth²,

Barnstable³

et al. 2005

J. Neurosci.

184

145

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Mitochondrial uncoupling proteins dissociate ATP synthesis from oxygen consumption in mitochondria and suppress free-radical production. We show that genetic manipulation of uncoupling protein-2 (UCP2) directly affects substantia nigra dopamine cell function. Overexpression of UCP2 increases mitochondrial uncoupling, whereas deletion of UCP2 reduces uncoupling in the substantia nigraventral tegmental area. Overexpression of UCP2 decreased reactive oxygen species (ROS) production, which was measured using dihydroethidium because it is specifically oxidized to fluorescent ethidium by the superoxide anion, whereas mice lacking UCP2 exhibited increased ROS relative to wild-type controls. Unbiased electron microscopic analysis revealed that the elevation of in situ mitochondrial ROS production in UCP2 knock-out mice was inversely correlated with mitochondria number in dopamine neurons. Lack of UCP2 increased the sensitivity of dopamine neurons to 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP), whereas UCP2 overexpression decreased MPTP-induced nigral dopamine cell loss. The present results expose the critical importance of UCP2 in normal nigral dopamine cell metabolism and offer a novel therapeutic target, UCP2, for the prevention/treatment of Parkinson's disease.

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“…The extent of RNI-mediated damage was expressed by comparing sample values to the provided nitrated BSA standards. Nitrated tyrosine residues are expressed as nitro-BSA equivalents (18).…”

Section: Animalsmentioning

confidence: 99%

Oxidative modification of the intestinal mucus layer is a critical but unrecognized component of trauma hemorrhagic shock-induced gut barrier failure

Fishman

Levy

Alli

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Oxidative modification of the intestinal mucus layer is a critical but unrecognized component of trauma hemorrhagic shock-induced gut barrier failure. Am J Physiol Gastrointest Liver Physiol 304: G57-G63, 2013. First published November 1, 2012; doi:10.1152/ajpgi.00170.2012.-Recent studies demonstrate that mechanisms underlying gut barrier failure include systemic processes and less studied luminal processes. We thus tested the hypothesis that mucus layer oxidation is a component of trauma/hemorrhagic shock-induced gut injury and dysfunction. Male Sprague-Dawley rats underwent trauma/hemorrhagic shock. Controls underwent trauma only. Mucus from the terminal 30 cm of the ileum was collected, processed, and analyzed for reactive nitrogen intermediates (RNI)-mediated damage, reactive oxygen species (ROS)-induced damage, and total antioxidant capacity. The distal ileum was stained to quantify the mucus layer; gut permeability was assessed physiologically. A time course study was conducted to determine the temporal sequence of mucus layer damage. The role of free radicalmediated damage to the gut barrier was investigated by the effect of the free radical scavenger dimethyl sulfoxide on trauma/hemorrhagic shock-induced changes on the mucus and on gut permeability. Trauma/hemorrhagic shock increased intestinal permeability, which was associated with evidence of loss of the unstirred mucus layer. These changes correlated with increased ROS-and RNI-mediated mucus damage and loss of mucus total antioxidant capacity. Based on the time course study, ROS-mediated mucus damage and loss of total antioxidant capacity were present immediately following shock, whereas RNI-mediated damage was delayed for 3 h. Dimethyl sulfoxide ameliorated gut barrier loss, ROS-mediated changes to the mucus layer, and loss of total antioxidant capacity. There was no change in RNI-induced changes to the mucus layer. These results support the hypothesis that trauma/hemorrhagic shock leads to mucus damage and gut dysfunction through the generation of free radical species.intestinal mucus layer; gut-mediated sepsis IN CERTAIN CLINICAL SCENARIOS, including major trauma and hemorrhage, gut injury and the subsequent loss of the gut barrier function have been implicated in the development of the acute respiratory distress syndrome, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome (8). Thus prevention or amelioration of gut injury in conditions associated with intestinal ischemia would be a key therapeutic strategy. Several such strategies, including early enteral nutrition, have been identified and instituted into clinical practice (1,20). However, the development of successful new clinical therapies is based on a complete knowledge of the mechanisms of the injuries they are being developed to treat. Consequently, a considerable amount of investigative attention has been committed to elucidating the pathogenesis of stress-and trauma/ shock-induced gut injury and gut barrier failure. These studies have largely focused on the ...

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Nitrotyrosine as a marker for peroxynitrite‐induced neurotoxicity: the beginning or the end of the end of dopamine neurons?

Cited by 65 publications

References 88 publications

Mitochondrial Complex I Inhibitor Rotenone Inhibits and Redistributes Vesicular Monoamine Transporter 2 via Nitration in Human Dopaminergic SH-SY5Y Cells

Mitochondrial Complex I Inhibitor Rotenone Inhibits and Redistributes Vesicular Monoamine Transporter 2 via Nitration in Human Dopaminergic SH-SY5Y Cells

Uncoupling Protein-2 Is Critical for Nigral Dopamine Cell Survival in a Mouse Model of Parkinson's Disease

Oxidative modification of the intestinal mucus layer is a critical but unrecognized component of trauma hemorrhagic shock-induced gut barrier failure

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