The metabolism of arachidonic acid, lipoxygenase-reaction products, prostaglandins and phospholipids in rat brain will be investigated during experimentally-induced seizures. Phosphatidylinositol, phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate, which are enriched in arachidonoyl groups, and their metabolites, inositol-1,4,5-trisphosphate and diacylglycerols, will be studied, to test the hypothesis that these particular components of neuronal cell signaling systems are the membrane target affected by convulsions. The accumulation of endogenous arachidonoyldiacylglycerol, known to occur as a result of seizures, is proposed to be a consequence of enhanced breakdown of polyphosphoinositides mediated by phospholipase C. The effects of the muscarinic cholinergic antagonist, atropine, and the inositol phosphatase inhibitor, lithium, on the phosphoinositide cycle, will be evaluated. The hypothesis to be tested also includes convulsion-induced changes in phospholipase A2, resulting in the release of arachidonic acid from synaptic membrane phospholipids, through a receptor-related mobilization of calcium. The role of calcium will be evaluated using calcium channel modulators. As a result of phospholipase A2 activation, subsequent production of oxygenated metabolites of arachidonic acid, particularly hydroxyeicosatetraenoic acids, may be enhanced. Emphasis will be placed on the membrane lipid sources, neuroanatomical and subcellular distribution, and fate of the rapidly released arachidonic acid and arachidonoyl-diacylglycerols that occur in the rat brain during bicuculline-induced status epilepticus and after electroconvulsive shock. Convulsions will be induced in mechanically ventilated, well-oxygenated animals. In some experiments 32P 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 data on the use of drugs that are potentially capable of halting or reversing membrane lipid breakdown, consequently preventing or limiting the brain damage caused by epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS023002-01
Application #
3405918
Study Section
Neurology A Study Section (NEUA)
Project Start
1986-04-01
Project End
1989-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
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
Bazan, Nicolas G (2005) Lipid signaling in neural plasticity, brain repair, and neuroprotection. Mol Neurobiol 32:89-103

Showing the most recent 10 out of 81 publications