Blocking leukotriene synthesis attenuates the pathophysiology of traumatic brain injury and associated cognitive deficits.
Blocking leukotriene synthesis attenuates the pathophysiology of traumatic brain injury and associated cognitive deficits.
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DOI：
10.1016/j.expneurol.2014.03.008
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发表时间：
2014-06
影响因子：
5.3
通讯作者：
Heidenreich KA
中科院分区：
文献类型：
--
作者：
Corser-Jensen CE;Goodell DJ;Freund RK;Serbedzija P;Murphy RC;Farias SE;Dell'Acqua ML;Frey LC;Serkova N;Heidenreich KA
神经炎症是创伤性脑损伤（TBI）后继发性损伤的一个组成部分，可以持续到急性期之后。白三烯是由膜磷脂产生的有效的促炎脂质介质。在没有损伤的情况下，白三烯在大脑中是检测不到的，但在创伤后，它们通过浸润中性粒细胞和内源性脑细胞的跨细胞事件迅速合成。在这里，我们研究了5-脂氧合酶激活蛋白（FLAP）抑制剂MK-886在脑损伤后阻断白三烯合成、继发性脑损伤、突触功能障碍和认知障碍的功效。雄性Sprague Dawley大鼠（9-11周）在遭受单侧中度液体撞击损伤（FPI）后接受MK-886或车辆，以评估皮瓣抑制剂在TBI中的潜在临床应用。在FPI之前也给予MK-886，以确定FLAP抑制剂的预防潜力。通过反相液相色谱-串联质谱（RP LC-MS/MS）和t2加权磁共振成像（MRI）测量脑水肿，损伤前后给予MK-886可显著阻断白三烯的产生。MK-886显著减轻了CA1海马区的血脑屏障破坏和CA1海马突触的长期增强（LTP）缺陷。MK-886在预防fpi诱导的突触功能障碍的同时，减少了桡臂水迷宫（RAWM）损伤后空间学习和记忆表现的缺陷。这些结果表明白三烯在继发性脑损伤和随后的认知缺陷中起着重要作用。皮瓣抑制剂代表了一种治疗人类TBI的新型抗炎方法，可用于干预和预防脑损伤和神经功能缺损。
Neuroinflammation is a component of secondary injury following traumatic brain injury (TBI) that can persist beyond the acute phase. Leukotrienes are potent, pro-inflammatory lipid mediators generated from membrane phospholipids. In the absence of injury, leukotrienes are undetectable in brain, but after trauma they are rapidly synthesized by a transcellular event involving infiltrating neutrophils and endogenous brain cells. Here, we investigate the efficacy of MK-886, an inhibitor of 5-lipoxygenase activating protein (FLAP), in blocking leukotriene synthesis, secondary brain damage, synaptic dysfunction, and cognitive impairments after TBI. Male Sprague Dawley rats (9-11 weeks) received either MK-886 or vehicle after they were subjected to unilateral moderate fluid percussion injury (FPI) to assess the potential clinical use of FLAP inhibitors for TBI. MK-886 was also administered before FPI to determine the preventative potential of FLAP inhibitors. MK-886 given before or after injury significantly blocked the production of leukotrienes, measured by reverse-phase liquid chromatography coupled to tandem mass spectrometry (RP LC-MS/MS), and brain edema, measured by T2-weighted magnetic resonance imaging (MRI). MK-886 significantly attenuated blood-brain barrier disruption in the CA1 hippocampal region and deficits in long-term potentiation (LTP) at CA1 hippocampal synapses. The prevention of FPI-induced synaptic dysfunction by MK-886 was accompanied by fewer deficits in post-injury spatial learning and memory performance in the radial arms water maze (RAWM). These results indicate that leukotrienes contribute significantly to secondary brain injury and subsequent cognitive deficits. FLAP inhibitors represent a novel anti-inflammatory approach for treating human TBI that is feasible for both intervention and prevention of brain injury and neurologic deficits.