Phenelzine Protects Brain Mitochondrial Function In Vitro and In Vivo following Traumatic Brain Injury by Scavenging the Reactive Carbonyls 4-Hydroxynonenal and Acrolein Leading to Cortical Histological Neuroprotection
Phenelzine Protects Brain Mitochondrial Function In Vitro and In Vivo following Traumatic Brain Injury by Scavenging the Reactive Carbonyls 4-Hydroxynonenal and Acrolein Leading to Cortical Histological Neuroprotection
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DOI：
10.1089/neu.2016.4624
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发表时间：
2017-04-01
影响因子：
4.2
通讯作者：
Hall, Edward D.
中科院分区：
文献类型：
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作者：
Cebak, John E.;Singh, Indrapal N.;Hall, Edward D.
脂质过氧化(LP)是创伤性脑损伤(TBI)的重要病理生理机制之一。传统的抗氧化剂疗法旨在清除引发或传播LP的自由基。最近探索的一种方法包括清除末端LP分解产物，这些产物是高度活性和神经毒性的羰基化合物，4-羟基壬烯醛(4-HNE)和丙烯醛(ACR)，以防止它们的共价修饰和呈现细胞蛋白质的非功能导致离子稳态丧失，线粒体失败，以及随后的神经元死亡。苯乙肼(PZ)是美国食品和药物管理局(FDA)批准的单胺氧化酶(MAO)抑制剂(MAO-I)，用于治疗难治性抑郁症，该药物含有联氨官能团，最近被其他研究人员发现可清除活性羰基。我们假设PZ将通过清除脂蛋白衍生的醛来保护线粒体功能并减少氧化损伤的标志物。在第一组体外研究中，我们发现，外源性应用4-HNE或ACR显著降低了未受损伤的大鼠大脑皮质线粒体的呼吸功能，增加了氧化损伤的标记物(p<；0.05)，而PZ以浓度相关的方式显著阻止了线粒体功能障碍和线粒体蛋白的氧化修饰(p<；0.05)。结构类似的MAO-I-pargyline没有这种作用，证实了PZ的线粒体保护作用与其清除羰基有关，而不是与MAO抑制有关。在随后的体内研究中，我们记录了在受控的皮质撞击后15分钟开始的PZ治疗显著减轻了损伤后72小时的线粒体呼吸功能障碍。皮质线粒体呼吸保护与皮质组织储备显著增加。
Lipid peroxidation (LP) is a key contributor to the pathophysiology of traumatic brain injury (TBI). Traditional antioxidant therapies are intended to scavenge the free radicals responsible for either initiation or propagation of LP. A more recently explored approach involves scavenging the terminal LP breakdown products that are highly reactive and neurotoxic carbonyl compounds, 4-hydroxynonenal (4-HNE) and acrolein (ACR), to prevent their covalent modification and rendering of cellular proteins nonfunctional leading to loss of ionic homeostasis, mitochondrial failure, and subsequent neuronal death. Phenelzine (PZ) is a U.S. Food and Drug Administration-approved monoamine oxidase (MAO) inhibitor (MAO-I) used for treatment of refractory depression that possesses a hydrazine functional group recently discovered by other investigators to scavenge reactive carbonyls. We hypothesized that PZ will protect mitochondrial function and reduce markers of oxidative damage by scavenging LP-derived aldehydes. In a first set of in vitro studies, we found that exogenous application of 4-HNE or ACR significantly reduced respiratory function and increased markers of oxidative damage (p < 0.05) in isolated noninjured rat brain cortical mitochondria, whereas PZ pretreatment significantly prevented mitochondrial dysfunction and oxidative modification of mitochondrial proteins in a concentration-related manner (p < 0.05). This effect was not shared by a structurally similar MAO-I, pargyline, which lacks the hydrazine group, confirming that the mitochondrial protective effects of PZ were related to its carbonyl scavenging and not to MAO inhibition. In subsequent in vivo studies, we documented that PZ treatment begun at 15 min after controlled cortical impact TBI significantly attenuated 72-h post-injury mitochondrial respiratory dysfunction. The cortical mitochondrial respiratory protection occurred together with a significant increase in cortical tissue sparing.