Recent studies have demonstrated that oxygen radicals such as superoxide, hydroxyl, and nitric oxide, are involved in neuronal cell death following cerebral ischemia and reperfusion. We have demonstrated that cerebral infarction and neurological deficits are significantly ameliorated in transgenic mice overexpressing human CuZn-superoxide dismutase (CuZn-SOD) activity, as compared to their non-transgenic littermates. Other studies have implicated the occurrence of programmed cell death (apoptosis) through internucleosomal DNA fragmentation following cerebral ischemia. Numerous cell culture studies have now suggested that oxidative stress plays a role in programmed cell death, since an overexpressed antioxidant gene such as bcl-2 or a supplement with superoxide dismutase can reduce neuronal cell death through the apoptosis pathway. Our hypothesis is that oxidative stress induced by cerebral ischemia and reperfusion in involved in neuronal cell death through both the necrosis and apoptosis pathways. It is our aim to test our hypothesis using transgenic mice overexpressing human CuZn-SOD (SOD-1) and knockout mutants that contain no (homozygous) or one-half of (heterozygous) SOD-a activity. Since mitochondria is known to be the site of oxygen radicals production, we also hypothesize 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 role of nitric oxide in ischemic brain injury associated with superoxide radicals, various combinations of SOD-1 transgenic and neuronal NOS knockout mutants will be employed. We believe these are unique and fresh approaches that will provide insights into the oxidative mechanisms of the pathogenesis of necrosis and apoptosis following cerebral ischemia and reperfusion.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
2P50NS014543-19
Application #
5215082
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
1996
Total Cost
Indirect Cost
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
Kim, Jong Youl; Kim, Nuri; Yenari, Midori A et al. (2013) Hypothermia and pharmacological regimens that prevent overexpression and overactivity of the extracellular calcium-sensing receptor protect neurons against traumatic brain injury. J Neurotrauma 30:1170-6
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
Tang, Xian Nan; Cairns, Belinda; Kim, Jong Youl et al. (2012) NADPH oxidase in stroke and cerebrovascular disease. Neurol Res 34:338-45
Cairns, Belinda; Kim, Jong Youl; Tang, Xian Nan et al. (2012) NOX inhibitors as a therapeutic strategy for stroke and neurodegenerative disease. Curr Drug Targets 13:199-206
Voloboueva, Ludmila A; Giffard, Rona G (2011) Inflammation, mitochondria, and the inhibition of adult neurogenesis. J Neurosci Res 89:1989-96
Tang, Xian N; Zheng, Zhen; Giffard, Rona G et al. (2011) Significance of marrow-derived nicotinamide adenine dinucleotide phosphate oxidase in experimental ischemic stroke. Ann Neurol 70:606-15
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
Xiong, Xiaoxing; Barreto, George E; Xu, Lijun et al. (2011) Increased brain injury and worsened neurological outcome in interleukin-4 knockout mice after transient focal cerebral ischemia. Stroke 42:2026-32

Showing the most recent 10 out of 103 publications