The accumulation of free arachidonic acid, diacylglycerols, prostaglandins, and lipoxygenase reaction products in the brain during experimental epilepsy.
There has been increasing biochemical evidence since 1970 that one of the targets for convulsion-induced changes is the cell membrane of neurons. This is partly based on the observation that following seizures, there are increased levels of diacylglycerols and free fatty acids, which are products of the degradation of the major component of cell membranes, phospholipids. In addition, the production of prostaglandins from the free fatty acid, arachidonic acid, is activated after convulsions. This implies that alterations in the metabolism of lipids in brain are a major effect of seizures, and that the further study of these biochemical pathways may reveal important information pertinent to defining the basic mechanism of seizures and seizure-related pathology and may help in the development of potentially effective treatments. The effects of seizures on brain lipid metabolism and some recent studies from our laboratory are described in this chapter. Our results demonstrate that in rat brain, dexamethasone--a phospholipase A2 inhibitor--attenuates bicuculline-induced free fatty acid accumulation in a dose-dependent manner; bicuculline-induced status epilepticus does not alter the activation (synthesis of arachidonoyl coenzyme A) or acylation of fatty acids as assayed in vitro, indicating that the availability of high-energy cofactors (ATP) may be the critical factor responsible for decreased fatty acid acylation in vivo; bicuculline-induced fatty acid accumulation is localized mainly in the synaptosomal fraction of the rat brain; induction of seizures in the rat by bicuculline treatment produces a marked stimulation of lipoxygenase activity in synaptosomes that, in turn, results in a large increase in the synthesis of hydroxyeicosatetraenoic acids (HETEs). This effect is also observed following membrane depolarization with 45 mM K+, and bicuculline-induced status epilepticus stimulates the synthesis of prostaglandin D2. Possible mechanisms and consequences of alterations in specific lipids are described. Also, the possible involvement of a stimulated arachidonic acid cascade, particularly of hydroxylated products, in the release of neurotransmitters is discussed. Other aspects of the interaction between neurotransmission and the production of eicosanoids are reviewed. The metabolic pathways leading to the "lipid effect"--i.e., the production of free fatty acids, diacylglycerols, and arachidonic acid metabolites (eicosanoids)--are numerous and involve a wide variety of enzymes. The mechanism of this "lipid effect" may involve a seizure-induced overstimulation of normal lipid pathways that operate in neurotransmission.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001696:Biomechanical Phenomena; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism*; D004827:Epilepsy / Q000201:enzymology / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007294:Inositol / Q000378:metabolism; D017572:Leukotriene A4; D050356:Lipid Metabolism; D008084:Lipoxygenase / Q000378:metabolism*; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D012640:Seizures / Q000378:metabolism; D013256:Steroids / Q000494:pharmacology; D013570:Synaptic Membranes / Q000378:metabolism
D001095:Arachidonic Acids; D004075:Diglycerides; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D005989:Glycerides; D006893:Hydroxyeicosatetraenoic Acids; D017572:Leukotriene A4; D010743:Phospholipids; D011453:Prostaglandins; D013256:Steroids; D016718:Arachidonic Acid; D007294:Inositol; D008084:Lipoxygenase