在一项新生儿脑病转化研究中,褪黑素能减轻炎症加重缺氧缺血后的脑损伤。

IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Journal of Pineal Research Pub Date : 2024-05-22 DOI:10.1111/jpi.12962
Raymand Pang, Christopher Meehan, George Maple, Georgina Norris, Ellie Campbell, Katie Tucker, Alison Mintoft, Francisco Torrealdea, Alan Bainbridge, Mariya Hristova, John Barks, Xavier Golay, Joseph Standing, Nicola J. Robertson
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引用次数: 0

摘要

中低收入国家(LMICs)的新生儿脑病(NE)负担最重,而治疗性低温疗法(HT)效果不佳,因此有必要在这些国家开发新生儿脑病疗法。我们的目的是评估褪黑素在新生仔猪发生炎症-加重缺氧-缺血(IA-HI)后的疗效。IA-HI模型考虑了感染/炎症在这种情况下的作用,而HT不具有细胞保护作用。我们假设,静脉注射褪黑素(5% 乙醇,20 毫克/千克,2 小时,HI 后 1 小时 + 10 毫克/千克/12 小时,24 至 60 小时)是安全的,并且与以下方面有关:(i) 磁共振波谱乳酸/N-乙酰天冬氨酸(MRS Lac/sNAA)减少;(ii) 磷MRS磷酸肌酸/磷酸盐交换池(PCr/Epp)保留;(iii) aEEG/EEG恢复改善;(iv) 免疫组化的细胞保护。在大肠杆菌脂多糖致敏(2 μg/kg 注射+1 μg/kg/h 12小时)4小时后,雌雄仔猪通过颈动脉闭塞接受IA-HI,并将FiO2降至6%。IA-HI后1小时,仔猪随机接受HI-盐水(n = 12)或褪黑素(n = 11)治疗。各组之间的损伤严重程度没有差异。褪黑素在 3 小时内达到目标水平(15-30 毫克/升),血液乙醇水平在基底神经节和丘脑 Lac/NAA 中为 10 单位(95% CrI [-0.366, -0.028],Pr(sup) 98.8%),在白质 Lac/NAA 中为 0.257 单位(95% CrI [-0.676, 0.164],Pr(sup) 89.3%)。PCr/Epp 在褪黑激素与 HI-saline 相比更高(Pr(sup) 97.6%)。褪黑素与 19 至 24 小时内较早的 aEEG/EEG 恢复有关(Pr(sup) 95.4%)。与HI-saline相比,褪黑激素与八个区域中五个区域的NeuN+细胞密度增加(Pr(sup) 99.3%)和TUNEL阳性细胞死亡减少(Pr(sup) 89.7%)有关。这项研究支持将褪黑素应用于早期临床试验。褪黑素对IA-HI后HT无效的情况具有保护作用。这些数据为下一阶段转化研究中未来剂量递增研究的设计提供了指导。
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Melatonin reduces brain injury following inflammation-amplified hypoxia–ischemia in a translational newborn piglet study of neonatal encephalopathy

There is a need to develop therapies for neonatal encephalopathy (NE) in low- and middle-income countries (LMICs) where the burden of disease is greatest and therapeutic hypothermia (HT) is not effective. We aimed to assess the efficacy of melatonin following inflammation-amplified hypoxia–ischaemia (IA-HI) in the newborn piglet. The IA-HI model accounts for the contribution of infection/inflammation in this setting and HT is not cytoprotective. We hypothesised that intravenous melatonin (5% ethanol, at 20 mg/kg over 2 h at 1 h after HI + 10 mg/kg/12 h between 24 and 60 h) is safe and associated with: (i) reduction in magnetic resonance spectroscopy lactate/N-acetylaspartate (MRS Lac/sNAA); (ii) preservation of phosphorus MRS phosphocreatine/phosphate exchange pool (PCr/Epp); (iii) improved aEEG/EEG recovery and (iv) cytoprotection on immunohistochemistry. Male and female piglets underwent IA-HI by carotid artery occlusion and reduction in FiO2 to 6% at 4 h into Escherichia coli lipopolysaccharide sensitisation (2 μg/kg bolus + 1 μg/kg/h over 12 h). At 1 h after IA-HI, piglets were randomised to HI-saline (n = 12) or melatonin (n = 11). There were no differences in insult severity between groups. Target melatonin levels (15–30 mg/L) were achieved within 3 h and blood ethanol levels were <0.25 g/L. At 60 h, compared to HI-saline, melatonin was associated with a reduction of 0.197 log10 units (95% CrI [−0.366, −0.028], Pr(sup) 98.8%) in basal-ganglia and thalamic Lac/NAA, and 0.257 (95% CrI [−0.676, 0.164], Pr(sup) 89.3%) in white matter Lac/NAA. PCr/Epp was higher in melatonin versus HI-saline (Pr(sup) 97.6%). Melatonin was associated with earlier aEEG/EEG recovery from 19 to 24 h (Pr(sup) 95.4%). Compared to HI-saline, melatonin was associated with increased NeuN+ cell density (Pr(sup) 99.3%) across five of eight regions and reduction in TUNEL-positive cell death (Pr(sup) 89.7%). This study supports the translation of melatonin to early-phase clinical trials. Melatonin is protective following IA-HI where HT is not effective. These data guide the design of future dose-escalation studies in the next phase of the translational pipeline.

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来源期刊
Journal of Pineal Research
Journal of Pineal Research 医学-内分泌学与代谢
CiteScore
17.70
自引率
4.90%
发文量
66
审稿时长
1 months
期刊介绍: The Journal of Pineal Research welcomes original scientific research on the pineal gland and melatonin in vertebrates, as well as the biological functions of melatonin in non-vertebrates, plants, and microorganisms. Criteria for publication include scientific importance, novelty, timeliness, and clarity of presentation. The journal considers experimental data that challenge current thinking and welcomes case reports contributing to understanding the pineal gland and melatonin research. Its aim is to serve researchers in all disciplines related to the pineal gland and melatonin.
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