We will focus on membrane lipid-derived second messenger during seizures. We will study alterations in the metabolism of phospholipids, diacylgycerols and fatty acids, specifically arachidonic acid and arachidonoyl-glycerolipids in discrete brain regions, and in synaptosomes and synaptoneurosomes of the rat, during experimentally-induced seizures. These studies will define the role of synaptic membrane components in the development of epileptic activity and the molecular pathogenesis of epileptic brain damage. Three models will be investigated: 1) a single electroconvulsive shock with minimal neuronal damage; 2) bicuculline-induced status epilepticus, where, brain damage is severe; and 3) audiogenic seizures in genetically epileptic rats. We will test the hypothesis that seizures lead to receptor-mediated activation of phospholipase A2 and phospholipase C, resulting in the degradation of synaptic membrane polyphosphoinositides and ether-linked phosphatidylcholine, and in the altered release of lipid-derived messengers, e.g. arachidonic acid (20:4) and its oxygenated metabolites, diacylglycerols (DG), platelet activating factor (PAF) and inositol phosphates (IP). We will assess exitotoxic amino acid agonists and antagonists in relation to epileptic brain damage as well as polyunsaturated fatty acid peroxidation. Specifically, we will use radiotracer techniques and measurement of endogenous lipids to study the metabolism of alkyl- acylglycerophosphocholine (the PAF cycle precursor) and polyphosphoinositides as targets for seizure-activated phospholipase. We will use hippocampus, striatum and cerebral cortex isolated from microwave-fixed rat brain for in vivo studies, and synaptosomes and synaptoneurosomes prepared from these brain areas for in vitro studies. In some experiments 14C choline or (14C) arachidonic acid will be injected intraventricularly to follow precursor-product relationships. This proposal will employ in vivo models and subcellular fractions. Very rapid fixation of the tissues within 1 second will be achieved by high-powered, head- focused microwave irradiation. Powerful analytical techniques, such as high performance liquid chromatography, gas-liquid chromatography, and gas chromatography-mass spectrometry, will be used to examine biochemical changes in phospholipids and fatty acids of neuronal membranes. The results of this study will have application in the management of epileptic seizures and will provide a model to evaluate drugs potentially capable of halting or reversing membrane lipid breakdown, consequently preventing or limiting the brain damage caused by epilepsy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology A Study Section (NEUA)
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Louisiana State University Hsc New Orleans
Schools of Medicine
New Orleans
United States
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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
Musto, Alberto E; Gjorstrup, Per; Bazan, Nicolas G (2011) The omega-3 fatty acid-derived neuroprotectin D1 limits hippocampal hyperexcitability and seizure susceptibility in kindling epileptogenesis. Epilepsia 52:1601-8
Belayev, Ludmila; Khoutorova, Larissa; Atkins, Kristal et al. (2009) LAU-0901, a novel platelet-activating factor receptor antagonist, confers enduring neuroprotection in experimental focal cerebral ischemia in the rat. Brain Res 1253:184-90
Lukiw, Walter J; Bazan, Nicolas G (2008) Docosahexaenoic acid and the aging brain. J Nutr 138:2510-4
Belayev, Ludmila; Khoutorova, Larissa; Atkins, Kristal et al. (2008) LAU-0901, a novel platelet-activating factor antagonist, is highly neuroprotective in cerebral ischemia. Exp Neurol 214:253-8
Musto, Alberto; Bazan, Nicolas G (2006) Diacylglycerol kinase epsilon modulates rapid kindling epileptogenesis. Epilepsia 47:267-76
Kolko, Miriam; Christoffersen, Nanna R; Barreiro, Sebastian G et al. (2006) Characterization and location of secretory phospholipase A2 groups IIE, V, and X in the rat brain. J Neurosci Res 83:874-82
Cole-Edwards, Kasie K; Musto, Alberto E; Bazan, Nicolas G (2006) c-Jun N-terminal kinase activation responses induced by hippocampal kindling are mediated by reactive astrocytes. J Neurosci 26:8295-304
Malcher-Lopes, Renato; Di, Shi; Marcheselli, Victor S et al. (2006) Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release. J Neurosci 26:6643-50
Lukiw, Walter J; Cui, Jian-Guo; Musto, Alberto E et al. (2005) Epileptogenesis in diacylglycerol kinase epsilon deficiency up-regulates COX-2 and tyrosine hydroxylase in hippocampus. Biochem Biophys Res Commun 338:77-81

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