Is ischaemic post-conditoning neuroprotective following perinatal asphyxia?

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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.