P4-383: Notch signaling induces neuronal cell death via the NFkB-Bim pathway in ischemic stroke

2011 ◽  
Vol 7 ◽  
pp. e47-e47
Author(s):  
Yuri Choi
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Notch Signaling ◽  
Neuronal Cell Death ◽  
Neuronal Cell

scholarly journals Interplay between Notch and p53 promotes neuronal cell death in ischemic stroke

2017 ◽  
Vol 38 (10) ◽  
pp. 1781-1795 ◽  
Author(s):  
Priyanka Balaganapathy ◽  
Sang-Ha Baik ◽  
Karthik Mallilankaraman ◽  
Christopher G Sobey ◽  
Dong-Gyu Jo ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Notch Signaling ◽  
Neural Progenitor Cells ◽  
Neuronal Cell Death ◽  
Active Form ◽  
Neuronal Cell ◽  
Membrane Receptors ◽  
Neuronal Membrane ◽  
Stroke Severity

Stroke is the world's second leading cause of mortality, with a high incidence of morbidity. Numerous neuronal membrane receptors are activated by endogenous ligands and may contribute to infarct development. Notch is a well-characterized membrane receptor involved in cell differentiation and proliferation, and now shown to play a pivotal role in cell death during ischemic stroke. Blockade of Notch signaling by inhibition of γ-secretase, an enzyme that generates the active form of Notch, is neuroprotective following stroke. We have also identified that Pin1, a peptidyl-prolyl isomerase that regulates p53 transactivation under stress, promotes the pathogenesis of ischemic stroke via Notch signaling. Moreover, Notch can also mediate cell death through a p53-dependent pathway, resulting in apoptosis of neural progenitor cells. The current study has investigated the interplay between Notch and p53 under ischemic stroke conditions. Using pharmacological inhibitors, we have demonstrated that a Notch intracellular domain (NICD)/p53 interaction is involved in transcriptional regulation of genes downstream of p53 and NICD to modify stroke severity. Furthermore, the NICD/p53 interaction confers stability to p53 by rescuing it from ubiquitination. Together, these results indicate that Notch contributes to the pathogenesis of ischemic stroke by promoting p53 stability and signaling.

scholarly journals miR-455 inhibits neuronal cell death by targeting TRAF3 in cerebral ischemic stroke

2016 ◽  
Vol Volume 12 ◽  
pp. 3083-3092 ◽  
Author(s):  
Shengtao Yao ◽  
Bo Tang ◽  
Gang Li ◽  
Ruiming Fan ◽  
Fang Cao
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

Abstract W P210: Plasma Kallikrein Induces Ischemic Brain Damage Through Cleavage-Dependent Activation of NMDA Receptors

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Gongxiong wu ◽  
Long-Jun Wu ◽  
David E. Clapham ◽  
Edward P. Feener
Keyword(s):  
Cell Culture ◽  
Cell Death ◽  
Ischemic Stroke ◽  
Nmda Receptor ◽  
Brain Damage ◽  
Infarct Volume ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Plasma Kallikrein ◽  
Ischemic Brain

Background and Purpose: Ischemic stroke ultimately leads to brain dysfunction and neurological deficits. However, the mechanisms that contribute to neuronal injury and dysfunction in ischemic stroke are not fully understood. Recent studies have shown that pharmacological inhibition of the serine protease plasma kallikrein (PK) reduced neuron death and neurological impairment in ischemic brain in mice. In this study, we examine the effects of PK on the neuronal cell death and brain damage in mice and investigate the molecular mechanism of PK-induced neuronal cell death in ischemic stroke. Methods: Ischemia was produced in wild-type (WT) and PK knockout mice by permanent middle cerebral artery occlusion (pMCAO). Infarct volume was quantified by TTC staining and brain function was evaluated by neurological scoring. The effect of PK on neuron cell death in cell culture was determined by lactate dehydrogenase (LDH) release. NMDA receptor function was measured by patch clamp and Ca2+ imaging. NR1 cleavage was detected by western blot. The effect of systemic PK inhibition on pMCAO-induced infarct volume was evaluated in mice treated with the PK inhibitor (BPCCB) or vehicle alone delivered using subcutaneously implanted osmotic pumps. Results: We show that PK deficiency in mice decreased MCAO-induced infarct volume by 39.8% (P<0.01) and improved neurological function compared responses in WT mice. Addition of PK to cell culture media enhanced NMDA-induced cell death of cortical neurons. We further show that PK induced cleavage of NR1 and identify the cleavage site in the extracellular N-terminal domain of NR1. The truncated form of NR1 displayed enhanced NMDA-stimulated current and calcium influx. Treatment of mice with a PK inhibitor reduced MCAO-induced brain damage and neuronal injury. Conclusions: PK enhances NMDA receptor-mediated excitotoxicity and ischemic neuronal death. These findings suggest that PK may serve as a potential therapeutic target for treatment of ischemic stroke.

