scholarly journals The Translational Repressor eIF4E-Binding Protein 2 (4E-BP2) Correlates with Selective Delayed Neuronal Death after Ischemia

2013 ◽  
Vol 33 (8) ◽  
pp. 1173-1181 ◽  
Author(s):  
María Irene Ayuso ◽  
Emma Martínez-Alonso ◽  
Cristina Cid ◽  
Maria Alonso de Leciñana ◽  
Alberto Alcázar
Keyword(s):  
Neuronal Death ◽  
Neuronal Apoptosis ◽  
Binding Protein ◽  
Ischemia Reperfusion ◽  
Initiation Factor ◽  
Delayed Neuronal Death ◽  
Ca1 Neurons ◽  
Translation Inhibition ◽  
Translational Repressor ◽  
Ca1 Region

Transient brain ischemia induces an inhibition of translational rates and causes delayed neuronal death in selective regions and cognitive deficits, whereas these effects do not occur in resistant areas. The translational repressor eukaryotic initiation factor (elF) 4E-binding protein-2 (4E-BP2) specifically binds to eIF4E and is critical in the control of protein synthesis. To link neuronal death to translation inhibition, we study the eIF4E association with 4E-BP2 under ischemia reperfusion in a rat model of transient forebrain ischemia. Upon reperfusion, a selective neuronal apoptosis in the hippocampal cornu ammonis 1 (CA1) region was induced, while it did not occur in the cerebral cortex. Confocal microscopy analysis showed a decrease in 4E-BP2/eIF4E colocalization in resistant cortical neurons after reperfusion. In contrast, in vulnerable CA1 neurons, 4E-BP2 remains associated to eIF4E with a higher degree of 4E-BP2/eIF4E colocalization and translation inhibition. Furthermore, the binding of a 4E-BP2 peptide to eIF4E induced neuronal apoptosis in the CA1 region. Finally, pharmacological-induced protection of CA1 neurons inhibited neuronal apoptosis, decreased 4E-BP2/eIF4E association, and recovered translation. These findings documented specific changes in 4E-BP2/eIF4E association during ischemic reperfusion, linking the translation inhibition to selective neuronal death, and identifying 4E-BP2 as a novel target for protection of vulnerable neurons in ischemic injury.

Abstract P800: Liposomal Delivery of PICK1 Inhibitor, FSC231, Prevents Ischemic/Reperfusion-Induced Degradation of GluA2 AMPA Receptor Subunit

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Lindsay Achzet ◽  
Darrell A Jackson
Keyword(s):  
Ischemic Stroke ◽  
Intracellular Calcium ◽  
Ampa Receptor ◽  
Neuronal Death ◽  
Research Effort ◽  
Ischemia Reperfusion ◽  
Hippocampal Slices ◽  
The United States ◽  
Delayed Neuronal Death ◽  
Ischemic Reperfusion

Stroke remains to be a leading cause of disability within the United States. Despite an enormous amount of research effort within the scientific community, very few therapeutics are available for stroke patients. Cytotoxic accumulation of intracellular calcium is a well-studied phenomenon that occurs following ischemic stroke. This intracellular calcium overload results from excessive release of the excitatory neurotransmitter glutamate, a process known as excitotoxicity, eventually leading to delayed neuronal death. The hippocampus is particularly susceptible to AMPA receptor-mediated delayed neuronal death. AMPA receptors (AMPARs) are homo- or hetero-tetramers composed of GluA1-4 subunits. The majority of AMPARs are impermeable to calcium due to a post-transcriptional modification in the channel pore of the GluA2 AMPAR subunit. Calcium-permeable AMPARs lacking the GluA2 subunit, contribute to calcium cytotoxicity and subsequent neuronal death. The internalization and subsequent degradation of GluA2 AMPAR subunits following oxygen-glucose deprivation/reperfusion (OGD/R) is, at least in part, mediated by protein-interacting with C Kinase-1 (PICK1). We hypothesize that disrupting the PICK1—GluA2 interaction will prevent the degradation of GluA2, thereby protecting neurons within the hippocampus from AMPAR-mediated delayed neuronal death. Pretreatment with liposome-encapsulated FSC231, an inhibitor of PICK1, in acute rodent hippocampal slices prevents the OGD/R-induced association of PICK1—GluA2. FSC231 treatment during OGD/R rescues total GluA2 AMPAR subunit protein levels. This work is the first to utilize a liposomal drug delivery system for the delivery of a small molecule in ex vivo acute rodent hippocampal slices exposed to ischemia/reperfusion injury. These results suggest that the interaction between GluA2 and PICK1 serves as an important step in the ischemic/reperfusion-induced reduction in total GluA2 levels and is a potential therapeutic target for the treatment of ischemic stroke.

