Bazan N G, Birkle D L, Tang W, Reddy T S
Adv Neurol. 1986;44:879-902.
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)
自1970年以来，越来越多的生化证据表明，惊厥诱导变化的目标之一是神经元的细胞膜。这部分基于以下观察结果：癫痫发作后，二酰基甘油和游离脂肪酸水平升高，它们是细胞膜主要成分磷脂降解的产物。此外，惊厥后，游离脂肪酸花生四烯酸生成前列腺素的过程被激活。这意味着大脑中脂质代谢的改变是癫痫发作的主要影响，对这些生化途径的进一步研究可能揭示与确定癫痫发作的基本机制以及与癫痫发作相关的病理学相关的重要信息，并可能有助于开发潜在有效的治疗方法。本章描述了癫痫发作对脑脂质代谢的影响以及我们实验室最近的一些研究。我们的结果表明，在大鼠脑中，地塞米松（一种磷脂酶A2抑制剂）以剂量依赖的方式减弱荷包牡丹碱诱导的游离脂肪酸积累；体外检测显示，荷包牡丹碱诱导的癫痫持续状态不会改变脂肪酸的活化（花生四烯酰辅酶A的合成）或酰化，这表明高能辅因子（ATP）的可用性可能是体内脂肪酸酰化减少的关键因素；荷包牡丹碱诱导的脂肪酸积累主要定位于大鼠脑的突触体部分；用荷包牡丹碱处理诱导大鼠癫痫发作会显著刺激突触体中的脂氧合酶活性，进而导致羟基二十碳四烯酸（HETEs）的合成大幅增加。在用45 mM K+进行膜去极化后也观察到这种效应，并且荷包牡丹碱诱导的癫痫持续状态会刺激前列腺素D2的合成。描述了特定脂质改变的可能机制和后果。此外，还讨论了受刺激的花生四烯酸级联反应，特别是羟基化产物，在神经递质释放中的可能作用。综述了神经传递与类花生酸生成之间相互作用的其他方面。导致“脂质效应”（即游离脂肪酸、二酰基甘油和花生四烯酸代谢产物（类花生酸）的产生）的代谢途径众多，涉及多种酶。这种 “脂质效应” 的机制可能涉及癫痫发作诱导的对在神经传递中起作用的正常脂质途径的过度刺激。（摘要截取自400字）
