scholarly journals Anesthetic Protection of Neurons Injured by Hypothermia and Rewarming

2012 ◽  
Vol 117 (2) ◽  
pp. 280-292 ◽  
Author(s):  
Philip E. Bickler ◽  
Daniel E. Warren ◽  
John P. Clark ◽  
Pablo Gabatto ◽  
Maren Gregersen ◽  
...  
Keyword(s):  
Cell Death ◽  
Hippocampal Neurons ◽  
Mild Hypothermia ◽  
Culture Media ◽  
Glutamate Excitotoxicity ◽  
Cell Swelling ◽  
Profound Hypothermia ◽  
Anesthetic Agents ◽  
Aspartate Receptor ◽  
Hypoxia Ischemia

Background Mild hypothermia is neuroprotective after cerebral ischemia but surgery involving profound hypothermia (PH, temperature less than 18°C) is associated with neurologic complications. Rewarming (RW) from PH injures hippocampal neurons by glutamate excitotoxicity, N-methyl-D-aspartate receptors, and intracellular calcium. Because neurons are protected from hypoxia-ischemia by anesthetic agents that inhibit N-methyl-D-aspartic acid receptors, we tested whether anesthetics protect neurons from damage caused by PH/RW. Methods Organotypic cultures of rat hippocampus were used to model PH/RW injury, with hypothermia at 4°C followed by RW to 37°C and assessment of cell death 1 or 24 h later. Cell death and intracellular Ca were assessed with fluorescent dye imaging and histology. Anesthetic agents were present in the culture media during PH and RW or only RW. Results Injury to hippocampal CA1, CA3, and dentate neurons after PH and RW involved cell swelling, cell rupture, and adenosine triphosphate (ATP) loss; this injury was similar for 4 through 10 h of PH. Isoflurane (1% and 2%), sevoflurane (3%) and xenon (60%) reduced cell loss but propofol (3 μM) and pentobarbital (100 μM) did not. Isoflurane protection involved reduction in N-methyl-D-aspartate receptor-mediated Ca influx during RW but did not involve γ-amino butyric acid receptors or KATP channels. However, cell death increased over the next day. Conclusion Anesthetic protection of neurons rewarmed from 4°C involves suppression of N-methyl-D-aspartate receptor-mediated Ca overload in neurons undergoing ATP loss and excitotoxicity. Unlike during hypoxia/ischemia, anesthetic agents acting predominantly on γ-aminobutyric acid receptors do not protect against PH/RW. The durability of anesthetic protection against cold injury may be limited.

Anesthetics and Mild Hypothermia Similarly Prevent Hippocampal Neuron Death in an In Vitro Model of Cerebral Ischemia

2000 ◽  
Vol 92 (5) ◽  
pp. 1343-1349 ◽  
Author(s):  
Robert Popovic ◽  
Richard Liniger ◽  
Philip E. Bickler
Keyword(s):  
Cerebral Ischemia ◽  
Mild Hypothermia ◽  
Cell Damage ◽  
Hippocampal Slices ◽  
Cell Loss ◽  
Glutamate Excitotoxicity ◽  
Neuron Death ◽  
In Vitro Ischemia ◽  
Aspartate Receptor

Background General anesthetics reduce neuron loss following focal cerebral ischemia in rodents. The relative efficacy of this action among different anesthetics clinically used for neuroprotection is uncertain. In addition, it remains unclear how anesthetics compare to neuroprotection afforded by mild hypothermia. This study was performed to evaluate the comparative effects of isoflurane, sodium pentothal, and mild hypothermia in a hippocampal slice model of cerebral ischemia and to determine if the mechanism of neuroprotection of isoflurane involves inhibition of glutamate excitotoxicity. Methods Survival and morphology of CA1, CA3, and dentate gyrus neurons in rat hippocampal slices were examined after 10 or 20 min of combined oxygen-glucose deprivation (in vitro ischemia) followed by a 5-h recovery period. Results 10 or 20 min in vitro ischemia at 37 degrees C killed 35-40% of neurons in CA1 (P < 0.001), 6% in CA3 (not significant) and 18% in dentate (P < 0.05). Isoflurane (0.7 and 2.0%, approximately 0.45 and 1.5 minimum alveolar concentration), pentothal (50 microm, approximately 1 minimum alveolar concentration equivalent) and mild hypothermia (34 degrees C) all reduced CA1 cell loss and morphologic damage to similar degrees in 10- and 20-min periods of ischemia (P < 0.001). The noncompetitive N-methyl-D-aspartate antagonist MK-801 prevented cell damage, showing that N-methyl-D-aspartate receptor activation is an important mechanism of injury in this model. Glutamate (1 mm) produced cell loss similar to in vitro ischemia. Isoflurane (2%) prevented cell damage from glutamate exposure. Conclusions In hippocampal slices, neuron death from simulated ischemia was predominately due to activation of glutamate receptors. Isoflurane, sodium pentothal, an N-methyl-D-aspartate receptor antagonist, and mild hypothermia prevented cell death to similar degrees. For isoflurane, the mechanism appears to involve attenuation of glutamate excitotoxicity.