scholarly journals Evidence that collaboration between HIF-1α and Notch-1 promotes neuronal cell death in ischemic stroke

2014 ◽  
Vol 62 ◽  
pp. 286-295 ◽  
Author(s):  
Yi-Lin Cheng ◽  
Jong-Sung Park ◽  
Silvia Manzanero ◽  
Yuri Choi ◽  
Sang-Ha Baik ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Notch 1

scholarly journals Calsenilin Contributes to Neuronal Cell Death in Ischemic Stroke

2012 ◽  
Vol 23 (4) ◽  
pp. 402-412 ◽  
Author(s):  
Jong-Sung Park ◽  
Silvia Manzanero ◽  
Jae-Woong Chang ◽  
Yuri Choi ◽  
Sang-Ha Baik ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Neuronal Cell Death ◽  
Neuronal Cell

P4-319: Notch signaling mediates ischemic neuronal cell death through the NFKB-Bim pathway

2012 ◽  
Vol 8 (4S_Part_21) ◽  
pp. S770-S771
Author(s):  
Yoon-Jee Lee ◽  
Yuri Choi ◽  
Yi-Lin Cheng ◽  
Thiruma V. Arumugam ◽  
Dong-Gyu Jo
Keyword(s):  
Cell Death ◽  
Notch Signaling ◽  
Neuronal Cell Death ◽  
Neuronal Cell

scholarly journals Calcium/Calmodulin–Dependent Protein Kinase II in Cerebrovascular Diseases

2021 ◽  
Author(s):  
Xuejing Zhang ◽  
Jaclyn Connelly ◽  
Edwin S. Levitan ◽  
Dandan Sun ◽  
Jane Q. Wang
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cerebrovascular Diseases ◽  
Biological Processes ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein ◽  
The Brain

AbstractCerebrovascular disease is the most common life-threatening and debilitating condition that often leads to stroke. The multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) is a key Ca2+ sensor and an important signaling protein in a variety of biological systems within the brain, heart, and vasculature. In the brain, past stroke-related studies have been mainly focused on the role of CaMKII in ischemic stroke in neurons and established CaMKII as a major mediator of neuronal cell death induced by glutamate excitotoxicity and oxidative stress following ischemic stroke. However, with growing understanding of the importance of neurovascular interactions in cerebrovascular diseases, there are clearly gaps in our understanding of how CaMKII functions in the complex neurovascular biological processes and its contributions to cerebrovascular diseases. Additionally, emerging evidence demonstrates novel regulatory mechanisms of CaMKII and potential roles of the less-studied CaMKII isoforms in the ischemic brain, which has sparked renewed interests in this dynamic kinase family. This review discusses past findings and emerging evidence on CaMKII in several major cerebrovascular dysfunctions including ischemic stroke, hemorrhagic stroke, and vascular dementia, focusing on the unique roles played by CaMKII in the underlying biological processes of neuronal cell death, neuroinflammation, and endothelial barrier dysfunction triggered by stroke. We also highlight exciting new findings, promising therapeutic agents, and future perspectives for CaMKII in cerebrovascular systems.

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