Intravenous Administration of Thioredoxin Decreases Brain Damage Following Transient Focal Cerebral Ischemia in Mice

Hattori, Itaro; Takagi, Yasushi; Nakamura, Hajime; Nozaki, Kazuhiko; Bai, Jie; Kondo, Norihiko; Sugino, Toshiyuki; Nakagawa, Masaki; Hashimoto, Nobuo; Yodoi, Junji

doi:10.1089/152308604771978372

Cited by 117 publications

(81 citation statements)

References 42 publications

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“…Immunostaining was apparent in both cytosolic and mitochondrial compartments and showed marked variation in intensity between individual cells. These results confirm and extend data from a recent report by using Western blot analysis demonstrating that systemically administered hTrx can enter ischemic͞reperfused brain tissue (20).…”

Section: Administration Of Htrx Before Reperfusion Reduces Mi͞r Myocasupporting

confidence: 91%

Cardioprotective effects of thioredoxin in myocardial ischemia and the reperfusion role of S-nitrosation

Tao

Gao

Bryan

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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179

158

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Apoptosis contributes to myocardial ischemia/reperfusion (MI/R) injury, and both thioredoxin (Trx) and nitric oxide have been shown to exert antiapoptotic effects in vitro . Recent evidence suggests that this particular action of Trx requires S-nitrosation at Cys-69. The present study sought to investigate whether or not exogenously applied Trx reduces MI/R injury in vivo and to which extent this effect depends on S-nitrosation. Adult mice were subjected to 30 min of MI and treated with either vehicle or human Trx (hTrx, 2 mg/kg, i.p.) 10 min before reperfusion. Native hTrx was incorporated into myocardial tissue as shown by immunostaining, and reduced MI/R injury as evidenced by decreased terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining, DNA fragmentation, caspase-3 activity, and infarct size. When hTrx was partially S-nitrosated by preincubation with S -nitrosoglutathione, its cardioprotective effect was markedly enhanced. Treatment with hTrx significantly reduced p38 mitogen-activated protein kinase (MAPK) activity, and this effect was also potentiated by S-nitrosation. To further address the role of S-nitrosation for the overall antiapoptotic effect to Trx, the action of Escherichia coli Trx (eTrx) was investigated in the same model. Whereas eTrx inhibited MI/R-induced apoptosis to a degree similar to hTrx, S-nitrosation of this protein, which lacks Cys-69, failed to further enhance its antiapoptotic action. Collectively, our results demonstrate that systemically applied Trx is taken up by the myocardium to exert potent cardioprotective effects in vivo , offering interesting therapeutic avenues. In the case of hTrx, these effects are further potentiated by S-nitrosation, but this posttranslational modification is not essential for protection.

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Section: Administration Of Htrx Before Reperfusion Reduces Mi͞r Myocasupporting

confidence: 91%

Cardioprotective effects of thioredoxin in myocardial ischemia and the reperfusion role of S-nitrosation

Tao

Gao

Bryan

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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179

158

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“…This study shows that TCP-1 levels are increased in ischemic brain injury, representing a compensatory cellular mechanism to recover cytoskeletal damage. Thioredoxin, a redox protein, inhibits apoptosis and protects against oxidative stress [10,26]. Thioredoxin overexpression decreases brain damage against focal cerebral ischemia and protects against oxidative stress [10,26].…”

Section: Discussionmentioning

confidence: 99%

“…Thioredoxin, a redox protein, inhibits apoptosis and protects against oxidative stress [10,26]. Thioredoxin overexpression decreases brain damage against focal cerebral ischemia and protects against oxidative stress [10,26]. Peroxiredoxin-2 has thioredoxin-dependent peroxidase activity utilizing thioredoxin and thioredoxin reductase as electron donors for anti-oxidation.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Focal Cerebral Ischemic Injury in Male Rats

