Is ischaemic post-conditoning neuroprotective following perinatal asphyxia?

研究背景在英国，每1000个足月新生儿中就有1-2例在分娩过程中出现问题，导致缺氧（出生窒息）和随后的脑损伤（新生儿脑病）。尽管治疗性低温疗法最近在发达国家的这一领域取得了重大进展，但它只对约50%的冷却婴儿提供大脑保护。因此，有一个重要的未满足的需求，即开发新的，非侵入性的方法，可以单独使用或与低温联合使用，以增强新生儿脑病的神经保护。目前还没有其他技术或其他治疗方法来解决这一未满足的需求。我们建议远程缺血后适应（IPostC）可以满足这一需求。IPostC源于1986年首次描述的预处理概念，其优势在于不需要事先了解缺血性损伤，因此临床翻译意义更深远。缺血再灌注损伤是临床上组织供血中断后又恢复的一种普遍现象。矛盾的是，对组织造成重大损伤的是再灌注而不是缺血。然而，在所有哺乳动物物种中都有一种强大的先天保护机制来对抗缺血再灌注损伤。短暂的短暂性缺血发作可以防止长时间的致死性缺血，这些发作可以在再灌注期间或指数缺血后的最初几个小时发生。如果在非重要器官（例如离受影响器官较远的肢体）上进行这种短暂的发作，也是有效的，这构成了远程邮资投寄的基础。我们将使用磁共振波谱（脑乳酸/N乙酰天冬氨酸水平）作为IPostC伴和不伴低温治疗的替代指标——与用于新生儿预测预后的替代指标相同。我们将使用近红外光谱来检测邮邮期间的脑氧合情况。这种多模态成像使该模型独特，是了解IPostC疗效以及机制和生理效应的重要资源。目的和目的本研究的目的是在大型动物模型中测试远程邮政学。主要目的是确定：1。如果远程邮政在复苏时保护大脑。复苏后延迟3小时的远程IPostC是否能保护大脑。是否远程IPostC（即时和延迟）增强了低温神经保护4。IPostC信号通路、低温及IPostC与低温的相互作用该项目的成功完成将使我们能够直接进行人体概念验证研究，因为不需要进行毒理学研究。在临床环境中，远程IPostC包括在婴儿出生后短暂地在双下肢周围充气袖带至超收缩压。这类似于多次测量血压，并让袖带膨胀几分钟。通过这样做，这种非致死性缺血被认为可以激活内源性神经保护通路，如抗凋亡蛋白、自由基产生减少、充血反应减弱和脑血流改善。将这项技术引入国民保健制度将解决国民保健制度四大优先事项中的两个（心脏病、癌症、儿童和产妇）。IPostC可能成为复苏时的一种简单治疗方法，可以减少出生窒息后的不良后果。IPostC还可以增强低温神经保护，低温神经保护已被引入作为目前婴儿出生时出现脑病的护理标准。此外，这项技术也有可能用于低温治疗无法获得或不安全的地方或情况。

Context of the researchProblems during birth leading to a lack of oxygen (birth asphyxia) and subsequent brain injury (neonatal encephalopathy) occur in 1-2 per 1000 full term births in the UK. Although therapeutic hypothermia has recently been a significant advance in this field in the developed world, it provides brain protection only to ~50% of those infants cooled. There is therefore a significant unmet need to develop novel, non-invasive approaches, which can be used alone or in combination with hypothermia to augment neuroprotection for neonatal encephalopathy. Currently there are no other technologies or other therapeutic approaches to address this unmet need. We propose that remote ischemic post-conditioning (IPostC) would meet this need. Born from the concept of pre-conditioning first described in 1986, IPostC is advantageous in that prior knowledge of the ischemic insult is not required and thus clinical translation is more far reaching.Ischaemia-reperfusion injury is a widespread phenomenon that occurs in clinical scenarios where blood supply to tissue is interrupted and then restored. Paradoxically, it is reperfusion rather than ischaemia that causes major damage to tissue. There is, however, a powerful innate protective mechanism against ischemia-reperfusion injury that has evolved in all mammalian species. Brief, transient episodes of ischemia protect against a prolonged period of lethal ischaemia and these episodes can be performed during reperfusion or the first few hours after the index ischaemia. The brief transient episodes are also effective if performed on a non-vital organ such as a limb remote to the affected organ, which forms the basis for remote IPostC.We will use magnetic resonance spectroscopy (brain lactate /N acetyl aspartate levels) as a surrogate marker of the benefit of IPostC with and without hypothermia - the same surrogate measure used in newborn infants to predict outcome. We will use near infrared spectroscopy to examine brain oxygenation during IPostC. Such multi-modal imaging makes the model unique and a significant resource for understanding efficacy as well and mechanistic and physiological effects of IPostC.Aims and ObjectivesThe proposal is to test remote IPostC in a large animal model. The main aims are to determine:1. if remote IPostC at resuscitation protects the brain2. if remote IPostC with a delay of 3h after resuscitation protects the brain3. if remote IPostC (both immediate and delayed) augments hypothermic neuroprotection4. signalling pathways of IPostC, hypothermia and the interaction between IPostC and hypothermia 5. haemodynamic and metabolic effects of IPostCIts potential applications and benefitsSuccessful completion of this project will enable us to proceed directly to a human proof of concept study since there are no toxicology studies needed. In the clinical setting, remote IPostC would involve inflating a cuff to supra-systolic pressure briefly around both lower limbs of the infant after birth. This is analogous to taking the blood pressure on several occasions and holding the cuff inflated for minutes. By doing so, this non-fatal ischaemia has been suggested to activate endogenous neuroprotective pathways, such as anti-apoptotic proteins, reduction in free radical production, attenuation of the hyperaemic response and improvement in cerebral blood flow. The introduction of this technology to NHS will address two of the top four priorities of NHS (heart disease, cancer, children and maternity). IPostC may become a simple treatment at resuscitation that reduces adverse outcome following birth asphyxia. IPostC may also augment hypothermic neuroprotection, which has been introduced as the current standard of care for infants presenting with encephalopathy at birth. Moreover, it would also be possible to use this technology in places or situations where hypothermia is not available or safe.