Brain Phospholipid Metabolism, In Relation To Function

体内代谢(1)连续3代缺乏营养必需的n-3(omega-3)多不饱和脂肪酸(PUFAs)的大鼠出现学习记忆障碍。他们的脑磷脂显示n-3二十二碳六烯酸的浓度降低，n-6花生四烯酸的浓度没有变化，而n-6二十二碳五烯酸的浓度增加。脑磷脂中二十二碳六烯酸的周转率明显降低，但仍有活性，而花生四烯酸的周转率不变。大脑的功能和结构取决于二十二碳六烯酸和花生四烯酸之间的竞争。周转率似乎由特定的几组酶独立调节。(2)大鼠脑中3-5%的花生四烯酸和2-8%的二十二碳六烯酸每天分别被血浆中未酯化的多不饱和脂肪酸取代。在人类中，花生四烯酸的替代率为每天0.3%。根据测量的大脑多不饱和脂肪酸浓度，这些比率给出了大鼠1-2周和人类10周的半衰期，从血浆中替代大脑多不饱和脂肪酸。在疾病状态下，多不饱和脂肪酸的替代可以通过饮食补充来增强。(3)放射性标记花生四烯酸可用于心脏和脑内磷脂代谢的显像和定量。在未麻醉的大鼠静脉注射时，它被选择性地结合到心脏的膜磷脂中。活体成像(1)临床方案是使用正电子发射计算机断层扫描(PET)成像花生四烯酸和二十二碳六烯酸进入人脑。慢性酒精中毒、双相情感障碍和帕金森病可以用这种方法来研究。(2)我们的脂肪酸方法表明，帕金森病患者的大脑多巴胺能信号过度活跃，这是异常运动的原因。在帕金森病(黑质慢性单侧病变)大鼠模型中，静脉注射放射性花生四烯酸到病变同侧的基底节-额叶皮质回路的摄取增加，对多巴胺能D2受体激动剂的反应。该受体与磷脂酶A2的激活和花生四烯酸的释放有关，用于信号转导。(3)大鼠长期给予多巴胺能D2拮抗剂氟哌啶醇，可减少放射性标记的花生四烯酸从血浆进入基底节-额叶环路。氟哌啶醇的抗精神病作用可能是由于D2受体介导的花生四烯酸信号在这些回路中的下调。(4)在DS模型Ts65Dn小鼠脑组织中升高的肌醇，在DS模型小鼠脑中也有升高。该模型可用于研究肌醇升高对信号转导和磷脂酰肌醇循环的影响。

In vivo metabolism (1) Rats deprived of nutritionally essential n-3 (omega-3) polyunsaturated fatty acids (PUFAs) for 3 generations had deficits in learning and memory. Their brain phospholipids showed a reduced concentration of n-3 docosahexaenoic acid, no change in the concentration of n-6 arachidonic acid, and an increased concentration of n-6 docosapentaenoic acid. The turnover rate of docosahexaenoate in brain phospholipids was markedly reduced but nevertheless active, whereas the turnover rate of arachidonic acid was unchanged. Brain function and structure depend on competition between docosahexaenoic and arachidonic acids. The turnover rates appear to be independently regulated by specific sets of enzymes. (2) In rats, 3-5% of brain arachidonic acid and 2-8% of brain docosahexaenoic acid are replaced daily by the respective unesterified PUFAs from plasma. In humans, the arachidonate replacement rate is 0.3% per day. Based on measured brain PUFA concentrations, these rates give half-lives of 1-2 weeks in rats and 10 weeks in humans for brain PUFA replacement from plasma. PUFA replacement in disease states can be enhanced by dietary supplementation. (3) Radiolabeled arachidonic acid can be used to image and quantify phospholipid metabolism in heart as well as in brain. When injected intravenously in unanesthetized rats, it is selectively incorporated into membrane phospholipids in the heart. In vivo Imaging (1) Clinical protocols were initiated to use PET to image incorporation of arachidonic and docosahexaenoic acids into the human brain. Chronic alcoholism, bipolar disorder and Parkinson disease can be studied with this method. (2) Our fatty acid method suggests that brain dopaminergic signaling is hyperactive in Parkinson disease, accounting for abnormal motor movements. In a rat model of Parkinson disease (chronic unilateral lesion of substantia nigra), uptake of intravenously injected radioactive arachidonic acid into basal ganglia-frontal cortex circuitry was increased ipsilateral to the lesion, in response to a dopaminergic D2 receptor agonist. This receptor is coupled to phospholipase A2 activation and the release of arachidonic acid for signal transduction. (3) Chronic administration to rats of the dopaminergic D2 antagonist, haloperidol, decreased radiolabeled arachidonic incorporation from plasma into basal ganglia-frontal cortex circuits. Haloperidol's antipsychotic effect may be due to downregulation of D2-receptor mediated arachidonate signaling in these circuits. (4) Myoinositol, which is elevated in the DS brain, also is elevated in the brain of the Ts65Dn mouse model for DS. This model thus can be used to study the effect of myoinositol elevation on signaling and the phosphatidylinositol cycle.