Melatonin and/or erythropoietin combined with hypothermia in a piglet model of perinatal asphyxia.
Melatonin and/or erythropoietin combined with hypothermia in a piglet model of perinatal asphyxia.
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DOI：
10.1093/braincomms/fcaa211
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发表时间：
2021
影响因子：
4.8
通讯作者：
Robertson NJ
中科院分区：
文献类型：
--
作者：
Pang R;Avdic-Belltheus A;Meehan C;Martinello K;Mutshiya T;Yang Q;Sokolska M;Torrealdea F;Hristova M;Bainbridge A;Golay X;Juul SE;Robertson NJ
由于治疗性低温对新生儿脑病仅具有部分保护作用，因此迫切需要安全有效的辅助治疗。褪黑激素和促红细胞生成素显示出安全有效的神经保护疗法的前景。我们假设褪黑激素和促红细胞生成素单独增加12小时低温（双重疗法）和低温+褪黑激素+促红细胞生成素（三联疗法）导致最佳的脑保护。在颈动脉闭塞和缺氧后，将49只雄性仔猪（<48小时龄）随机分配至：（i）低温+媒介物（n = 12），（ii）低温+褪黑激素（20 mg/kg，2小时）（n = 12），（iii）低温+促红细胞生成素（3000 U/kg推注）（n = 13）或（iv）三联疗法（n = 12）。在缺氧缺血后1、24和48 h给予褪黑激素、促红细胞生成素或溶媒。各组间缺氧-缺血严重程度相似。褪黑激素在缺氧缺血后3小时（15-30 mg/l）和促红细胞生成素给药后30分钟内（最大浓度10 000 mU/ml）达到治疗水平。与低温+载体相比，我们观察到低温+褪黑激素（P = 0.02）和低温+促红细胞生成素（P = 0.033）在25至30 h以及三联疗法（P = 0.042）在55至60 h的幅度积分EEG恢复更快。磁共振波谱乳酸/N-乙酰天冬氨酸峰值比在66 h时低于低温+褪黑激素组（P = 0.012）和三联疗法组（P = 0.032）。在低温+褪黑激素组，感觉运动皮层中末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记阳性细胞减少（P = 0.017），海马（P = 0.014）和脑室周围白色物质（P = 0.039）中少突胶质细胞转录因子2标记阳性细胞计数增加。亚低温+促红细胞生成素组的末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记阳性细胞数没有减少，但在8个脑区中的5个中，少突胶质细胞转录因子2标记阳性细胞数增加（P < 0.05）。总的来说，褪黑激素和促红细胞生成素是安全有效的辅助治疗低温。低温+褪黑激素双重治疗导致更快的振幅整合EEG恢复，改善乳酸/N-乙酰天冬氨酸上升和减少在感觉运动皮层中的末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记阳性细胞。亚低温+促红细胞生成素双重治疗与EEG恢复相关，对促进少突胶质细胞存活最有效。在这项72小时研究中，三联疗法与双联疗法相比没有额外的获益。褪黑激素和促红细胞生成素对细胞死亡和少突胶质细胞存活的影响不同，反映了不同的神经保护机制，这可能在长期研究中变得更加明显。交错给予早期褪黑激素和后期促红细胞生成素（低温后）的治疗可能提供更好的保护;每种治疗具有互补作用，在缺氧-缺血后的神经毒性级联反应中可能是时间关键的。由于治疗性低温对新生儿脑病具有部分保护作用，因此需要辅助治疗。在围产期窒息的仔猪模型中，Pang等人报告称褪黑激素和促红细胞生成素是安全的，并通过不同的机制单独增强冷却。交错给药而不是伴随给药可能是脑保护的最佳选择。
As therapeutic hypothermia is only partially protective for neonatal encephalopathy, safe and effective adjunct therapies are urgently needed. Melatonin and erythropoietin show promise as safe and effective neuroprotective therapies. We hypothesized that melatonin and erythropoietin individually augment 12-h hypothermia (double therapies) and hypothermia + melatonin + erythropoietin (triple therapy) leads to optimal brain protection. Following carotid artery occlusion and hypoxia, 49 male piglets (<48 h old) were randomized to: (i) hypothermia + vehicle (n = 12), (ii) hypothermia + melatonin (20 mg/kg over 2 h) (n = 12), (iii) hypothermia + erythropoietin (3000 U/kg bolus) (n = 13) or (iv) tripletherapy (n = 12). Melatonin, erythropoietin or vehicle were given at 1, 24 and 48 h after hypoxia–ischaemia. Hypoxia–ischaemia severity was similar across groups. Therapeutic levels were achieved 3 hours after hypoxia–ischaemia for melatonin (15–30 mg/l) and within 30 min of erythropoietin administration (maximum concentration 10 000 mU/ml). Compared to hypothermia + vehicle, we observed faster amplitude-integrated EEG recovery from 25 to 30 h with hypothermia + melatonin (P = 