Lucke-Wold Brandon P, Naser Zachary J, Logsdon Aric F, Turner Ryan C, Smith Kelly E, Robson Matthew J, Bailes Julian E, Lee John M, Rosen Charles L, Huber Jason D
Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WVa; The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WVa.
Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WVa; The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WVa; Department of Medicine, Professional Studies in Health Sciences, Drexel University College of Medicine, Philadelphia, PA.
Transl Res. 2015 Dec;166(6):509-528.e1. doi: 10.1016/j.trsl.2015.08.005. Epub 2015 Sep 8.
A total of 1.7 million traumatic brain injuries (TBIs) occur each year in the United States, but available pharmacologic options for the treatment of acute neurotrauma are limited. Oxidative stress is an important secondary mechanism of injury that can lead to neuronal apoptosis and subsequent behavioral changes. Using a clinically relevant and validated rodent blast model, we investigated how nicotinamide adenine dinucleotide phosphate oxidase (Nox) expression and associated oxidative stress contribute to cellular apoptosis after single and repeat blast injuries. Nox4 forms a complex with p22phox after injury, forming free radicals at neuronal membranes. Using immunohistochemical-staining methods, we found a visible increase in Nox4 after single blast injury in Sprague Dawley rats. Interestingly, Nox4 was also increased in postmortem human samples obtained from athletes diagnosed with chronic traumatic encephalopathy. Nox4 activity correlated with an increase in superoxide formation. Alpha-lipoic acid, an oxidative stress inhibitor, prevented the development of superoxide acutely and increased antiapoptotic markers B-cell lymphoma 2 (t = 3.079, P < 0.05) and heme oxygenase 1 (t = 8.169, P < 0.001) after single blast. Subacutely, alpha-lipoic acid treatment reduced proapoptotic markers Bax (t = 4.483, P < 0.05), caspase 12 (t = 6.157, P < 0.001), and caspase 3 (t = 4.573, P < 0.01) after repetitive blast, and reduced tau hyperphosphorylation indicated by decreased CP-13 and paired helical filament staining. Alpha-lipoic acid ameliorated impulsive-like behavior 7 days after repetitive blast injury (t = 3.573, P < 0.05) compared with blast exposed animals without treatment. TBI can cause debilitating symptoms and psychiatric disorders. Oxidative stress is an ideal target for neuropharmacologic intervention, and alpha-lipoic acid warrants further investigation as a therapeutic for prevention of chronic neurodegeneration.
在美国，每年发生170万例创伤性脑损伤（TBI），但用于治疗急性神经创伤的药物选择有限。氧化应激是一种重要的继发性损伤机制，可导致神经元凋亡及随后的行为改变。利用一种临床相关且经过验证的啮齿动物爆炸模型，我们研究了烟酰胺腺嘌呤二核苷酸磷酸氧化酶（Nox）表达及相关氧化应激如何在单次和重复爆炸损伤后导致细胞凋亡。损伤后，Nox4与p22phox形成复合物，在神经元膜上形成自由基。使用免疫组织化学染色方法，我们发现斯普拉格-道利大鼠单次爆炸损伤后Nox4明显增加。有趣的是，在从被诊断患有慢性创伤性脑病的运动员身上获取的尸检人类样本中，Nox4也有所增加。Nox4活性与超氧化物形成增加相关。氧化应激抑制剂α-硫辛酸可急性阻止超氧化物的产生，并在单次爆炸后增加抗凋亡标志物B细胞淋巴瘤2（t = 3.079，P < 0.05）和血红素加氧酶1（t = 8.169，P < 0.001）。亚急性时，α-硫辛酸治疗可在重复爆炸后降低促凋亡标志物Bax（t = 4.483，P < 0.05）、半胱天冬酶12（t = 6.157，P < 0.001）和半胱天冬酶3（t = 4.573，P < 0.01），并通过降低CP-13和双螺旋丝染色表明的tau过度磷酸化。与未治疗的爆炸暴露动物相比，α-硫辛酸可改善重复爆炸损伤7天后的冲动样行为（t = 3.573，P < 0.05）。创伤性脑损伤可导致使人衰弱的症状和精神障碍。氧化应激是神经药理学干预的理想靶点，α-硫辛酸作为预防慢性神经退行性变的治疗药物值得进一步研究。
