Recent studies supported by this grant have begun to fill a major gap in our knowledge regarding neuroinflammation, survival signaling, and protection of the penumbra in experimental stroke. We have found that docosahexaenoic acid (DHA), an omega-3 essential fatty acid-family member, which is selectively enriched and avidly retained in the central nervous system (CNS), upregulates cellular and molecular events when systemically administered that counteract injury and, in turn, exert protection after transient middle cerebral artery occlusion (MCAo). We have discovered that DHA is the precursor of the stereospecific and potent mediator, neuroprotectin D1 (NPD1), and very recently we uncovered during MCAo in the penumbra a novel DHA-derived mediator, which we named neuroprotectin D2 (NPD2). These two docosanoids, through synergizing of their bioactivity, may be critical in driving the protective beneficial effects of DHA. In addition, we have demonstrated that a low molecular weight platelet-activating factor (PAF)-receptor antagonist, LAU-0901 (developed in our laboratory), downregulates neuroinflammation and elicits protection. In both instances, protection has relatively ample windows of post-occlusion, is long-lasting, and correlates with neurobehavioral improvement. Our central hypothesis for the next funding period is that upregulation of DHA survival signaling elicits sustained cellular and behavioral protection of the penumbra after MCAo. We will test this hypothesis in experiments where we drive upregulation of survival signaling by DHA-derived mediators (NPD1 and NPD2) and by neuroinflammatory antagonism (LAU-0901) using MCAo, high resolution magnetic resonance imaging (MRI), primary cell cultures, and LC-PDA-ESI-MS/MS-based mediator lipidomic analysis. We will test the following specific aims:
Specific Aim 1 - To test the prediction that the novel DHA-derived mediator, NPD2, which is generated in the penumbra during brain ischemia-reperfusion, elicits neuroprotection;
Specific Aim 2 - To test the prediction that NPD1 and NPD2 target survival signaling and pro-inflammatory genes;
Specific Aim 3 - To test the prediction that blockage of the PAF receptor elicits penumbra protection after MCAo, downregulating neuroinflammatory signaling.
Specific Aim 4 - To test the hypothesis that neuroinflammatory antagonism in combination with docosanoid-mediated survival signaling promotes sustained protection of the penumbra. These findings have the potential to open a new translational avenue for clinical therapies of cerebrovascular diseases.
Docosahexaenoic acid (DHA), an omega-3 essential fatty acid-family member that is selectively enriched and avidly retained in the central nervous system (CNS), upregulates the formation of novel mediators in the penumbra that counteract injury and, in turn, exert protection after transient middle cerebral artery occlusion (MCAo), which includes platelet activating factor (PAF) antagonism. Our central hypothesis is that upregulation of DHA survival signaling elicits sustained cellular and behavioral protection of the penumbra after MCAo. These findings have the potential to open a new translational avenue for clinical therapies of cerebrovascular diseases.
|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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