Caffeine Releasable Stores of Ca2+ Show Depletion Prior to the Final Steps in Delayed CA1 Neuronal Death

2004 ◽  
Vol 92 (5) ◽  
pp. 2960-2967 ◽  
Author(s):  
Hong Xing ◽  
Aryan Azimi-Zonooz ◽  
C. William Shuttleworth ◽  
John A. Connor
Keyword(s):  
Endoplasmic Reticulum ◽  
Neuronal Death ◽  
Carotid Arteries ◽  
Cell Function ◽  
Mean Amplitude ◽  
Delayed Neuronal Death ◽  
Ischemic Insult ◽  
Cell Degeneration ◽  
Ca1 Neurons ◽  
The Mean

In addition to their role in signaling, Ca2+ ions in the endoplasmic reticulum also regulate important steps in protein processing and trafficking that are critical for normal cell function. Chronic depletion of Ca2+ in the endoplasmic reticulum has been shown to lead to cell degeneration and has been proposed as a mechanism underlying delayed neuronal death following ischemic insults to the CNS. Experiments here have assessed the relative content of ryanodine receptor-gated stores in CA1 neurons by measuring cytoplasmic Ca2+ increases induced by caffeine. These measurements were performed on CA1 neurons, in slice, from normal gerbils, and compared with responses from this same population of neurons 54–60 h after animals had undergone a standard ischemic insult: 5-min bilateral occlusion of the carotid arteries. The mean amplitude of responses in the postischemic population were less than one-third of those in control or sham-operated animals, and 35% of the neurons from postischemic animals showed very small responses that were ∼10% of the control population mean. Refilling of these stores after caffeine challenges was also impaired in postischemic neurons. These observations are consistent with our earlier finding that voltage-gated influx is sharply reduced in postischemic in CA1 neurons and the hypothesis that the resulting depletion in endosomal Ca2+ is an important cause of delayed neuronal death.

Evidence for a Role of Second Pathophysiological Stress in Prevention of Delayed Neuronal Death in the Hippocampal CA1 Region

2005 ◽  
Vol 30 (11) ◽  
pp. 1397-1405 ◽  
Author(s):  
Jozef Burda ◽  
Milina Matiašová ◽  
Miroslav Gottlieb ◽  
Viera Danielisová ◽  
Miroslava Némethová ◽  
...  
Keyword(s):  
Neuronal Death ◽  
Delayed Neuronal Death ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Hippocampal Ca1

scholarly journals DNA Fragmentation Follows Delayed Neuronal Death in CA1 Neurons Exposed to Transient Global Ischemia in the Rat

1997 ◽  
Vol 17 (9) ◽  
pp. 967-976 ◽  
Author(s):  
Carol K. Petito ◽  
Jorge Torres-Munoz ◽  
Brenda Roberts ◽  
John-Paul Olarte ◽  
Thaddeus S. Nowak ◽  
...  
Keyword(s):  
Dna Fragmentation ◽  
Neuronal Death ◽  
Nuclear Dna ◽  
P53 Protein ◽  
Global Ischemia ◽  
Delayed Neuronal Death ◽  
Ca1 Neurons ◽  
Morphological Studies ◽  
Eosinophilic Cytoplasm

