Abstract TMP3: Low Concentration Normobaric Oxygen Enhanced Therapeutic Effect of Mild Hypothermia or Ethanol Through a Reduction in Apoptosis

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Kaiyin Liu ◽  
Lipeng Cai ◽  
Changya Peng ◽  
Xiaokun Geng ◽  
Xunming Ji ◽  
...  
Keyword(s):  
Cell Death ◽  
Therapeutic Effect ◽  
Mild Hypothermia ◽  
Apoptotic Cell ◽  
Artery Occlusion ◽  
Apoptotic Cell Death ◽  
Tissue Type ◽  
Neuroprotective Effects ◽  
Normobaric Oxygen ◽  
Low Concentration

Introduction: Neuroprotective effects of normobaric oxygen (NBO) and ethanol (EtOH) has been shown. In a clinically relevant autologous embolus rat stroke model in which reperfusion was established by tissue-type plasminogen activator (rt-PA), the present study further evaluated whether low concentration NBO enhanced therapeutic effect of mild hypothermia (Hypo) or EtOH through a reduction in apoptosis and whether EtOH can substitute for hypothermia. Hypothesis: Hypo and EtOH has been shown to have neuroprotective effects through similar mechanisms. We assessed the hypothesis that low concentration NBO, whose neuroprotective effects are currently debated, has benefit in our stroke models, and we further assessed the hypothesis that EtOH can substitute for Hypo in the presence of tPA and NBO. Methods: At 1 hour of middle cerebral artery occlusion (MCAO) by an autologous embolus, rats (96 total, 12 in each treatment group) received rt-PA and other treatments of either EtOH (1.0 g/kg) or Hypo (33 °C for 3 hours) in combination with NBO (60% for 3 hours). Apoptotic cell death was measured by ELISA. Western immunoblotting was performed for pro- (AIF, Caspase-3, Bax) and anti-apoptotic (Bcl-2) protein expression at 3 and 24 hours of reperfusion. Results: Compared to ischemic rats treated only with rt-PA, animals with NBO, hypothermia or EtOH had significantly reduced apoptotic cell death by 32.5%, 43.1% and 36.0% respectively. However, combination therapy that included NBO+EtOH or NBO+Hypo with rt-PA exhibited a much larger decline (p<0.01) in the cell death by 71.1% and 73.6%, respectively. Similarly, NBO+EtOH or NBO+Hypo treatment in addition to rt-PA enhanced beneficial effects on both pro- and anti-apoptotic protein expressions as compared to other options. Conclusions: Neuroprotection after reperfusion with rt-PA in ischemic stroke induced by thromboembolism are enhanced by combination treatment with either EtOH or Hypo in the presence of 60% NBO through reduced apoptosis. Since the effects produced by EtOH and Hypo are comparable, their mechanism of action may not only be similar but also could be interchangeable. Since EtOH administration does not lead to temperature decrease, EtOH may a better alternative than Hypo.

Abstract TP266: Phenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Ischemia/Reperfusion Injury

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Hong An ◽  
Joshua Wright ◽  
Yunxia Duan ◽  
Di Wu ◽  
Xunming Ji ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemia Reperfusion Injury ◽  
Mild Hypothermia ◽  
Apoptotic Cell ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Neuroprotective Effects ◽  
Apoptotic Proteins

