scholarly journals Roles of NAD+, PARP-1, and Sirtuins in Cell Death, Ischemic Brain Injury, and Synchrotron Radiation X-Ray-Induced Tissue Injury

Scientifica ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Weihai Ying
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Synchrotron Radiation ◽  
Brain Damage ◽  
Tissue Injury ◽  
Ischemic Brain Injury ◽  
Biological Processes ◽  
Ischemic Brain ◽  
X Ray ◽  
Parp 1

NAD+plays crucial roles in a variety of biological processes including energy metabolism, aging, and calcium homeostasis. Multiple studies have also shown that NAD+administration can profoundly decrease oxidative cell death and ischemic brain injury. A number of recent studies have further indicated that NAD+administration can decrease ischemic brain damage, traumatic brain damage and synchrotron radiation X-ray-induced tissue injury by such mechanisms as inhibiting inflammation, decreasing autophagy, and reducing DNA damage. Our latest study that applies nano-particles as a NAD+carrier has also provided first direct evidence demonstrating a key role of NAD+depletion in oxidative stress-induced ATP depletion. Poly(ADP-ribose) polymerase-1 (PARP-1) and sirtuins are key NAD+-consuming enzymes that mediate multiple biological processes. Recent studies have provided new information regarding PARP-1 and sirtuins in cell death, ischemic brain damage and synchrotron radiation X-ray-induced tissue damage. These findings have collectively supported the hypothesis that NAD+metabolism, PARP-1 and sirtuins play fundamental roles in oxidative stress-induced cell death, ischemic brain injury, and radiation injury. The findings have also supported “the Central Regulatory Network Hypothesis”, which proposes that a fundamental network that consists of ATP, NAD+and Ca2+as its key components is the essential network regulating various biological processes.

scholarly journals Ischemic Brain Injury is Mediated by the Activation of Poly(ADP-Ribose)Polymerase

1997 ◽  
Vol 17 (11) ◽  
pp. 1143-1151 ◽  
Author(s):  
Matthias Endres ◽  
Zhao-Qi Wang ◽  
Shobu Namura ◽  
Christian Waeber ◽  
Michael A. Moskowitz
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Tissue Injury ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Ischemic Brain Injury ◽  
Cell Nuclei ◽  
Ischemic Brain ◽  
Nad Depletion

Poly(ADP-ribose)polymerase (PARP, EC 2.4.2.30), an abundant nuclear protein activated by DNA nicks, mediates cell death in vitro by nicotinamide adenine dinucleotide (NAD) depletion after exposure to nitric oxide. The authors examined whether genetic deletion of PARP (PARP null mice) or its pharmacologic inhibition by 3-aminobenzamide (3-AB) attenuates tissue injury after transient cerebral ischemia. Twenty-two hours after reperfusion following 2 hours of filamentous middle cerebral artery occlusion, ischemic injury was decreased in PARP−/− and PARP+/− mice compared with PARP+/+ litter mates, and also was attenuated in 129/SV wild-type mice after 3-AB treatment compared with controls. Infarct sparing was accompanied by functional recovery in PARP−/− and 3-AB–treated mice. Increased poly(ADP-ribose) immunostaining observed in ischemic cell nuclei 5 minutes after reperfusion was reduced by 3-AB treatment. Levels of NAD—the substrate of PARP—were reduced 2 hours after reperfusion and were 35% of contralateral levels at 24 hours. The decreases were attenuated in PARP−/− mice and in 3-AB–treated animals. Poly(ADP-ribose)polymerase cleavage by caspase-3 (CPP-32) has been proposed as an important step in apoptotic cell death. Markers of apoptosis, such as oligonucleosomal DNA damage, total DNA fragmentation, and the density of terminal deoxynucleotidyl transferase dUTP nick-end–labelled (TUNEL +) cells, however, did not differ in ischemic brain tissue of PARP−/− mice or in 3-AB–treated animals versus controls, although there were differences in the number of TUNEL-stained cells reflecting the decrease in infarct size. Thus, ischemic brain injury activates PARP and contributes to cell death most likely by NAD depletion and energy failure, although the authors have not excluded a role for PARP in apoptotic cell death at earlier or later stages in ischemic cell death. Inhibitors of PARP activation could provide a potential therapy in acute stroke.

