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 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 Genetic inactivation of RIP1 kinase activity in rats protects against ischemic brain injury

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Kimberly Stark ◽  
Tatiana Goncharov ◽  
Eugene Varfolomeev ◽  
Luke Xie ◽  
Hai Ngu ◽  
...  
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Neurological Disorders ◽  
Kinase Activity ◽  
Artery Occlusion ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Genetic Inactivation ◽  
Cell Death Pathways ◽  
Cerebral Artery Occlusion

AbstractRIP1 kinase-mediated inflammatory and cell death pathways have been implicated in the pathology of acute and chronic disorders of the nervous system. Here, we describe a novel animal model of RIP1 kinase deficiency, generated by knock-in of the kinase-inactivating RIP1(D138N) mutation in rats. Homozygous RIP1 kinase-dead (KD) rats had normal development, reproduction and did not show any gross phenotypes at baseline. However, cells derived from RIP1 KD rats displayed resistance to necroptotic cell death. In addition, RIP1 KD rats were resistant to TNF-induced systemic shock. We studied the utility of RIP1 KD rats for neurological disorders by testing the efficacy of the genetic inactivation in the transient middle cerebral artery occlusion/reperfusion model of brain injury. RIP1 KD rats were protected in this model in a battery of behavioral, imaging, and histopathological endpoints. In addition, RIP1 KD rats had reduced inflammation and accumulation of neuronal injury biomarkers. Unbiased proteomics in the plasma identified additional changes that were ameliorated by RIP1 genetic inactivation. Together these data highlight the utility of the RIP1 KD rats for target validation and biomarker studies for neurological disorders.

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

Abstract TMP69: Endoglin Deficiency Exacerbates Ischemic Brain Injury

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Fanxia Shen ◽  
Vincent Degos ◽  
Zhenying Han ◽  
Eun-Jung Choi ◽  
William L. Young ◽  
...  
Keyword(s):  
Brain Injury ◽  
Infarct Volume ◽  
Paradoxical Embolism ◽  
Artery Occlusion ◽  
Vascular Density ◽  
Ischemic Brain Injury ◽  
Myocardial Repair ◽  
Ischemic Brain ◽  
Removal Time ◽  
Adhesive Removal

Background and Objective: Endoglin (Eng) deficiency causes hereditary hemorrhagic telangiectasia (HHT) and impairs myocardial repair. Pulmonary arteriovenous malformations in HHT patients are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that Eng deficiency exacerbates ischemic brain injury. Methods: Eng heterozygous ( Eng +/- ) mice and wild type (WT) mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Infarct volume and CD68 + cells were quantified 3 days and vascular density was determined 60 days after pMCAO. Behavior was assessed by corner test and adhesive removal test at 3, 15, 30 and 60 days after pMCAO. Matrix metalloproteinase 9 (Mmp9) and Notch1 expression in bone marrow (BM)-derived macrophages from Eng +/- and WT were analyzed using real-time RT-PCR. Results: Eng +/- mice had a larger Infarct volume than WT mice (22±6% of the affected hemisphere vs. 16±6%, p=0.04). Eng +/- mice had longer adhesive-removal time (p<0.05) and more frequent turning to the lesion side than WT mice at 15, 30 and 60 days (p<0.05) after pMCAO. Both groups had similar numbers of CD68 + cells in the peri-infarct area at 3 days after pMCAO (370±80 vs 338±44 cells/mm 2 , p=0.37), but Eng +/- mice had lower peri-infarct vessel density (417±69 vs 490±52 vessels/mm 2 , p=0.05) at 60 days after pMCAO. Up-regulation of Mmp9 and Notch1 expression in response to VEGF was attenuated in Eng +/- BM-derived macrophages. Conclusions: Endoglin deficiency exacerbated brain injury and behavior dysfunction in mice after pMCAO and was associated with reduced angiogenesis. Although macrophage homing was not affected, reduced expression of two angiogenic-related genes, Mmp9 and Notch1 , by Eng +/- BM-derived macrophages suggests a potential role of these cells in recovery from an ischemic injury.

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 AMP-Dependent Hypothermia Affords Protection from Ischemic Brain Injury

2012 ◽  
Vol 33 (2) ◽  
pp. 171-174 ◽  
Author(s):  
Mirko Muzzi ◽  
Francesco Blasi ◽  
Alberto Chiarugi
Keyword(s):  
Brain Injury ◽  
Brain Ischemia ◽  
Adenosine Monophosphate ◽  
Artery Occlusion ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Stroke Treatment ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Cerebral Artery Occlusion

In light of the relevance of therapeutic hypothermia to stroke treatment, we investigated whether 5′-adenosine monophosphate (AMP)-dependent cooling affords protection from ischemic brain injury. We show that hypothermia by AMP is because of adenosine A1 receptor (A1R) activation and is not invariantly associated with hypotension. Inhibition of ecto-5′-nucleotidase-dependent constitutive degradation of brain extracellular AMP by methylene-ADP (AMPCP) also suffices to prompt A1R-dependent hypothermia without hypotension. Both intraischemic and postischemic hypothermia by AMP or AMPCP reduce infarct volumes and mortality of mice subjected to transient middle cerebral artery occlusion. Data disclose that AMP-dependent hypothermia is of therapeutic relevance to treatment of brain ischemia.

scholarly journals Adenovirus-Mediated Gene Transfer of Glial Cell Line-Derived Neurotrophic Factor Prevents Ischemic Brain Injury after Transient Middle Cerebral Artery Occlusion in Rats

1999 ◽  
Vol 19 (12) ◽  
pp. 1336-1344 ◽  
Author(s):  
Hisashi Kitagawa ◽  
Chihoko Sasaki ◽  
Kenichi Sakai ◽  
Atsushi Mori ◽  
Yasuhide Mitsumoto ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Brain Injury ◽  
Gene Transfer ◽  
Neurotrophic Factor ◽  
Treated Group ◽  
Artery Occlusion ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Gdnf Gene ◽  
Cerebral Artery Occlusion

To examine a possible protective effect of exogenous glial cell line-derived neurotrophic factor (GDNF) gene expression against ischemic brain injury, a replication-defective adenoviral vector containing GDNF gene (Ad-GDNF) was directly injected into the cerebral cortex at 1 day before 90 minutes of transient middle cerebral artery occlusion (MCAO) in rats. 2,3,5-Triphenyltetrazolium chloride staining showed that infarct volume of the Ad-GDNF-injected group at 24 hours after the transient MCAO was significantly smaller than that of vehicle- or Ad-LacZ-treated group. Enzyme-linked immunosorbent assay (ELISA) for immunoreactive GDNF demonstrated that GDNF gene products in the Ad-GDNF-injected group were higher than those of vehicle-treated group at 24 hours after transient MCAO. Immunoreactive GDNF staining was obviously detected in the cortex around the needle track just before or 24 hours after MCAO in the Ad-GDNF group, whereas no or slight GDNF staining was detected in the vehicle group. The numbers of TUNEL, immunoreactive caspase-3, and cytochrome c-positive neurons induced in the ipsilateral cerebral cortex at 24 hours after transient MCAO were markedly reduced by the Ad-GDNF group. These results suggest that the successful exogenous GDNF gene transfer ameliorates ischemic brain injury after transient MCAO in association with the reduction of apoptotic signals.

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