Introduction: Hypothermia is an effective neuroprotectant against stroke, but its application is limited by delayed onset, prolonged duration, and significant complications. Mild hypothermia is more clinically practical but offers weaker neuroprotection. This study investigated whether the neuroprotective effects of mild hypothermia can be enhanced by phenothiazine neuroleptics (chlorpromazine and promethazine), which were reported to have depressive or hibernation-like roles on the CNS. We also worked to elucidate the role of the PI3K/Akt signaling pathway in this protective mechanism. Methods: A total of 131 adult male Sprague-Dawley rats were randomly divided into 6 groups: sham, stroke without treatment (2-hour right middle cerebral artery occlusion), and 4 treatment groups with 1) mild hypothermia (anal temperature 33-35 0 C), 2) phenothiazines (1mg/kg chlorpromazine & 1mg/kg promethazine, anal temperature 37.8-38.3 0 C), 3) combination of mild hypothermia and phenothiazines, and 4) both therapies with the addition of a p-Akt antagonist (LY294002 was injected into the lateral ventricle 30 minutes before ischemia). Infarct volume, neurological deficit, and apoptotic cell death were determined 24h post reperfusion. Expression of p-Akt, cleaved Caspase-3, pro-apoptotic (AIF & Bax) and anti-apoptotic proteins (Bcl-2 & Bcl-xL) was assessed by Western blot at 6h and 24h after reperfusion. Results: The combination of hypothermia and phenothiazines decreased (P<0.01) infarct volume and neurological deficit. This change was associated with a reduction (P<0.01) of apoptotic cell death. Each treatment alone did not induce significant neuroprotection. The combination therapy, but not each alone, promoted (P<0.01) the expression of p-Akt, accompanied with increased expression of anti-apoptotic proteins and decreased expression of pro-apoptotic proteins. The neuroprotective effects were blocked by p-Akt inhibition. Conclusion: Mild hypothermia-induced neuroprotection was enhanced by phenothiazines in an experimental ischemia/reperfusion injury model. This study supports the involvement of the PI3K/Akt signaling pathway. This novel therapeutic strategy could be developed as an effective treatment for acute ischemic stroke.

Neuroprotective effects of corn silk maysin via inhibition of H2O2-induced apoptotic cell death in SK-N-MC cells

Life Sciences ◽  
2014 ◽  
Vol 109 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Doo Jin Choi ◽  
Sun-Lim Kim ◽  
Ji Won Choi ◽  
Yong Il Park
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Neuroprotective Effects ◽  
Corn Silk

Neuroprotective effects of the Phellinus linteus ethyl acetate extract against H2O2-induced apoptotic cell death of SK-N-MC cells

2016 ◽  
Vol 36 (1) ◽  
pp. 31-43 ◽  
Author(s):  
Doo Jin Choi ◽  
Sarang Cho ◽  
Jeong Yeon Seo ◽  
Hyang Burm Lee ◽  
Yong Il Park
Keyword(s):  
Cell Death ◽  
Ethyl Acetate ◽  
Ethyl Acetate Extract ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Phellinus Linteus ◽  
Neuroprotective Effects

scholarly journals Attenuation of Delayed Neuronal Death after Mild Focal Ischemia in Mice by Inhibition of the Caspase Family

1998 ◽  
Vol 18 (3) ◽  
pp. 238-247 ◽  
Author(s):  
Matthias Endres ◽  
Shobu Namura ◽  
Masao Shimizu-Sasamata ◽  
Christian Waeber ◽  
Lin Zhang ◽  
...  
Keyword(s):  
Cell Death ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Apoptotic Cell ◽  
Artery Occlusion ◽  
Apoptotic Cell Death ◽  
Therapeutic Window ◽  
Mk 801 ◽  
Cerebral Artery Occlusion

Inhibitors of apoptosis and of excitotoxic cell death reduce brain damage after transient and permanent middle cerebral artery occlusion. We compared the neuroprotective effects of two caspase family inhibitors with the N-methyl-d-aspartate receptor antagonist (+)-MK-801 hydrogen maleate (MK-801) in a newly characterized cycloheximidesensitive murine model of transient middle cerebral artery occlusion (30 minutes) in which apoptotic cell death is prominent. Ischemic infarction, undetected by 2,3,5-triphenyltetrazolium chloride staining at 24-hour reperfusion, featured prominently in the striatum at 72 hours and 7 days on hematoxylin-eosin—stained sections. Markers of apoptosis, such as oligonucleosomal DNA damage (laddering) and terminal deoxynucleotidyl transferase—mediated dUTP-biotin nick-end labeling (TUNEL)–positive cells first appeared at 24 hours and increased significantly at 72 hours and 7 days after reperfusion. The TUNEL-labeled cells were mostly neurons and stained negative for glial (GFAP, glial fibrillary acid protein) and leukocyte specific markers (CD-45). The caspase inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD.FMK; 120 ng intracerebroventricularly) or N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (z-DEVD.FMK; 480 ng intracerebroventricularly) decreased infarct size and neurologic deficits when administered 6 hours after reperfusion. The extent of protection was greater than in models of more prolonged ischemia or after permanent occlusion, and the therapeutic window was extended from 0 to 1 hours after 2-hour middle cerebral artery occlusion to at least 6 hours after brief ischemia. Also, z-VAD.FMK and z-DEVD.FMK treatment decreased oligonucleosomal DNA damage (DNA laddering) as assessed by quantitative autoradiography after gel electrophoresis. By contrast, MK-801 protected brain tissue only when given before ischemia (3 mg/kg intraperitoneally), but not at 3 or 6 hours after reperfusion. Despite a decrease in infarct size after MK-801 pretreatment, the amount of DNA laddering did not decrease 72 hours after reperfusion, thereby suggesting a mechanism distinct from inhibition of apoptosis. Hence, 30 minutes of reversible ischemia augments apoptotic cell death, which can be attenuated by delayed z-VADPMK and z-DEVD.FMK administration with preservation of neurologic function. By contrast, the therapeutic window for MK-801 does not extend beyond the time of occlusion, probably because its primary mechanism of action does not block the development of apoptotic cell death.