Apoptosis is an active, gene-directed process of cell death in which early fragmentation of nuclear DNA precedes morphological changes in the nucleus and, later, in the cytoplasm. In ischemia, biochemical studies have detected oligonucleosomes of apoptosis whereas sequential morphological studies show changes consistent with necrosis rather than apoptosis. To resolve this apparent discrepancy, we subjected rats to 10 minutes of transient forebrain ischemia followed by 1 to 14 days of reperfusion. Parameters evaluated in the CA1 region of the hippocampus included morphology, in situ end labeling (ISEL) of fragmented DNA, and expression of p53. Neurons were indistinguishable from controls at postischemic day 1 but displayed cytoplasmic basophilia or focal condensations at day 2; some neurons were slightly swollen and a few appeared normal. In situ end labeling was absent. At days 3 and 5, approximately 40 to 60% of CA1 neurons had shrunken eosinophilic cytoplasm and pyknotic nuclei, but only half of these were ISEL. By day 14, many of the necrotic neurons had been removed by phagocytes; those remaining retained mild ISEL. Neither p53 protein nor mRNA were identified in control or postischemic brain by in situ hybridization with riboprobes or by northern blot analysis. These results show that DNA fragmentation occurs after the development of delayed neuronal death in CA1 neurons subjected to 10 minutes of global ischemia. They suggest that mechanisms other than apoptosis may mediate the irreversible changes in the CA1 neurons in this model.

scholarly journals Neuroprotective Effect of Sodium Orthovanadate on Delayed Neuronal Death after Transient Forebrain Ischemia in Gerbil Hippocampus

2001 ◽  
Vol 21 (11) ◽  
pp. 1268-1280 ◽  
Author(s):  
Takayuki Kawano ◽  
Kohji Fukunaga ◽  
Yusuke Takeuchi ◽  
Motohiro Morioka ◽  
Shigetoshi Yano ◽  
...  
Keyword(s):  
Neuronal Death ◽  
Neuroprotective Effect ◽  
Delayed Neuronal Death ◽  
Intraventricular Injection ◽  
Mongolian Gerbils ◽  
Sodium Orthovanadate ◽  
Forebrain Ischemia ◽  
Neuroprotective Effects ◽  
Transient Forebrain Ischemia ◽  
Ca1 Region

In transient forebrain ischemia, sodium orthovanadate as well as insulinlike growth factor-1 (IGF-1) rescued cells from delayed neuronal death in the hippocampal CA1 region. Adult Mongolian gerbils were subjected to 5-minute forebrain ischemia. Immunoblotting analysis with anti–phospho-Akt/PKB (Akt) antibody showed that phosphorylation of Akt at serine-473 (Akt-Ser-473) in the CA1 region decreased immediately after reperfusion, and in turn transiently increased 6 hours after reperfusion. The decreased phosphorylation of Akt-Ser-473 was not observed in the CA3 region. The authors then tested effects of intraventricular injection of orthovanadate and IGF-1, which are known to activate Akt. Treatment with orthovanadate or IGF-1 30 minutes before ischemia blocked delayed neuronal death in the CA1 region. The neuroprotective effects of orthovanadate and IGF-1 were associated with preventing decreased Akt-Ser-473 phosphorylation in the CA1 region observed immediately after reperfusion. Immunohistochemical studies with the anti–phospho-Akt-Ser-473 antibody also demonstrated that Akt was predominantly in the nucleus and was moderately activated in the cell bodies and dendrites of pyramidal neurons after orthovanadate treatment. The orthovanadate treatment also prevented the decrease in phosphorylation of mitogen-activated protein kinase (MAPK). Pretreatment with combined blockade of phosphatidylinositol 3-kinase and MAPK pathways totally abolished the orthovanadate-induced neuroprotective effect. These results suggest that the activation of both Akt and MAPK activities underlie the neuroprotective effects of orthovanadate on the delayed neuronal death in the CA1 region after transient forebrain ischemia.

