The Role of Zinc in Neuronal Injury and Death in an Oxygen-Glucose Deprivation Model of Ischemic Stroke
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Ohio University / OhioLINK
2010
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ndltd-OhioLink-oai-etd.ohiolink.edu-ohiou12926030272021-08-03T05:46:45Z The Role of Zinc in Neuronal Injury and Death in an Oxygen-Glucose Deprivation Model of Ischemic Stroke Stork, Christian J. Molecular Biology zinc ischemia calcium hippocampus fluorescence <p>Stroke injury is a devastating medical condition in which less than 3% of victims can even meet the qualifications to receive the one FDA-approved treatment, tissue plasminogen activator (tPA). The dominant theory to describe how cerebral ischemia damages the brain is centered on excessive Ca2+ influx into ischemic neurons where a resultant "Ca2+-overload" triggers neuron death and overall injury. Directed by this theory, dozens of potential stroke therapeutics designed to prevent Ca2+-overload have been developed and tested in clinical trials, showing mixed results.</p><p>Much of the evidence that has provided experimental support for the theory of Ca2+-overload has been made where Ca2+ was identified on the basis of detection with fluorescent Ca2+ indicators. Zn2+ also accumulates in neurons under ischemic conditions. In the current work results are presented that demonstrated Zn2+ accumulation in ischemic neurons comprised the majority of the signal from a popular fluorescent Ca2+ indicator, showing how the Zn2+ transient in ischemia could be readily interpreted as support for Ca2+-overload. Moreover, the Zn2+ accumulation with ischemia was shown to correlate significantly with neuronal injury. And, prevention of the Zn2+ accumulation prevented the development of damage from simulated ischemic injury. The source of the ischemically-evolved Zn2+ was determined to be of intracellular origin, and results of the investigation to localize sites of intracellular Zn2+ storage are presented in the present work. Under basal conditions, primary cultured cells from the rat cerebral cortex showed labile Zn2+ within mitochondria, the Golgi apparatus, and the endoplasmic reticulum. Zn2+ localized in the endoplasmic reticulum was found to be released by thapsigargin and IP3. </p><p>To further investigate ischemic Zn2+ liberation and characterize the specific effects of this event independent from that of Ca2+-overload, the respective effects of Ca2+ and Zn2+ were tested to compare their relative toxicity, and the relative neuroprotection afforded by treatments targeting each ion in ischemia. As shown in this study, the induced elevation of Zn2+ resulted in significantly greater neuronal injury compared to the induced elevation of Ca2+. Further, preventing Zn2+ accumulation under ischemic conditions was highly protective for both 10 min and 30 min insult; whereas preventing Ca2+ influx showed a protective effect for up to only 10 min of simulated ischemia. </p><p>The collective work presented here shows how Zn2+ can be misconstrued as Ca2+ under ischemic conditions. It demonstrated that the Zn2+-mediated damage was of greater consequence than the Ca2+-mediated damage. Collectively, these data support Zn2+ accumulation to be a more significant causal factor of the neuronal injury and death resultant from simulated ischemia. These findings have implications that are relevant to ischemic stroke and to the development of therapeutic interventions for ischemic stroke.</p> 2010 English text Ohio University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1292603027 http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1292603027 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Molecular Biology zinc ischemia calcium hippocampus fluorescence |
| spellingShingle |
Molecular Biology zinc ischemia calcium hippocampus fluorescence Stork, Christian J. The Role of Zinc in Neuronal Injury and Death in an Oxygen-Glucose Deprivation Model of Ischemic Stroke |
| author |
Stork, Christian J. |
| author_facet |
Stork, Christian J. |
| author_sort |
Stork, Christian J. |
| title |
The Role of Zinc in Neuronal Injury and Death in an Oxygen-Glucose Deprivation Model of Ischemic Stroke |
| title_short |
The Role of Zinc in Neuronal Injury and Death in an Oxygen-Glucose Deprivation Model of Ischemic Stroke |
| title_full |
The Role of Zinc in Neuronal Injury and Death in an Oxygen-Glucose Deprivation Model of Ischemic Stroke |
| title_fullStr |
The Role of Zinc in Neuronal Injury and Death in an Oxygen-Glucose Deprivation Model of Ischemic Stroke |
| title_full_unstemmed |
The Role of Zinc in Neuronal Injury and Death in an Oxygen-Glucose Deprivation Model of Ischemic Stroke |
| title_sort |
role of zinc in neuronal injury and death in an oxygen-glucose deprivation model of ischemic stroke |
| publisher |
Ohio University / OhioLINK |
| publishDate |
2010 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1292603027 |
| work_keys_str_mv |
AT storkchristianj theroleofzincinneuronalinjuryanddeathinanoxygenglucosedeprivationmodelofischemicstroke AT storkchristianj roleofzincinneuronalinjuryanddeathinanoxygenglucosedeprivationmodelofischemicstroke |
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1719425164787056640 |