scholarly journals p53-mediated neuronal cell death in ischemic brain injury

2010 ◽  
Vol 26 (3) ◽  
pp. 232-240 ◽  
Author(s):  
Li-Zhi Hong ◽  
Xiao-Yuan Zhao ◽  
Hui-Ling Zhang
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ischemic Brain Injury ◽  
Ischemic Brain

scholarly journals Hsp70 Overexpression Sequesters AIF and Reduces Neonatal Hypoxic/Ischemic Brain Injury

2005 ◽  
Vol 25 (7) ◽  
pp. 899-910 ◽  
Author(s):  
Yasuhiko Matsumori ◽  
Shwuhuey M Hong ◽  
Koji Aoyama ◽  
Yang Fan ◽  
Takamasa Kayama ◽  
...  
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Ischemic Brain Injury ◽  
Wild Type ◽  
Hsp 70 ◽  
Artery Ligation ◽  
Ischemic Brain ◽  
Carotid Artery Ligation ◽  
High Level ◽  
Apoptosis Inducing Factor

Apoptosis is implicated in neonatal hypoxic/ischemic (H/I) brain injury among various forms of cell death. Here we investigate whether overexpression of heat shock protein (Hsp) 70, an antiapoptotic protein, protects the neonatal brain from H/I injury and the pathways involved in the protection. Postnatal day 7 (P7) transgenic mice overexpressing rat Hsp70 (Tg) and their wild-type littermates (Wt) underwent unilateral common carotid artery ligation followed by 30 mins exposure to 8% O2. Significant neuroprotection was observed in Tg versus Wt mice on both P12 and P21, correlating with a high level of constitutive but not inducible Hsp70 in the Tg. More prominent injury was observed in Wt and Tg mice on P21, suggesting its continuous evolution after P12. Western blot analysis showed that translocation of cytochrome c, but not the second mitochondria-derived activator of caspase (Smac)/DIABLO and apoptosis-inducing factor (AIF), from mitochondria into cytosol was significantly reduced in Tg 24 h after H/I compared with Wt mice. Coimmunoprecipitation detected more Hsp70 bound to AIF in Tg than Wt mice 24 h after H/I, inversely correlating with the amount of nuclear, but not cytosolic, AIF translocation. Our results suggest that interaction between Hsp70 and AIF might have reduced downstream events leading to cell death, including the reduction of nuclear AIF translocation in the neonatal brains of Hsp70 Tg mice after H/I.

scholarly journals Differential Modulation of Estrogen Receptors (ERs) in Ischemic Brain Injury: A Role for ERα in Estradiol-Mediated Protection against Delayed Cell Death

Endocrinology ◽  
2006 ◽  
Vol 147 (6) ◽  
pp. 3076-3084 ◽  
Author(s):  
Dena B. Dubal ◽  
Shane W. Rau ◽  
Paul J. Shughrue ◽  
Hong Zhu ◽  
Jin Yu ◽  
...  
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Estrogen Receptors ◽  
Expression Profiles ◽  
Artery Occlusion ◽  
Aging Brain ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Delayed Cell Death ◽  
Injured Brain

Abstract Estradiol enhances plasticity and survival of the injured brain. Our previous work demonstrates that physiological levels of estradiol protect against cerebral ischemia in the young and aging brain through actions involving estrogen receptors (ERs) and alterations in gene expression. The major goal of this study was to establish mechanisms of neuroprotective actions induced by low levels of estradiol. We first examined effects of estradiol on the time-dependent evolution of ischemic brain injury. Because estradiol is known to influence apoptosis, we hypothesized that it acts to decrease the delayed phase of cell death observed after middle cerebral artery occlusion (MCAO). Furthermore, because ERs are pivotal to neuroprotection, we examined the temporal expression profiles of both ER subtypes, ERα and ERβ, after MCAO and delineated potential roles for each receptor in estradiol-mediated neuroprotection. We quantified cell death in brains at various times after MCAO and analyzed ER expression by RT-PCR, in situ hybridization, and immunohistochemistry. We found that during the first 24 h, the mechanisms of estradiol-induced neuroprotection after MCAO are limited to attenuation of delayed cell death and do not influence immediate cell death. Furthermore, we discovered that ERs exhibit distinctly divergent profiles of expression over the evolution of injury, with ERα induction occurring early and ERβ modulation occurring later. Finally, we provide evidence for a new and functional role for ERα in estradiol-mediated protection of the injured brain. These findings indicate that physiological levels of estradiol protect against delayed cell death after stroke-like injury through mechanisms requiring ERα.

