Oxidative Damage to the Endoplasmic Reticulum is Implicated in Ischemic Neuronal Cell Death

Hayashi, Takeshi; Saito, Atsushi; Okuno, Sachiko; Ferrand-Drake, Michel; Dodd, Robert; Nishi, Tatsuro; Maier, Carolina M.; Kinouchi, Hiroyuki; Chan, Pak H.

doi:10.1097/01.wcb.0000089600.87125.ad

Cited by 116 publications

(99 citation statements)

References 60 publications

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“…In contrast, superoxide is known to instantly react with nitric oxide to form peroxynitrite, which can directly nitrosylate protein and impair protein function (Beckman and Crow, 1993). We recently demonstrated nitrosylated protein in ER fractions of rat brain proteins obtained from transient global cerebral ischemia (Hayashi et al, 2003b), which supports the role of ROS in ER damage.…”

Section: Discussionmentioning

confidence: 67%

Damage to the Endoplasmic Reticulum and Activation of Apoptotic Machinery by Oxidative Stress in Ischemic Neurons

Hayashi

Saito

Okuno

et al. 2005

J Cereb Blood Flow Metab

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158

119

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The endoplasmic reticulum (ER), which plays a role in apoptosis, is susceptible to oxidative stress. Because superoxide is produced in the brain after ischemia/reperfusion, oxidative injury to this organelle may be implicated in ischemic neuronal cell death. Activating transcription factor-4 (ATF-4) and C/EBP-homologous protein (CHOP), both of which are involved in apoptosis, are induced by severe ER stress. Using wild-type and human copper/zinc superoxide dismutase transgenic rats, we observed induction of these molecules in the brain after global cerebral ischemia and compared them with neuronal degeneration. In ischemic, wild-type brains, expression of ATF-4 and CHOP was increased in the hippocampal CA1 neurons that would later undergo apoptosis. Transgenic rats had a mild increase in ATF-4 and CHOP and minimal neuronal degeneration, indicating that superoxide was involved in ER stress-induced cell death. We further confirmed attenuation on induction of these molecules in transgenic mouse brains after focal ischemia. When superoxide was visualized with ethidium, signals for ATF-4 and superoxide overlapped in the same cells. Moreover, lipids in the ER were robustly peroxidized by ischemia but were attenuated in transgenic animals. This indicates that superoxide attacked and damaged the ER, and that oxidative ER damage is implicated in ischemic neuronal cell death.

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Section: Discussionmentioning

confidence: 67%

Damage to the Endoplasmic Reticulum and Activation of Apoptotic Machinery by Oxidative Stress in Ischemic Neurons

Hayashi

Saito

Okuno

et al. 2005

J Cereb Blood Flow Metab

Self Cite

158

119

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“…Its content responses to speed and intensity of lipid peroxidation, it indirectly responds to the damage degree of free radical. Furthermore, we detected 4-hydroxynonenal (HNE) production in hippocampus which is produced when superoxide peroxidates arachidonic acid in the lipid bilayer, and is a well-known oxidative stress marker (Hayashi et al, 2003). Analysis of AD brains demonstrates an increase in free HNE in amygdala, hippocampus, and parahippocampal gyrus of the AD brain compared with age-matched controls (Markesbery et al, 1998 ).…”

Section: Discussionmentioning

confidence: 99%

Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer's disease by reduction of oxidative stress

