Koutsogiannidis Charilaos-Panagiotis C, Ananiadou Olga G, Ampatzidou Fotini C, Savvas Ioannis P, Mytilinaios Dimitrios G, Nikolopoulou Elena N, Troupis Theodore G, Charchanti Antonia V, Drossos George E, Johnson Elizabeth O
Cardiothoracic Surgery Department, General Hospital "G. Papanikolaou", Thessaloniki, Greece.
Department of Anatomy-Histology-Embryology, University of Ioannina Medical School, Ioannina, Greece.
J Card Surg. 2015 Jun;30(6):525-31. doi: 10.1111/jocs.12544. Epub 2015 Apr 9.
We have previously reported that the neocortex is selectively vulnerable to injury in an acute porcine model of hypothermic circulatory arrest (HCA) at 18°C. In view of recent evidence showing that pharmacologic preconditioning with a single dose of erythromycin induces tolerance against transient global cerebral ischemia in rats, we hypothesized that erythromycin would reduce the number of apoptotic neurons in the neocortex in an acute porcine model of HCA at 18°C.
Fourteen piglets underwent 75 min of HCA at 18°C following pretreatment with erythromycin (25 mg/kg, IV) (n = 8) or vehicle (Normal Saline 0.9%) (n = 6), applied 12 hr before arrest. Three served as normal controls. After gradual rewarming to a temperature of 36°C, treatment animals were sacrificed and brains were perfusion-fixed and cryopreserved. Neuronal apoptosis after HCA was observed morphologically with hematoxylin and eosin staining, and characterized by in situ DNA fragmentation using terminal deoxynucleotidyl-transferase-mediated biotin-dUTP nick end-labeling (TUNEL) histochemistry.
Pre-ischemic conditioning with a single dose of the antibiotic erythromycin reduced neuronal apoptosis in the neocortex of the porcine brain. TUNEL-positive cells indicating DNA fragmentation and neuronal injury were significantly greater in the neocortex of animals treated with 18°C HCA (2.55 ± 1.17) compared to animals undergoing HCA after erythromycin preconditioning (1.76 ± 0.91) (p ≤ 0.001).
These results suggest that cerebral protection during HCA may be achieved with erythromycin pharmacological preconditioning in the porcine model.
我们之前报道过，在18°C低温循环骤停（HCA）的急性猪模型中，新皮质对损伤具有选择性易损性。鉴于最近有证据表明，单剂量红霉素进行药物预处理可诱导大鼠对短暂性全脑缺血产生耐受性，我们推测红霉素会减少18°C HCA急性猪模型中新皮质凋亡神经元的数量。
14只仔猪在18°C下接受75分钟的HCA，其中8只在骤停前12小时静脉注射红霉素（25mg/kg）进行预处理，6只注射溶媒（0.9%生理盐水）。3只作为正常对照。在逐渐复温至36°C后，处死处理组动物，对大脑进行灌注固定并冷冻保存。用苏木精-伊红染色从形态学上观察HCA后的神经元凋亡情况，并用末端脱氧核苷酸转移酶介导的生物素-dUTP缺口末端标记（TUNEL）组织化学法对原位DNA片段化进行表征。
单剂量抗生素红霉素进行缺血预处理可减少猪脑新皮质中的神经元凋亡。与红霉素预处理后接受HCA的动物相比，18°C HCA处理的动物新皮质中显示DNA片段化和神经元损伤的TUNEL阳性细胞明显更多（2.55±1.17 vs 1.76±0.91）（p≤0.001）。
这些结果表明，在猪模型中，红霉素药物预处理可在HCA期间实现脑保护。