scholarly journals The role of oxidative stress in perinatal hypoxic-ischemic brain injury

2012 ◽  
Vol 140 (1-2) ◽  
pp. 35-41 ◽  
Author(s):  
Brankica Vasiljevic ◽  
Svjetlana Maglajlic-Djukic ◽  
Miroslava Gojnic ◽  
Sanja Stankovic
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Brain Damage ◽  
Ischemic Brain Injury ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Hypoxic Ischemic Brain Injury ◽  
Gpx Activity ◽  
Neurodevelopment Outcome

Introduction. The pathogenesis of perinatal hypoxic-ischemic brain damage is highly complex. Objective. The aim of this study was to assess the role of oxidative stress in hypoxic-ischemic brain injury and subsequent abnormal neurological outcome in infants with perinatal hypoxic-ischemic encephalopathy (HIE). We estimated perinatal oxidative brain damage measuring activity of glutathione peroxidase (GPX) in cerebrospinal fluid (CSF) as an indirect biomarker of free radical production during cerebral hypoxia-ischemia in correlation with the level of intracellular enzyme neuron specific enolase (NSE) in CSF as a biomarker of extend of brain injury. Methods. Ninety neonates (>32 GA) with perinatal HIE were enrolled prospectively. HIE was categorized into three stages according Sarnat and Sarnat clinical scoring system and changes seen on amplitude integrated EEG. CSF for GPX analysis and NSE analysis was taken in the first 72 hours of life. Neurodevelopment outcome was assessed at 12 months of corrected gestational age. Results. GPX activity in CSF was in good relation with clinical stage of HIE (p<0.0001) and GA (p<0.0001) and significantly corresponded with subsequent neurodevelopment outcome (p<0.001). GPX activity in CSF showed a strong correlation with NSE levels in CSF (p<0.001) as the biomarker of extent of brain injury. Conclusion. Our results suggest that oxidative stress might be important contributing factor in perinatal hypoxic-ischemic brain damage, particularly in preterm neonates.

scholarly journals Microglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortex

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Shi-Yang Ye ◽  
Joanna E. Apple ◽  
Xiao Ren ◽  
Fu-Lei Tang ◽  
Ling-Ling Yao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Brain Damage ◽  
Hippocampal Neurogenesis ◽  
Conditional Knockout ◽  
Microglial Cells ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Sensorimotor Deficits ◽  
Anti Inflammatory

Abstract Background Vacuolar sorting protein 35 (VPS35), a critical component of retromer, is essential for selective endosome-to-Golgi retrieval of membrane proteins. It is highly expressed in microglial cells, in addition to neurons. We have previously demonstrated microglial VPS35’s functions in preventing hippocampal, but not cortical, microglial activation, and in promoting adult hippocampal neurogenesis. However, microglial VPS35’s role in the cortex in response to ischemic stroke remains largely unclear. Methods We used mice with VPS35 cKO (conditional knockout) in microglial cells and examined and compared their responses to ischemic stroke with control mice. The brain damage, cell death, changes in glial cells and gene expression, and sensorimotor deficits were assessed by a combination of immunohistochemical and immunofluorescence staining, RT-PCR, Western blot, and neurological functional behavior tests. Results We found that microglial VPS35 loss results in an increase of anti-inflammatory microglia in mouse cortex after ischemic stroke. The ischemic stroke-induced brain injury phenotypes, including brain damage, neuronal death, and sensorimotor deficits, were all attenuated by microglial VPS35-deficiency. Further analysis of protein expression changes revealed a reduction in CX3CR1 (CX3C chemokine receptor 1) in microglial VPS35-deficient cortex after ischemic stroke, implicating CX3CR1 as a potential cargo of VPS35 in this event. Conclusion Together, these results reveal an unrecognized function of microglial VPS35 in enhancing ischemic brain injury-induced inflammatory microglia, but suppressing the injury-induced anti-inflammatory microglia. Consequently, microglial VPS35 cKO mice exhibit attenuation of ischemic brain injury response.

scholarly journals Ethyl pyruvate protects against hypoxic-ischemic brain injury via anti-cell death and anti-inflammatory mechanisms

