It is well established that a brief period of global brain ischemia causes delayed cell death in vulnerable hippocampal CA1 pyramidal neurons days after reperfusion in animals and humans. Although numerous factors have been suggested to account for this phenomenon, the mechanisms underlying this delayed vulnerability for neuronal death are still poorly understood. Reperfusion after cerebral ischemia is known to produce oxidative stress in mitochondria, which mediate apoptotic cell death. An increase in the cytosolic antioxidant copper/zinc-superoxide dismutase in transgenic mice and transgenic rats significantly ameliorates molecular and cellular signaling events and the subsequent reduction in delayed death of hippocampal CA1 neurons. Also, transcription-independent activity of p53, a tumor suppressor gene and a central player in cell death, translocates to mitochondria and mediates the release of cytochrome c in the vulnerable hippocampal CA1 subregion after transient global cerebral ischemia (tGCI). We hypothesize that p53 and oxidative stress act in concert to mediate apoptotic signaling in vulnerable hippocampal CA1 neurons after global cerebral ischemia. It is our goal to test this hypothesis using various molecular, genetic, and pharmacological strategies in rodent models of global cerebral ischemia.
Our specific aims are: 1) to elucidate the role of p53 signaling in the intrinsic mitochondrial apoptotic pathway in hippocampal CA1 neuronal death/survival after tGCI;2) to elucidate the role of oxidative stress and endogenous superoxide dismutases during reperfusion in p53- mediated hippocampal neuronal death after tGCI;and 3) to elucidate the role of reduced nicotinamide-adenine dinucleotide phosphate oxidase in hippocampal CA1 death and its crosstalk in p53 signaling after tGCI.

Public Health Relevance

Reperfusion after global cerebral ischemia generates oxygen free radicals that kill vulnerable neurons in hippocampi. The mechanism underlying this selective neuronal death is unclear. With this application, we seek to elucidate this cell death mechanism and provide therapeutic strategies to prevent or to ameliorate brain damage in stroke patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038653-14
Application #
8197049
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Hicks, Ramona R
Project Start
1998-09-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
14
Fiscal Year
2012
Total Cost
$343,333
Indirect Cost
$128,958
Name
Stanford University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Wakai, Takuma; Sakata, Hiroyuki; Narasimhan, Purnima et al. (2014) Transplantation of neural stem cells that overexpress SOD1 enhances amelioration of intracerebral hemorrhage in mice. J Cereb Blood Flow Metab 34:441-9
Yoshioka, Hideyuki; Katsu, Masataka; Sakata, Hiroyuki et al. (2013) The role of PARL and HtrA2 in striatal neuronal injury after transient global cerebral ischemia. J Cereb Blood Flow Metab 33:1658-65
Okami, Nobuya; Narasimhan, Purnima; Yoshioka, Hideyuki et al. (2013) Prevention of JNK phosphorylation as a mechanism for rosiglitazone in neuroprotection after transient cerebral ischemia: activation of dual specificity phosphatase. J Cereb Blood Flow Metab 33:106-14
Yang, Jiwon; Ahn, Hye-Na; Chang, Minsun et al. (2013) Complement component 3 inhibition by an antioxidant is neuroprotective after cerebral ischemia and reperfusion in mice. J Neurochem 124:523-35
Kim, Gab Seok; Jung, Joo Eun; Narasimhan, Purnima et al. (2012) Release of mitochondrial apoptogenic factors and cell death are mediated by CK2 and NADPH oxidase. J Cereb Blood Flow Metab 32:720-30
Sakata, Hiroyuki; Niizuma, Kuniyasu; Yoshioka, Hideyuki et al. (2012) Minocycline-preconditioned neural stem cells enhance neuroprotection after ischemic stroke in rats. J Neurosci 32:3462-73
Kim, Gab Seok; Jung, Joo Eun; Narasimhan, Purnima et al. (2012) Induction of thioredoxin-interacting protein is mediated by oxidative stress, calcium, and glucose after brain injury in mice. Neurobiol Dis 46:440-9
Chen, Hai; Kim, Gab Seok; Okami, Nobuya et al. (2011) NADPH oxidase is involved in post-ischemic brain inflammation. Neurobiol Dis 42:341-8
Yoshioka, Hideyuki; Niizuma, Kuniyasu; Katsu, Masataka et al. (2011) NADPH oxidase mediates striatal neuronal injury after transient global cerebral ischemia. J Cereb Blood Flow Metab 31:868-80
Yoshioka, Hideyuki; Niizuma, Kuniyasu; Katsu, Masataka et al. (2011) Consistent injury to medium spiny neurons and white matter in the mouse striatum after prolonged transient global cerebral ischemia. J Neurotrauma 28:649-60

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