0.02) and hypothermia + erythropoietin (P = 0.033) and from 55 to 60 h with tripletherapy (P = 0.042). Magnetic resonance spectroscopy lactate/N-acetyl aspartate peak ratio was lower at 66 h in hypothermia + melatonin (P = 0.012) and tripletherapy (P = 0.032). With hypothermia + melatonin, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells were reduced in sensorimotor cortex (P = 0.017) and oligodendrocyte transcription factor 2 labelled-positive counts increased in hippocampus (P = 0.014) and periventricular white matter (P = 0.039). There was no reduction in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells with hypothermia + erythropoietin, but increased oligodendrocyte transcription factor 2 labelled-positive cells in 5 of 8 brain regions (P < 0.05). Overall, melatonin and erythropoietin were safe and effective adjunct therapies to hypothermia. Hypothermia + melatonin double therapy led to faster amplitude-integrated EEG recovery, amelioration of lactate/N-acetyl aspartate rise and reduction in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells in the sensorimotor cortex. Hypothermia + erythropoietin doubletherapy was in association with EEG recovery and was most effective in promoting oligodendrocyte survival. Tripletherapy provided no added benefit over the double therapies in this 72-h study. Melatonin and erythropoietin influenced cell death and oligodendrocyte survival differently, reflecting distinct neuroprotective mechanisms which may become more visible with longer-term studies. Staggering the administration of therapies with early melatonin and later erythropoietin (after hypothermia) may provide better protection; each therapy has complementary actions which may be time critical during the neurotoxic cascade after hypoxia–ischaemia. As therapeutic hypothermia is partially protective in neonatal encephalopathy, adjunct therapies are required. In a piglet model of perinatal asphyxia, Pang et al. report that melatonin and erythropoietin are safe and individually augment cooling through different mechanisms. Staggered rather than concomitant dosing may be optimal for brain protection.
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影响因子：
3.7
作者：
Broad KD;Hassell J;Fleiss B;Kawano G;Ezzati M;Rocha-Ferreira E;Hristova M;Bennett K;Fierens I;Burnett R;Chaban B;Alonso-Alconada D;Oliver-Taylor A;Tachsidis I;Rostami J;Gressens P;Sanders RD;Robertson NJ
通讯作者：
Robertson NJ
影响因子：
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作者：
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通讯作者：
Day RM
影响因子：
2.5
作者：
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通讯作者：
Balduini, Walter
影响因子：
8.3
作者：
Alonso-Alconada D;Broad KD;Bainbridge A;Chandrasekaran M;Faulkner SD;Kerenyi Á;Hassell J;Rocha-Ferreira E;Hristova M;Fleiss B;Bennett K;Kelen D;Cady E;Gressens P;Golay X;Robertson NJ
通讯作者：
Robertson NJ
影响因子：
4.6
作者：
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通讯作者：
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