Vasogenic edema is the most common form of brain edema observed in clinical practice. It is characterized by an increased permeability of brain capillary endothelial cells to macromolecules and by an increased extracellular space and brain water. Although the causes of vasogenic edema following brain ischemia and injury appear to be multifactorial, the basic mechanisms are dependent upon alteration sin 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 the endothelial cells. We have demonstrated that cerebral edema and infarction induced by either cold injury or by focal cerebral ischemia and reperfusion are significantly reduced in transgenic (Tg) mice overexpressing human CuZn-superoxide dismutase (SOD-1) activity. We now propose to continue to investigate the role of oxidative stress in the pathogenesis of vasogenic edema using both in vivo mouse models of focal cerebral ischemia and reperfusion and in vitro cerebral capillary endothelial cell cultures.
Our specific aims are: 1) to elucidate the role of CuZn-SOD in vasogenic edema and infarction following focal cerebral ischemia and reperfusion in SOD-1 transgenic mice and in sod-1 knockout mutants; 2) to investigate the temporal pattern of bcl-2 and hsp 70 gene expression in neurons and endothelial cells in mice that overexpress SOD-1 transgene, wild-type or in mutant mice with reduced sod-1 expression following focal cerebral ischemia and reperfusion; 3) to elucidate the superoxide-dependent oxidative pathways involving the pathogenesis of vasogenic edema after focal cerebral ischemia using genetically modified mice with altered levels of glutathione peroxidase and nitric oxide synthase activities; 4) to investigate the role of oxidative stress in vasogenic edema and infarction in a newly developed mitochondrial manganese superoxide dismutase (sod-2) knockout mutant mouse; and 5) to study the role of superoxide dismutase on hypoxia-induced injury and degeneration in primary culture of cerebral endothelial cells of Tg and knockout mutants. These studies have therapeutic implications and will further shed light on molecular and cellular mechanisms underlying the pathogenesis of vasogenic edema following ischemia and reperfusion.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS025372-15
Application #
6499338
Study Section
Neurology A Study Section (NEUA)
Program Officer
Jacobs, Tom P
Project Start
1988-02-01
Project End
2004-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
15
Fiscal Year
2002
Total Cost
$342,802
Indirect Cost
Name
Stanford University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
800771545
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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