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)