Upregulated miR-29b promotes neuronal cell death by inhibiting Bcl2L2 after ischemic brain injury

Programmed cell death (PCD) is an ordered and tightly controlled set of changes in gene expression and protein activity that results in neuronal cell death during brain development. This article reviews the molecular pathways by which PCD is executed in mammalian cells and the potential relation of these pathways to pathologic neuronal cell death. Whereas the classical patterns of apoptotic morphologic change often do not appear in the brain after ischemia, there is emerging biochemical and pharmacologic evidence suggesting a role for PCD in ischemic brain injury. The most convincing evidence for the induction of PCD after ischemia includes the altered expression and activity in the ischemic brain of deduced key death-regulatory genes. Furthermore, studies have shown that alterations in the activity of these gene products by peptide inhibitors, viral vector-mediated gene transfer, antisense oligonucleotides, or transgenic mouse techniques determine, at least in part, whether ischemic neurons live or die after stroke. These studies provide strong support for the hypothesis that PCD contributes to neuronal cell death caused by ischemic injury. However, many questions remain regarding the precise pathways that initiate, sense, and transmit cell death signals in ischemic neurons and the molecular mechanisms by which neuronal cell death is executed at different stages of ischemic injury. Elucidation of these pathways and mechanisms may lead to the development of novel therapeutic strategies for brain injury after stroke and related neurologic disorders.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600080 ◽

2005 ◽

Vol 25 (7) ◽

pp. 899-910 ◽

Cited By ~ 140

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.

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The LPA-CDK5-Tau Pathway Mediates Neuronal Injury in an In Vitro Model of Ischemia-Reperfusion Insult

10.21203/rs.3.rs-685165/v1 ◽

2021 ◽

Author(s):

Yaya Wang ◽

Jie Zhang ◽

Liqin Huang ◽

Yanhong Mo ◽

Changyu Wang ◽

...

Keyword(s):

Brain Injury ◽

Molecular Mechanisms ◽

Biological Effects ◽

Ischemia Reperfusion ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ischemic Brain ◽

Pathophysiological Process ◽

Vitro Model

Abstract Lysophosphatidic acid (LPA) is a common glycerol phospholipid and an important extracellular signaling molecule. LPA binds to its receptors and mediates a variety of biological effects, including the pathophysiological process underlying ischemic brain damage and traumatic brain injury. However, the molecular mechanisms mediating the pathological role of LPA are not clear. Here, we found that LPA activates cyclin-dependent kinase 5 (CDK5). CDK5 phosphorylates tau, which leads to neuronal cell death. Inhibition of LPA production or blocking its receptors reduced the abnormal activation of CDK5 and phosphorylation of tau, thus reversing the death of neurons. Our data indicate that the LPA-CDK5-Tau pathway plays an important role in the pathophysiological process after ischemic stroke. Inhibiting the LPA pathway may be a potential therapeutic target for treating ischemic brain injury.

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

Endocrinology ◽

10.1210/en.2005-1177 ◽

2006 ◽

Vol 147 (6) ◽

pp. 3076-3084 ◽

Cited By ~ 137

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.

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Disruption of Bax Protein Prevents Neuronal Cell Death but Produces Cognitive Impairment in Mice following Traumatic Brain Injury

Journal of Neurotrauma ◽

10.1089/neu.2007.0441 ◽

2008 ◽

Vol 25 (7) ◽

pp. 755-767 ◽

Cited By ~ 39

Author(s):

Roya Tehranian ◽

Marie E. Rose ◽

Vincent Vagni ◽

Alicia M. Pickrell ◽

Raymond P. Griffith ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Cognitive Impairment ◽

Brain Injury ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Bax Protein

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

Scientifica ◽

10.1155/2013/691251 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 7

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.

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