? The long-term objective of this project is to define the significance of lipid signaling for neuronal survival in ischemia-reperfusion damage associated with stroke. In ischemia-reperfusion damage, phospholipase A2 activation, arachidonic and docosahexaenoic acid release, and the accumulation of prostaglandins, lipoxygenase products, and platelet-activating factor are up-regulated. We will test the hypotheses (a) that PAF, a messenger of NMDA-receptor signaling, when overproduced becomes a mediator of neuronal damage in focal stroke; (b) that ischemiareperfusion activates the synthesis of endogenous neuroprotective docosanoid signaling that has the potential for counteracting pro-inflammatory responses (e.g., PMN activation and proinflammatory gene expression); and (c) that PAF antagonism elicits neuroprotection in ischemia-reperfusion. We will also test a corollary of these hypotheses, that PAF-blocking compounds elicit neuroprotection in ischemia-reperfusion damage, in addition to attenuating PAF-mediated neuronal damage, by up-regulating the expression of neuroprotective genes. We will use mice deficient in PAF receptor to define the significance of PAF in the injured brain. Powerful experimental approaches including LC-PDE-MS-MS lipidomic analysis in combination with transient middle cerebral artery occlusion, immunohistochemistry, and molecular biology will be used to study lipid signaling in experimental stroke. These studies will (a) define signaling and novel neuroprotective mechanisms in ischemia-reperfusion; (b) characterize novel docosanoid signaling; and (c) identify new drug strategies to prevent or limit neuronal cell damage or death in stroke. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Jacobs, Tom P
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Louisiana State University Hsc New Orleans
Schools of Medicine
New Orleans
United States
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Belayev, Ludmila; Hong, Sung-Ha; Menghani, Hemant et al. (2018) Docosanoids Promote Neurogenesis and Angiogenesis, Blood-Brain Barrier Integrity, Penumbra Protection, and Neurobehavioral Recovery After Experimental Ischemic Stroke. Mol Neurobiol 55:7090-7106
Bazan, Nicolas G (2018) Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection. Mol Aspects Med 64:18-33
Bhattacharjee, Surjyadipta; Jun, Bokkyoo; Belayev, Ludmila et al. (2017) Elovanoids are a novel class of homeostatic lipid mediators that protect neural cell integrity upon injury. Sci Adv 3:e1700735
Asatryan, Aram; Bazan, Nicolas G (2017) Molecular mechanisms of signaling via the docosanoid neuroprotectin D1 for cellular homeostasis and neuroprotection. J Biol Chem 292:12390-12397
Bazan, Nicolas G; Carman, George M (2017) Thematic Minireview Series: Inflammatory transcription confronts homeostatic disruptions. J Biol Chem 292:12373-12374
Belayev, Ludmila; Mukherjee, Pranab K; Balaszczuk, Veronica et al. (2017) Neuroprotectin D1 upregulates Iduna expression and provides protection in cellular uncompensated oxidative stress and in experimental ischemic stroke. Cell Death Differ 24:1091-1099
Bazan, Nicolas G (2016) Molecular Principles for Decoding Homeostasis Disruptions in the Retinal Pigment Epithelium: Significance of Lipid Mediators to Retinal Degenerative Diseases. Adv Exp Med Biol 854:385-91
Hong, Sung-Ha; Belayev, Ludmila; Khoutorova, Larissa et al. (2014) Docosahexaenoic acid confers enduring neuroprotection in experimental stroke. J Neurol Sci 338:135-41
Bazan, Nicolas G (2014) Is there a molecular logic that sustains neuronal functional integrity and survival? Lipid signaling is necessary for neuroprotective neuronal transcriptional programs. Mol Neurobiol 50:1-5
Williams, Jill J; Mayurasakorn, Korapat; Vannucci, Susan J et al. (2013) N-3 fatty acid rich triglyceride emulsions are neuroprotective after cerebral hypoxic-ischemic injury in neonatal mice. PLoS One 8:e56233

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