Delayed neuronal death in ischemic hippocampus involves stimulation of protein tyrosine phosphorylation

1996 ◽  
Vol 271 (4) ◽  
pp. C1085-C1097 ◽  
Author(s):  
T. Ohtsuki ◽  
M. Matsumoto ◽  
K. Kitagawa ◽  
T. Mabuchi ◽  
K. Mandai ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Kainic Acid ◽  
Neuronal Death ◽  
Tyrosine Kinases ◽  
Ischemia Reperfusion ◽  
Delayed Neuronal Death ◽  
Mongolian Gerbils ◽  
Protein Tyrosine Phosphorylation ◽  
Protein Tyrosine ◽  
Stimulation Of

Glutamate triggers neuronal degeneration after ischemia-reperfusion in the brain. However, the details of intracellular signal transduction that propagates cell death remain unknown. The present work investigated whether protein tyrosine phosphorylation mediates neuronal death in the ischemic brain. Transient forebrain ischemia for 5-10 min in Mongolian gerbils or intoxication with the glutamate analogue kainic acid (12 mg/kg) in Sprague-Dawley rats caused neuronal death selectively in the hippocampus 2-4 days or 1 day later, respectively. Under these conditions, 160-, 115-, 105-, 92-, and 85-kDa proteins showed a significant increase in tyrosyl residue phosphorylation selectively in the hippocampus 3-12 h after ischemia or 4-8 h after kainic acid-induced seizures. Tyrosine kinases, including pp60c-src, were activated without a change of tyrosine phosphatases. Administration of radicicol, a selective inhibitor of tyrosine kinases, attenuated stimulation of tyrosine phosphorylation and hippocampal degeneration after ischemia or kainic acid injection. The results suggest that protein tyrosine phosphorylation might propagate delayed neuronal death in the mature hippocampus through glutamate overload after ischemia-reperfusion.

Abstract T P84: Neuroprotective Effect of Probenecid in a Rat Model of Transient Global Cerebral Ischemia-Reperfusion

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Rui-li Wei ◽  
Yan Xu ◽  
Jing-ye Wang ◽  
Ben-yan Luo
Keyword(s):  
Cerebral Ischemia ◽  
Protective Effect ◽  
Neuronal Death ◽  
Ischemia Reperfusion ◽  
Cerebral Injury ◽  
Therapeutic Drug ◽  
Ca1 Region ◽  
Cerebral Ischemia Reperfusion ◽  
Hippocampal Ca1

Background and Purpose: Probenecid (PROB) has been used for decades to treat gouty arthritis with few side effects and recent studies revealed that it is also a specific inhibitor of pannexin-1 channel. Panx1 channel was activated by ischemic injury and inhibition of the panx1 channel maybe efficacious in stroke treatment. However, the role of PROB in cerebral ischemia /reperfusion (I/R) injury remains unclear. The aim of this study was to investigate the role of PROB in the transient global cerebral I/R injury in rats and its protective mechanisms. Methods: Twenty minutes of transient global cerebral I/R was induced using the four-vessel occlusion (4-VO) method in rats. PROB was given in the different dose, time and administration routes to verify its neuroprotective effects. Neuronal death in the hippocampal CA1 region was observed using H & E staining 7 days after ischemia. Molecular mechanisms of activation of calpain-cathepsin pathway and inflammatory cells by I/R injury were also investigated. Results: Treatment with PROB (0.1, 1 and 10 mg/kg ) 10 min before ischemia protected against I/R-induced hippocampal CA1 neuronal death significantly, and 1 mg/kg has best protective effect. Post-insult treatment 2h after reperfusion also protected against neuronal death and prolonged use for continuous 7 days could improve its protective effects compared to the single use 6h after reperfusion.Furthermore,oral administration also had protective effect. Cathepsin B expression was inceased significantly in CA-1 region after ischemia and PROB treatment could inhibit its expression. Expression of both calpain-1 and hsp70 at 1d ,2d and 3d after reperfusion were upregulated, whereas the expression of calpain-1 was inhibited and hsp70 was strengthened by pre-treatment with PROB. Prolonged PROB treatment suppressed the activation of microglia and astrocytes, reduced the number of microglia in CA1 region. Conclusions: Our study indicates that PROB protects against transient global cerebral I/R injury administrated before ischemia and even 6h after reperfusion by reducing calpain-1 expression , inhibiting lysosomal rupture and the activation of the glia, which suggests RPOB may be a promising therapeutic drug for clinical treatment of ischemic cerebral injury.

Sign in / Sign up

Export Citation Format

Share Document