Myeloperoxidase Nuclear Imaging for Epileptogenesis.
Myeloperoxidase Nuclear Imaging for Epileptogenesis.
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DOI：
10.1148/radiol.2015141922
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发表时间：
2016-03
期刊：
影响因子：
19.7
通讯作者：
Yinian Zhang;D.P. Seeburg;B. Pulli;G. Wojtkiewicz;Lionel Buré;Wendy Atkinson;S. Schob;Y. Iwamoto;Muhammad Ali;Wei Zhang;E. Rodríguez;Andrew Milewski;E. Keliher;Cuihua Wang;Yawen Pan;F. Swirski;John W. Chen
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文献类型：
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作者：
Yinian Zhang;D.P. Seeburg;B. Pulli;G. Wojtkiewicz;Lionel Buré;Wendy Atkinson;S. Schob;Y. Iwamoto;Muhammad Ali;Wei Zhang;E. Rodríguez;Andrew Milewski;E. Keliher;Cuihua Wang;Yawen Pan;F. Swirski;John W. Chen
目的确定髓过氧化物酶（MPO）是否参与癫痫的发生，以及分子核成像是否可用于非侵入性地绘制癫痫发生中的炎症变化。材料和方法动物和人类研究由机构审查委员会批准。用4-氨基苯甲酸酰肼（n = 46）（一种特异性不可逆MPO抑制剂）或生理盐水（n = 42）处理匹罗卡品诱导的癫痫小鼠。使用铟-111-双-5-羟色胺-二亚乙基三胺五乙酸盐通过单光子发射计算机断层扫描/计算机断层扫描对脑MPO活性进行成像（4-氨基苯甲酸酰肼和盐水组n = 6;假手术组n = 5）。通过临床症状、生化和组织病理学数据评估MPO在自发性反复发作发展中的作用。对癫痫患者和非癫痫患者的人脑标本进行MPO染色。使用Student t检验、单因素方差分析以及Mann-Whitney和Kruskal-Wallis检验。如果P小于0.05，则差异被认为是显著的。结果癫痫发作时脑内MPO和白细胞均明显升高（P <0.05）。阻断MPO可延迟自发性反复发作（99.6 vs 142 h，P = 0.016），改善自发性反复发作的严重程度（P <0.05），并抑制苔藓纤维发芽（Timm指数，0.31 vs 0.03; P = 0.003）。基质金属蛋白酶活性在癫痫发生过程中以MPO依赖性方式上调（1.44 vs 0.94 U/mg，P = 0.049），表明MPO作用于基质金属蛋白酶的上游。MPO活性被映射在癫痫发生在体内海马区。从患有难治性癫痫的人类患者中切除的颞叶组织而不是来自没有癫痫发作的患者的颞叶组织表现出阳性MPO免疫染色，表明这种成像技术的高转化潜力。结论MPO在癫痫发病中起重要作用，是癫痫治疗的潜在靶点和影像学标志物。
PURPOSE To determine if myeloperoxidase (MPO) is involved in epileptogenesis and if molecular nuclear imaging can be used to noninvasively map inflammatory changes in epileptogenesis. MATERIALS AND METHODS The animal and human studies were approved by the institutional review boards. Pilocarpine-induced epileptic mice were treated with 4-aminobenzoic acid hydrazide (n = 46), a specific irreversible MPO inhibitor, or saline (n = 42). Indium-111-bis-5-hydroxytryptamide-diethylenetriaminepentaacetate was used to image brain MPO activity (n = 6 in the 4-aminobenzoic acid hydrazide and saline groups; n = 5 in the sham group) by using single photon emission computed tomography/computed tomography. The role of MPO in the development of spontaneous recurrent seizures was assessed by means of clinical symptoms and biochemical and histopathologic data. Human brain specimens from a patient with epilepsy and a patient without epilepsy were stained for MPO. The Student t test, one-way analysis of variance, and Mann-Whitney and Kruskal-Wallis tests were used. Differences were regarded as significant if P was less than .05. RESULTS MPO and leukocytes increased in the brain during epileptogenesis (P < .05). Blocking MPO delayed spontaneous recurrent seizures (99.6 vs 142 hours, P = .016), ameliorated the severity of spontaneous recurrent seizures (P < .05), and inhibited mossy fiber sprouting (Timm index, 0.31 vs 0.03; P = .003). Matrix metalloproteinase activity was upregulated during epileptogenesis in an MPO-dependent manner (1.44 vs 0.94 U/mg, P = .049), suggesting that MPO acts upstream of matrix metalloproteinases. MPO activity was mapped during epileptogenesis in vivo in the hippocampal regions. Resected temporal lobe tissue from a human patient with refractory epilepsy but not the temporal lobe tissue from a patient without seizures demonstrated positive MPO immunostaining, suggesting high translational potential for this imaging technology. CONCLUSION The findings of this study highlight an important role for MPO in epileptogenesis and show MPO to be a potential therapeutic target and imaging biomarker for epilepsy.