scholarly journals Neuroprotective Effects of Pharmacological Hypothermia on Glucose Metabolism in Ischemic Rats

2021 ◽  
Author(s):  
Longfei Guan ◽  
Hangil Lee ◽  
Xiaokun Geng ◽  
Fengwu Li ◽  
Jiamei Shen ◽  
...  
Keyword(s):  
Cell Death ◽  
Glucose Metabolism ◽  
Apoptotic Cell ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Apoptotic Cell Death ◽  
Neurological Deficits ◽  
Neuroprotective Effects ◽  
Glut 1 ◽  
Atp Levels ◽  
Neuroprotective Strategy

Abstract Stroke is a leading threat to human life. Metabolic dysfunction of glucose may play a key role in stroke pathophysiology. Pharmacological hypothermia (PH) is a potential neuroprotective strategy for stroke in which the temperature can be decreased safely. The present study determined whether neuroprotective PH with chlorpromazine and promethazine (C+P) plus dihydrocapsaicin (DHC) improved glucose metabolism in acute ischemic stroke. A total of 208 adult male Sprague-Dawley rats were randomly divided into the following groups: sham, stroke, and stroke with various treatments including C+P, DHC, C+P+DHC, phloretin (glucose transporter (GLUT)-1 inhibitor), cytochalasin B (GLUT-3 inhibitor), TZD (thiazolidinedione, phosphoenolpyruvate carboxykinase (PCK) inhibitor) and apocynin (nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor). Stroke was induced by middle cerebral artery occlusion (MCAO) for 2 h followed by 6 or 24 h of reperfusion. Rectal temperature was monitored before, during, and after PH. Infarct volume and neurological deficits were measured to assess the neuroprotective effects. Reactive oxygen species (ROS), NOX activity, lactate, apoptotic cell death, glucose, and ATP levels were measured. Protein expressions of GLUT-1, GLUT-3, phosphofructokinase (PFK), lactate dehydrogenase (LDH), PCK1, PCK2, and NOX subunit gp91 were measured with Western blotting. PH with combination of C+P and DHC induced a faster, longer, and deeper hypothermia as compared to each alone. PH significantly improved every measured outcome as compared to stroke and monotherapy. PH reduced brain infarction, neurological deficits, protein levels of glycolytic enzymes (GLUT-1, GLUT-3, PFK and LDH), gluconeogenic enzymes (PCK1 and PCK2), NOX activity and its subunit gp91, ROS, apoptotic cell death, glucose, and lactate, while raising ATP levels. In conclusion, stroke impaired glucose metabolism by enhancing hyperglycolysis and gluconeogenesis, which led to ischemic injury, all of which were reversed by PH induced by a combination of C+P and DHC.

Modulation of Apoptotic Cell Death and Neuroprotective Effects of Glutathione—L-Dopa Codrug against H2O2-Induced Cellular Toxicity: A Recent Study

2021 ◽  
pp. 113-129
Author(s):  
Sara Franceschelli ◽  
Paola Lanuti ◽  
Alessio Ferrone ◽  
Daniela Maria Pia Gatta ◽  
Lorenza Speranza ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Neuroprotective Effects ◽  
Cellular Toxicity
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