Oxidative stress generated during cerebral ischemia and reperfusion is a critical event leading to damage of the neurovascular unit that causes blood-brain barrier disruption, with secondary vasogenic edema and hemorrhagic transformation of infarcted brain tissue, restricting the benefit of tissue reperfusion with thrombolytic agents. However, little is known about the cellular and molecular mechanisms and signaling pathways that underlie oxidative stress in the damage of the neurovascular unit that consists mainly of endothelial cells, astrocytes, and neurons. Our working hypothesis is that NADPH oxidase, a pro-oxidant enzyme that localizes in all the cells of the neurovascular unit, initiates oxidative stress and downstream signaling that cause neurovascular damage and intracerebral hemorrhage in the stroke brain. This Program consists of three interactive projects and two supporting cores. Project 1 is to investigate the role of endothelial NADPH oxidase in oxidative stress, endothelial cell damage, and intracerebral hemorrhage. Project 2 will elucidate the role of the interplay between hyperglycemia and oxidative stress generated by NADPH oxidase in ischemic neuronal injury. Project 3 will elucidate astrocytic HSP70 and NADPH oxidase in endothelial protection and injury in the ischemic brain. We believe these are novel studies that will provide insights into the oxidative mechanisms in neurovascular dysfunction after cerebral ischemia. The long-term goal of these studies is to develop therapeutic interventions that target neurovascular function for stroke patients.

Public Health Relevance

Lay statement: Most strokes are caused by occlusion of the cerebral artery by a thrombus (ischemic stroke). Early restoration of cerebral blood flow (reperfusion) with a thrombolytic agent or spontaneous reperfusion can salvage brain tissue, but can also have a deleterious effect by generating reactive oxygen species by NADPH oxidase. The latter can further damage neurons and vessels. This Program aims to elucidate the role of NADPH-oxidase in reperfusion injury and to provide strategies to prevent or to ameliorate brain damage in patients with acute stroke.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1-SRB-M (45))
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
Voloboueva, Ludmila A; Emery, John F; Sun, Xiaoyun et al. (2013) Inflammatory response of microglial BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose-regulated protein 75/mortalin. FEBS Lett 587:756-62
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
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

Showing the most recent 10 out of 36 publications