Intraischemic mild hypothermia prevents neuronal cell death and tissue loss after neonatal cerebral hypoxia-ischemia

2006 ◽  
Vol 23 (2) ◽  
pp. 387-393 ◽  
Author(s):  
Changlian Zhu ◽  
Xiaoyang Wang ◽  
Falin Xu ◽  
Lin Qiu ◽  
Xiuyong Cheng ◽  
...  
Keyword(s):  
Cell Death ◽  
Mild Hypothermia ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Tissue Loss ◽  
Cerebral Hypoxia ◽  
Hypoxia Ischemia

scholarly journals A microRNA signature of toxic extrasynaptic N-methyl-D-aspartate (NMDA) receptor signaling

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Carlos Bas-Orth ◽  
Mirja Koch ◽  
David Lau ◽  
Bettina Buchthal ◽  
Hilmar Bading
Keyword(s):  
Cell Death ◽  
Nmda Receptor ◽  
Gene Transcription ◽  
Hippocampal Neurons ◽  
De Novo ◽  
Synaptic Activity ◽  
Aspartate Receptor ◽  
De Novo Gene ◽  
Bath Application ◽  
Stimulation Of

AbstractThe cellular consequences of N-Methyl-D-Aspartate receptor (NMDAR) stimulation depend on the receptors’ subcellular localization. Synaptic NMDARs promote plasticity and survival whereas extrasynaptic NMDARs mediate excitotoxicity and contribute to cell death in neurodegenerative diseases. The mechanisms that couple activation of extrasynaptic NMDARs to cell death remain incompletely understood. We here show that activation of extrasynaptic NMDARs by bath application of NMDA or L-glutamate leads to the upregulation of a group of 19 microRNAs in cultured mouse hippocampal neurons. In contrast, none of these microRNAs is induced upon stimulation of synaptic activity. Increased microRNA expression depends on the pri-miRNA processing enzyme Drosha, but not on de novo gene transcription. These findings suggest that toxic NMDAR signaling involves changes in the expression levels of particular microRNAs.

scholarly journals Mild Hypothermia Reduces Zinc Translocation, Neuronal Cell Death, and Mortality after Transient Global Ischemia in Mice

2002 ◽  
Vol 22 (10) ◽  
pp. 1231-1238 ◽  
Author(s):  
Daisuke Tsuchiya ◽  
Shwuhuey Hong ◽  
Sang Won Suh ◽  
Takamasa Kayama ◽  
S. Scott Panter ◽  
...  
Keyword(s):  
Cell Death ◽  
Hippocampal Neurons ◽  
Mild Hypothermia ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Global Ischemia ◽  
Doppler Flowmetry ◽  
Transient Global Ischemia ◽  
Hematoxylin Eosin ◽  
Cortical Perfusion

The authors sought to determine whether Zn2+ translocation associated with neuronal cell death occurs after transient global ischemia (TGI) in mice, as has been previously shown in rats, and to determine the effect of mild hypothermia on this reaction. To validate the TGI model, carbon-black injection and laser-Doppler flowmetry were compared in three strains of mice (C57BL/6, SV129, and HSP70 transgenic mice) to assess posterior communicating artery (PcomA) development and cortical perfusion. In C57BL/6 mice, optimal results were obtained when subjected to 20-minute TGI. Brain and rectal temperature measurements were compared to monitor hypothermia. Results of TGI were compared in normothermia (NT; 37°C) and mild hypothermia groups (HT; 33°C) by staining with Zn2+-specific fluorescent dye, N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) and hematoxylin– eosin 72 hours after reperfusion. The Zn2+ translocation observed in hippocampus CA1, CA2, and Hilus 72 hours after 20 minutes of TGI was significantly reduced by mild hypothermia. The number of degenerating neurons in the HT group was significantly less than in the NT group. Mild hypothermia reduced mortality significantly (7.1% in HT, 42.9% in NT). Results suggest that mild hypothermia may reduce presynaptic Zn2+ release in mice, which protects vulnerable hippocampal neurons from ischemic necrosis. Future studies may further elucidate mechanisms of Zn2+-induced ischemic injury.

