Kornecki E, Lenox R H, Hardwick D H, Bergdahl J A, Ehrlich Y H
Department of Psychiatry, University of Vermont College of Medicine, Burlington 05405.
Adv Exp Med Biol. 1987;221:477-88. doi: 10.1007/978-1-4684-7618-7_34.
PAF-acether, a naturally occurring phospholipid, is a potent activator of various biological processes, including platelet aggregation. The mechanisms of action of PAF are largely unknown. We have found that the psychotropic triazolobenzodiazepine drugs, alprazolam and triazolam, potently (IC50 less than 1 microM) inhibit PAF-induced shape change, aggregation and secretion of human platelets. These effects are specific for PAF-activation, since the responses of human platelets to other agonists (ADP, thrombin, epinephrine, collagen, arachidonate and the Ca++ ionophore, A23187) are not inhibited by these triazolobenzodiazepines. The action of triazolobenzodiazepines on PAF-induced platelet function has clinical relevance, especially in diseases where enhanced platelet aggregability may lead to thrombosis and atherosclerosis. In addition, the ability of triazolobenzodiazepines to inhibit other PAF-mediated cellular-responses, such as anaphylactic shock or bronchoconstriction, suggests that these drugs may be useful in preventing several known pathophysiological effects of PAF. The specific antagonism of PAF action by psychotropic drugs also suggests that PAF or PAF-like phospholipids may play a role in neuronal function. This possibility was tested by examining the effects of PAF on neural cells of the clonal line NG108-15, grown in culture in a chemically defined, serum-free medium. Low concentrations of PAF (0.5-2.5 microM) induced neurite extension in NG108-15 cells, whereas higher concentrations (greater than 3 microM) were cytotoxic. Using NG108-15 cells preloaded with aequorin, it was found that PAF causes an increase in intracellular ionized calcium concentration, which is dependent on the presence of extracellular calcium. These results suggest that PAF-induced Ca++ uptake may play a role in neuronal development, and that circulating PAF may contribute to the neuronal degeneration caused by the exposure of neural tissues to blood in situations such as spinal cord injury, trauma, or stroke.
血小板活化因子（PAF - 乙酰醚）是一种天然存在的磷脂，是包括血小板聚集在内的各种生物过程的有效激活剂。PAF的作用机制在很大程度上尚不清楚。我们发现，精神类三唑并苯二氮䓬类药物阿普唑仑和三唑仑能有效（IC50小于1微摩尔）抑制PAF诱导的人血小板形态变化、聚集和分泌。这些作用对PAF激活具有特异性，因为人血小板对其他激动剂（二磷酸腺苷、凝血酶、肾上腺素、胶原、花生四烯酸和钙离子载体A23187）的反应不受这些三唑并苯二氮䓬类药物抑制。三唑并苯二氮䓬类药物对PAF诱导的血小板功能的作用具有临床相关性，特别是在血小板聚集性增强可能导致血栓形成和动脉粥样硬化的疾病中。此外，三唑并苯二氮䓬类药物抑制其他PAF介导的细胞反应（如过敏性休克或支气管收缩）的能力表明，这些药物可能有助于预防PAF的几种已知病理生理效应。精神类药物对PAF作用的特异性拮抗也表明PAF或PAF样磷脂可能在神经元功能中起作用。通过检查PAF对在化学成分明确的无血清培养基中培养的克隆系NG108 - 15神经细胞的影响来测试这种可能性。低浓度的PAF（0.5 - 2.5微摩尔）诱导NG108 - 15细胞的神经突延伸，而较高浓度（大于3微摩尔）具有细胞毒性。使用预先装载水母发光蛋白的NG108 - 15细胞，发现PAF导致细胞内游离钙浓度增加，这取决于细胞外钙的存在。这些结果表明，PAF诱导的钙离子摄取可能在神经元发育中起作用，并且循环中的PAF可能在诸如脊髓损伤、创伤或中风等情况下神经组织暴露于血液所导致的神经元变性中起作用。