et al. 2010

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Cao, Xue-jun Sun, Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer's disease by reduction of oxidative stress, Brain Research (2010Research ( ), doi: 10.1016Research ( /j.brainres.2010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.A C C E P T E D M A N U S C R I P T A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 2 AbstractThis study is to examine if hydrogen-rich saline reduced amyloid β (Aβ) induced neural inflammation, and learning and memory deficits in a rat model. S-D male rats (n = 84, 280-330g) were divided into three groups, sham operated, Aβ1-42 injected and Aβ1-42 plus hydrogen-rich saline treated animals. Hydrogen-rich saline (5 ml/kg, i.p., daily) was injected for 14 days after intracerebroventricular injection of Aβ1-42. The levels of MDA, IL-6 and TNF-α were assessed by biochemical and ELISA analysis. Morris Water Maze and open field task were used to assess the memory dysfunction and motor dysfunction, respectively. LTP were used to detect the electrophysiology changes, HNE and GFAP immunohistochemistry were used to assess the oxidative stress and glial cell activation. After Aβ1-42 injection, the levels of MDA, IL-6, and TNF-α were increased in brain tissues and hydrogen-rich saline treatment suppressed MDA, IL-6, and TNF-α concentration. Hydrogen-rich saline treatment improved Morris Water Maze and enhanced LTP in hippocampus blocked by Aβ1-42.Furthermore, hydrogen-rich saline treatment also decreased the immunoreactivitiy of HNE and GFAP in hippocampus induced by Aβ1-42. In conclusion, hydrogen-rich saline prevented Aβ-induced neuroinflammation and oxidative stress, which may contribute to the improvement of memory dysfunction in this rat model.

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“…Therefore, keeping cells in a reducing condition with DTT weakens such a possibility. An opposite mechanism can also be hypothesized, where oxidative stress or mitochondrial damage can lead to the generation of ER stress [43][44][45]. It has also been suggested that mitochondria play a role in ER stress and ER-induced apoptosis [46][47][48].…”

Section: Discussionmentioning

confidence: 99%

Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2

Tehrani

Douglas

Lawhorn-Crews

et al. 2008

Eur J Nucl Med Mol Imaging

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Purpose-Fluoropyrimidines like 1-(2 -deoxy-2 -fluoro--D-arabinofuranosyl)-thymine (FMAU) and 3 -deoxy-3 -fluorothymidine (FLT) accumulate in tumors and are being used as positron emission tomography tumor-imaging tracers. Proliferating tissues with high thymidine kinase 1 (TK1) activity retain FLT; however, the mechanism of selective accumulation of FMAU in tumors and certain other tissues requires further study.Methods-Retention of [ 3 H]FLT and [ 3 H]FMAU was measured in prostate cancer cell lines PC3, LNCaP, DU145, and the breast cancer cell line MD-MBA-231, and the tracer metabolites were analyzed by high-performance liquid chromatography (HPLC). FMAU retention, thymidine kinase 2 (TK2) activity, and mitochondrial mass were determined in cells stressed by depleted cell culture medium or by treating with oxidative, reductive, and energy stress, or specific adenosine monophosphate-activated protein kinase activator, or eIF2 inhibitor. TK1 and TK2 activities and mitochondrial mass were determined by FLT phosphorylation, 1--D-arabinofuranosylthymine (Ara-T) phosphorylation, and flow cytometry, respectively.Results-FMAU retention in rapidly proliferating cancer cell lines was five to ten times lower than FLT after 10 min incubation. HPLC analysis of the cellular extracts showed that phosphorylated tracers are the main retained metabolites. Nutritional stress decreased TK1 activity and FLT retention but increased retained FMAU. TK2 inhibition decreased FMAU retention and phosphorylation with negligible effects on FLT. Oxidative, reductive, or energy stress increased FMAU retention and correlated with mitochondrial mass (r 2 = 0.88, p=0.006). FMAU phosphorylation correlated with increased TK2 activity (r 2 =0.87, p=0.0002).Conclusion-FMAU is preferably phosphorylated by TK2 and can track TK2 activity and mitochondrial mass in cellular stress. FMAU may provide an early marker of treatment effects.

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Oxidative Damage to the Endoplasmic Reticulum is Implicated in Ischemic Neuronal Cell Death

Cited by 116 publications

References 60 publications

Damage to the Endoplasmic Reticulum and Activation of Apoptotic Machinery by Oxidative Stress in Ischemic Neurons

Damage to the Endoplasmic Reticulum and Activation of Apoptotic Machinery by Oxidative Stress in Ischemic Neurons

Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer's disease by reduction of oxidative stress

Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2

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