The global working hypothesis is that oxidative stress induced by cerebral ischemia and reperfusion is involved in neuronal cell death through both the necrosis and apoptosis pathways. The hypothesis will be tested using transgenic mice overexpressing human CuZn-SOD (SOD-1) and knockout mutants that contain no (homozygous) or one-half of (heterozygous) SOD-1 activity. Since mitochondria are known to be the site of oxygen radical production, it is also hypothesized that increased oxidative stress to mitochondria by either mitochondrial toxins or by the null mutation of mitochondrial manganese SOD (sod-2) in knockout mutants will increase neuronal susceptibility to necrosis and/or apoptosis following cerebral ischemia and reperfusion. In order to dissect out the rule of nitric oxide in ischemic brain injury associated with superoxide radicals, various combinations of SOD-1 transgenic mice and neuronal NOS knockout mutants will be employed.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology B Subcommittee 2 (NEUB)
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Behar, Toby
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Stanford University
Schools of Medicine
United States
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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
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
Chen, Hai; Yoshioka, Hideyuki; Kim, Gab Seok et al. (2011) Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection. Antioxid Redox Signal 14:1505-17
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
Jung, Joo Eun; Kim, Gab Seok; Chan, Pak H (2011) Neuroprotection by interleukin-6 is mediated by signal transducer and activator of transcription 3 and antioxidative signaling in ischemic stroke. Stroke 42:3574-9
Song, Yun Seon; Kim, Min-Soo; Kim, Hyun-Ae et al. (2010) Oxidative stress increases phosphorylation of IkappaB kinase-alpha by enhancing NF-kappaB-inducing kinase after transient focal cerebral ischemia. J Cereb Blood Flow Metab 30:1265-74
Niizuma, Kuniyasu; Yoshioka, Hideyuki; Chen, Hai et al. (2010) Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia. Biochim Biophys Acta 1802:92-9
Katsu, Masataka; Niizuma, Kuniyasu; Yoshioka, Hideyuki et al. (2010) Hemoglobin-induced oxidative stress contributes to matrix metalloproteinase activation and blood-brain barrier dysfunction in vivo. J Cereb Blood Flow Metab 30:1939-50
Jung, Joo Eun; Kim, Gab Seok; Chen, Hai et al. (2010) Reperfusion and neurovascular dysfunction in stroke: from basic mechanisms to potential strategies for neuroprotection. Mol Neurobiol 41:172-9

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