2010 ◽  
Vol 37 (3) ◽  
pp. 711-722 ◽  
Author(s):  
Hongxia Shen ◽  
Xiaoming Hu ◽  
Can Liu ◽  
Suping Wang ◽  
Wenting Zhang ◽  
...  
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Ethyl Pyruvate ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Hypoxic Ischemic Brain Injury ◽  
Anti Inflammatory

scholarly journals STAT1 is Activated in Neurons after Ischemia and Contributes to Ischemic Brain Injury

2002 ◽  
Vol 22 (11) ◽  
pp. 1311-1318 ◽  
Author(s):  
Yasushi Takagi ◽  
Jun Harada ◽  
Alberto Chiarugi ◽  
Michael A. Moskowitz
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Strain Differences ◽  
Cell Types ◽  
Interferon Γ ◽  
Artery Occlusion ◽  
Cytokine Signaling ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Phosphorylated Akt

Signal transducers and activators of transcription (STAT) proteins are a family of transcription factors that play a crucial role in growth and differentiation in a variety of cell types. Among them, STAT1, which is expressed in the brain and directly activated by reactive oxygen species, participates in the regulation of cytokine-signaling and cellular responses, particularly to interferon-γ. Very little, however, is known about the importance of STAT1 during brain injury. The authors found that STAT1 was phosphorylated at tyrosine701 and serine727 and translocated into neuronal nuclei within hours after middle cerebral artery occlusion. At later time points, STAT1 immunoreactivity colocalized with TUNEL-positive neurons, thereby suggesting a role in cell death. In mice genetically deficient in STAT1 expression, the volume of ischemic brain injury was reduced, neurologic deficits were less severe, and TUNEL-positive neurons were also less numerous compared with wild-type mice. STAT1-knockout mice showed increased phosphorylated Akt and decreased pro-***caspase-3 cleavage. Major strain differences in phosphorylated STAT3 or cyclooxygenase-2 protein expression were not found after ischemia. These results indicate that STAT1 is activated and translocated within ischemic neurons and may contribute to brain injury by regulating transcription and phosphorylation of proteins related to apoptosis and cell death.

scholarly journals Neuroprotection against Focal Ischemic Brain Injury by Inhibition of c-Jun N-Terminal Kinase and Attenuation of the Mitochondrial Apoptosis-Signaling Pathway

2005 ◽  
Vol 25 (6) ◽  
pp. 694-712 ◽  
Author(s):  
Yanqin Gao ◽  
Armando P. Signore ◽  
Wei Yin ◽  
Guodong Cao ◽  
Xiao-Ming Yin ◽  
...  
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Signaling Pathway ◽  
Strong Support ◽  
Serine Phosphorylation ◽  
Ischemic Brain Injury ◽  
Mitochondrial Apoptosis ◽  
Ischemic Brain ◽  
Jnk Activation

c-Jun N-terminal kinase (JNK) is an important stress-responsive kinase that is activated by various forms of brain insults. In this study, we have examined the role of JNK activation in neuronal cell death in a murine model of focal ischemia and reperfusion; furthermore, we investigated the mechanism of JNK in apoptosis signaling, focusing on the mitochondrial-signaling pathway. We show here that JNK activity was induced in the brain 0.5 to 24 h after ischemia. Systemic administration of SP600125, a small molecule JNK-specific inhibitor, diminished JNK activity after ischemia and dose-dependently reduced infarct volume. c-Jun N-terminal kinase inhibition also attenuated ischemia-induced expression of Bim, Hrk/DP5, and Fas, but not the expression of Bcl-2 or FasL. In strong support of a role for JNK in promoting the mitochondrial apoptosis-signaling pathway, JNK inhibition prevented ischemia-induced mitochondrial translocation of Bax and Bim, release of cytochrome c and Smac, and activation of caspase-9 and caspase-3. The potential mechanism by which JNK promoted Bax translocation after ischemia was further studied using coimmunoprecipitation, and the results revealed that JNK activation caused serine phosphorylation of 14-3-3, a cytoplasmic sequestration protein of Bax, leading to Bax disassociation from 14-3-3 and subsequent translocation to mitochondria. These results confirm the role of JNK as a critical cell death mediator in ischemic brain injury, and suggest that one of the mechanisms by which JNK triggers the mitochondrial apoptosis-signaling pathway is via promoting Bax and Bim translocation.

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