scholarly journals Moderately Inducing Autophagy Reduces Tertiary Brain Injury after Perinatal Hypoxia-Ischemia

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 898
Author(s):  
Brian H. Kim ◽  
Maciej Jeziorek ◽  
Hur Dolunay Kanal ◽  
Viorica Raluca Contu ◽  
Radek Dobrowolski ◽  
...  
Keyword(s):  
Cell Death ◽  
Structural Integrity ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Brain Slices ◽  
Brain Structures ◽  
Improved Outcomes ◽  
Hypoxia Ischemia ◽  
Tgfβ Receptor ◽  
Progressive Neurodegeneration

Recent studies of cerebral hypoxia-ischemia (HI) have highlighted slowly progressive neurodegeneration whose mechanisms remain elusive, but if blocked, could considerably improve long-term neurological function. We previously established that the cytokine transforming growth factor (TGF)β1 is highly elevated following HI and that delivering an antagonist for TGFβ receptor activin-like kinase 5 (ALK5)—SB505124—three days after injury in a rat model of moderate pre-term HI significantly preserved the structural integrity of the thalamus and hippocampus as well as neurological functions associated with those brain structures. To elucidate the mechanism whereby ALK5 inhibition reduces cell death, we assessed levels of autophagy markers in neurons and found that SB505124 increased numbers of autophagosomes and levels of lipidated light chain 3 (LC3), a key protein known to mediate autophagy. However, those studies did not determine whether (1) SB was acting directly on the CNS and (2) whether directly inducing autophagy could decrease cell death and improve outcome. Here we show that administering an ALK5 antagonist three days after HI reduced actively apoptotic cells by ~90% when assessed one week after injury. Ex vivo studies using the lysosomal inhibitor chloroquine confirmed that SB505124 enhanced autophagy flux in the injured hemisphere, with a significant accumulation of the autophagic proteins LC3 and p62 in SB505124 + chloroquine treated brain slices. We independently activated autophagy using the stimulatory peptide Tat-Beclin1 to determine if enhanced autophagy is directly responsible for improved outcomes. Administering Tat-Beclin1 starting three days after injury preserved the structural integrity of the hippocampus and thalamus with improved sensorimotor function. These data support the conclusion that intervening at this phase of injury represents a window of opportunity where stimulating autophagy is beneficial.

scholarly journals Seizure-like activity leads to the release of BAD from 14-3-3 protein and cell death in hippocampal neurons in vitro

2003 ◽  
Vol 10 (5) ◽  
pp. 539-547 ◽  
Author(s):  
R Meller ◽  
C K Schindler ◽  
X P Chu ◽  
Z G Xiong ◽  
J A Cameron ◽  
...  
Keyword(s):  
Cell Death ◽  
Hippocampal Neurons

scholarly journals N-methyl-D-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium channels in hippocampal neurons.

1996 ◽  
Vol 93 (8) ◽  
pp. 3362-3367 ◽  
Author(s):  
J. W. Hell ◽  
R. E. Westenbroek ◽  
L. J. Breeze ◽  
K. K. Wang ◽  
C. Chavkin ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Hippocampal Neurons ◽  
Aspartate Receptor ◽  
Class C

scholarly journals Mild Hypothermia after Severe Transient Hypoxia-Ischemia Ameliorates Delayed Cerebral Energy Failure in the Newborn Piglet

1995 ◽  
Vol 37 (5) ◽  
pp. 667-670 ◽  
Author(s):  
Marianne Thoresen ◽  
Juliet Penrice ◽  
Ann Lorek ◽  
E B Cady ◽  
Marzena Wylezinska ◽  
...  
Keyword(s):  
Mild Hypothermia ◽  
Newborn Piglet ◽  
Hypoxia Ischemia ◽  
Energy Failure

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.

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