Abstract:
Neonatal encephalopathy (NE) caused by hypoxia-ischemia (HI) affects around 1 per 1000 term newborns and is the leading cause of acquired brain injury and neurodisability. Despite the use of hypothermia (HT) as a standard of care, the incidence of NE and its devastating outcomes remains a major issue. Ongoing research surrounding add-on neuroprotective strategies against NE is important as HT effects are limited, leaving 50% of treated patients with neurological sequelae. Little is known about the interaction between necroptotic blockade and HT in neonatal HI. Using a preclinical Lewis rat model of term human NE induced by HI, we showed a neuroprotective effect of Necrostatin-1 (Nec-1: a compound blocking necroptosis) in combination with HT. The beneficial effect of Nec-1 added to HT against NE injuries was observed at the mechanistic level on both pMLKL and TNF-α, and at the anatomical level on brain volume loss visualized by magnetic resonance imaging (MRI). HT alone showed no effect on activated necroptotic effectors and did not preserve the brain MRI volume. This study opens new avenues of research to understand better the specific cell death mechanisms of brain injuries as well as the potential use of new therapeutics targeting the necroptosis pathway.
摘要:
由缺氧缺血(HI)引起的新生儿脑病(NE)影响每1000个足月新生儿约1个,是获得性脑损伤和神经残疾的主要原因。尽管使用低温(HT)作为护理标准,NE的发病率及其破坏性后果仍然是一个主要问题.正在进行的研究围绕着针对NE的附加神经保护策略是重要的,因为HT的影响是有限的,留下50%的治疗患者神经后遗症。关于新生儿HI中坏死阻滞与HT之间的相互作用知之甚少。使用HI诱导的足月人NE的临床前Lewis大鼠模型,我们显示了Necrostatin-1(Nec-1:阻断坏死性凋亡的化合物)与HT的神经保护作用。在pMLKL和TNF-α的机制水平上观察到Nec-1添加到HT对NE损伤的有益作用,并在解剖学水平上通过磁共振成像(MRI)可视化脑容量损失。仅HT对激活的坏死效应子没有影响,并且不能保持脑MRI体积。这项研究开辟了新的研究途径,以更好地了解脑损伤的特定细胞死亡机制以及针对坏死途径的新疗法的潜在用途。