Vasogenic edema is the most common form of brain edema observed in clinical practice. It is characterized by increased permeability of brain capillary endothelial cells to macromolecules and by increased extracellular space and brain water. Although the causes of vasogenic edema after brain ischemia and injury appear to be multifactorial, the basic mechanisms are dependent on alterations in the structural and functional integrity of brain endothelial cells. We have postulated that oxygen radicals, superoxide radicals in particular, are involved in the perturbation of the structural and functional integrity of endothelial cells. We have demonstrated that cerebral edema and infarction induced by cold injury brain trauma, mitochondrial toxin or focal cerebral ischemia and reperfusion are significantly reduced in transgenic mice that overexpress human CuZn-superoxide dismutase (SOD1) activity, whereas vasogenic edema and infarction are exacerbated in mice that are deficient in SOD1 or mitochondrial SOD (SOD2) activity. We have also demonstrated that overexpression of SOD1 in mice could reduce the intrinsic mitochondrial signaling pathways in brain cells, whereas the endogenous survival signaling is upregulated. We propose to continue investigating the role of oxidative stress in the pathogenesis of vasogenic edema using both in vivo mouse models of focal cerebral ischemia and reperfusion, and cold injury, and in vitro cerebral capillary endothelial cell cultures.
Our specific aims are: 1) To elucidate the intrinsic signaling pathways involving mitochondria in endothelial cell death by apoptosis after CNS injuries. 2) To elucidate the role of mitochondrial dysfunction and oxidative stress in endothelial cell death after CNS injuries. 3) To elucidate the endogenous survival signaling pathway in endothelial cell survival after CNS injuries. 4) To study the compartmentalization and compensatory signaling mechanisms between SOD1 and SOD2 on endothelial cell death/survival in CNS injuries. These studies have therapeutic implications and will shed further light on molecular and cellular mechanisms underlying the pathogenesis of vasogenic edema after CNS injuries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS025372-18
Application #
6844685
Study Section
Brain Disorders and Clinical Neuroscience 5 (BDCN)
Program Officer
Jacobs, Tom P
Project Start
1988-02-01
Project End
2009-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
18
Fiscal Year
2005
Total Cost
$375,388
Indirect Cost
Name
Stanford University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Wakai, Takuma; Narasimhan, Purnima; Sakata, Hiroyuki et al. (2016) Hypoxic preconditioning enhances neural stem cell transplantation therapy after intracerebral hemorrhage in mice. J Cereb Blood Flow Metab 36:2134-2145
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
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
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
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) Release of mitochondrial apoptogenic factors and cell death are mediated by CK2 and NADPH oxidase. J Cereb Blood Flow Metab 32:720-30
Nito, Chikako; Kamada, Hiroshi; Endo, Hidenori et al. (2012) Involvement of mitogen-activated protein kinase pathways in expression of the water channel protein aquaporin-4 after ischemia in rat cortical astrocytes. J Neurotrauma 29:2404-12
Sakata, Hiroyuki; Narasimhan, Purnima; Niizuma, Kuniyasu et al. (2012) Interleukin 6-preconditioned neural stem cells reduce ischaemic injury in stroke mice. Brain 135:3298-310
Sakata, Hiroyuki; Niizuma, Kuniyasu; Wakai, Takuma et al. (2012) Neural stem cells genetically modified to overexpress cu/zn-superoxide dismutase enhance amelioration of ischemic stroke in mice. Stroke 43:2423-9

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