Koh

2010

J. Vet. Med. Sci.

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ABSTRACT. The present study identified the proteins that are differentially expressed during ischemic brain injury. Adult male rats were performed a middle cerebral artery occlusion (MCAO) to induce cerebral ischemia, and brains were collected at 24 hr after MCAO. Protein analysis was performed on the cerebral cortex using two-dimensional gel electrophoresis. Protein spots with a greater than 3 fold change in intensity between the sham and MCAO groups were identified by mass spectrometry. Among these proteins, 60 kDa heat shock protein, dehydropyrimidinase-related protein 2, t-complex protein 1, and Rho GDP dissociation inhibitor levels were significantly increased in MCAO group compared to those of the sham group. In contrast, thioredoxin, peroxiredoxin-2, stathmin, ubiquitin carboxyterminal hydrolase L1, guanine nucleotide-binding protein , pyridoxal-5'-phosphate phosphatase, and apoplipoprotein A-I levels were significantly decreased in MCAO group. These results suggest that cerebral ischemia induces neuronal cells death by changing expression levels of several proteins. Neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and stroke are a major cause of adult disability and mortality. Among these disorders, stroke is a serious cerebrovascular disorder and the most common cause of death. A previous study demonstrated that cerebral ischemia in an experimental stroke model involves apoptotic and survival signaling pathways and leads to neuronal cells death [24]. Oxidative stress, metabolic compromise, and mitochondrial dysfunction may trigger neuronal apoptosis in neurodegenerative disorders [17]. The mechanisms of neuronal cell death are very complex and vague. At present, little is known about the changes in protein expression in damaged brain region during ischemic injury. The purpose of this study was to investigate these changes in expression in the cerebral cortex following ischemic brain injury. MATERIALS AND METHODSExperimental animals: Male Sprague-Dawley rats (225-250 g, n=40) were purchased from Samtako Co. (Animal Breeding Center, Osan, Korea) and were randomly divided into two groups, sham-operated group and middle cerebral artery occlusion (MCAO)-operated group (n=20 per group). Animals were maintained under controlled temperature (25C) and lighting (14L:10D), and allowed free access to food and water. All animal experiments were carried out in accordance with the Guide for care and use of laboratory animals, and use of Gyeongsang National University.Middle cerebral artery occlusion: The MCAO model was prepared following the previously described method of intra-luminal vascular occlusion [16]. Animals were anesthetized with sodium pentobarbital (100 mg/kg). The right common carotid artery, internal carotid artery, and external carotid artery were exposed through a midline cervical incision. A 4/0 monofilament nylon was inserted from the external carotid artery into the lumen of the internal carotid artery until it obstructed the origin of the middle cerebral artery. At ...

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“…The same mice were also more resistant to hippocampal damage produced by administration of the excitotoxin kainic acid (401). In mice, intravenous infusion of recombinant human Trx for 2 h after 90 min of MCAO reduced infarct volume, neurological deficit, and protein carbonyl content (i.e., a marker of protein oxidation) (153). Overexpression of Trx in PC12 cells prolonged their survival in culture medium lacking nerve growth factor (NGF) and serum, suggesting that Trx can delay neuronal apoptosis (170); subsequent studies showed that Trx was a direct inhibitor of the apoptosis signal-regulating kinase (ASK) 1 (352).…”

Section: Sod2mentioning

confidence: 97%

Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia

Obrenovitch¹

2008

Physiological Reviews

230

176

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Ischemic tolerance describes the adaptive biological response of cells and organs that is initiated by preconditioning (i.e., exposure to stressor of mild severity) and the associated period during which their resistance to ischemia is markedly increased. This topic is attracting much attention because preconditioning-induced ischemic tolerance is an effective experimental probe to understand how the brain protects itself. This review is focused on the molecular and related functional changes that are associated with, and may contribute to, brain ischemic tolerance. When the tolerant brain is subjected to ischemia, the resulting insult severity (i.e., residual blood flow, disruption of cellular transmembrane gradients) appears to be the same as in the naive brain, but the ensuing lesion is substantially reduced. This suggests that the adaptive changes in the tolerant brain may be primarily directed against postischemic and delayed processes that contribute to ischemic damage, but adaptive changes that are beneficial during the subsequent test insult cannot be ruled out. It has become clear that multiple effectors contribute to ischemic tolerance, including: 1) activation of fundamental cellular defense mechanisms such as antioxidant systems, heat shock proteins, and cell death/survival determinants; 2) responses at tissue level, especially reduced inflammatory responsiveness; and 3) a shift of the neuronal excitatory/inhibitory balance toward inhibition. Accordingly, an improved knowledge of preconditioning/ischemic tolerance should help us to identify neuroprotective strategies that are similar in nature to combination therapy, hence potentially capable of suppressing the multiple, parallel pathophysiological events that cause ischemic brain damage.

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Intravenous Administration of Thioredoxin Decreases Brain Damage Following Transient Focal Cerebral Ischemia in Mice

Cited by 117 publications

References 42 publications

Cardioprotective effects of thioredoxin in myocardial ischemia and the reperfusion role of S-nitrosation

Cardioprotective effects of thioredoxin in myocardial ischemia and the reperfusion role of S-nitrosation

Proteomic Analysis of Focal Cerebral Ischemic Injury in Male Rats

Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia

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