New horizons for newborn brain protection: enhancing endogenous neuroprotection

Abstract

Intrapartum-related events are the third leading cause of childhood mortality worldwide and result in one million neurodisabled survivors each year. Infants exposed to a perinatal insult typically present with neonatal encephalopathy (NE). The contribution of pure hypoxia-ischaemia (HI) to NE has been debated; over the last decade, the sensitising effect of inflammation in the aetiology of NE and neurodisability is recognised. Therapeutic hypothermia is standard care for NE in high-income countries; however, its benefit in encephalopathic babies with sepsis or in those born following chorioamnionitis is unclear. It is now recognised that the phases of brain injury extend into a tertiary phase, which lasts for weeks to years after the initial insult and opens up new possibilities for therapy.There has been a recent focus on understanding endogenous neuroprotection and how to boost it or to supplement its effectors therapeutically once damage to the brain has occurred as in NE. In this review, we focus on strategies that can augment the body's own endogenous neuroprotection. We discuss in particular remote ischaemic postconditioning whereby endogenous brain tolerance can be activated through hypoxia/reperfusion stimuli started immediately after the index hypoxic-ischaemic insult. Therapeutic hypothermia, melatonin, erythropoietin and cannabinoids are examples of ways we can supplement the endogenous response to HI to obtain its full neuroprotective potential. Achieving the correct balance of interventions at the correct time in relation to the nature and stage of injury will be a significant challenge in the next decade.

Keywords: Birth asphyxia; Melatonin; Neonatal encephalopathy; Neuroprotection; Post Conditioning.

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Figures

Figure 1

Schematic diagram illustrating the different pathological phases of cerebral injury after cerebral HI. The primary phase (acute HI), latent phase, secondary energy failure phase and tertiary brain injury phase are shown. (A) Magnetic resonance spectra showing the biphasic pattern of NTP/EPP decline and lactate/NAA increase during primary and secondary phases following HI insult. Persisting lactic alkalosis is shown in tertiary phase. (B) Amplitude-integrated EEG showing normal trace at baseline, flat tract following HI, burst-suppression pattern in latent phase, emergence of seizures in secondary phase and normalisation with sleep–wake cycling in tertiary phase. (C) Following HI, there is a period of hypoperfusion associated with hypometabolism during latent phase, followed by relative hyperperfusion in secondary phase. (D) Cellular energetics and mitochondrial function are reflected in the biphasic response shown on magnetic resonance spectroscopy (A), with a period of recovery in latent phase followed by deterioration in secondary phase. There is partial recovery in tertiary phase. (E) The most important pathogenic changes are shown for each phase (see main text for description), including generation of toxic free radical species, accumulation of EAAs, cytotoxic oedema, seizures and inflammation. Cell lysis occurs immediately following HI, while programmed cell death occurs in secondary phase; latent phase provides a therapeutic window. Persisting inflammation and epigenetic changes impede long-term repair. (F) Damage is maximal in the secondary phase, but persists into the tertiary phase as inflammation and gliosis evolve. (G) In the future, neuroprotective treatments are likely to involve a ‘cocktail’ of therapies to be administered intrapartum, in the latent phase to prevent secondary energy failure and through secondary and tertiary phases to offset evolving damage. HI, hypoxia-ischaemia; EAAs, excitatory amino acids; EPP, exchangeable phosphate pool; NAA, N-acetylaspartate; NO, nitric oxide; NTP, nucleoside triphosphate (this is mainly ATP); OFRs, oxygen free radicals; RIPostC, remote ischaemic postconditioning.

Figure 2

(A) The neuroprotective mechanisms of RIPostC are thought to involve three inter-related pathways induced by remote limb ischaemia. (1) The neuronal pathway involves activation of both local sensory nerves and the autonomic nervous system to mediate protective effects, including the release of humoral factors; (2) the humoral pathway involves endogenous protective factors, including locally acting autocoids and bloodborne humoral factors that travel to the brain and (3) the systemic response includes immune modulation and blood pressure regulation. (B) Within the brain, the three pathways converge to increase cerebral blood flow, ameliorate neuroinflammation and to activate cell survival mechanisms. Direct pro-survival actions within cells are mediated via G-protein-coupled (GPC) receptors and include mitochondrial protection (maintenance of potassium-sensitive ATP channel, prevention of mitochondrial permeability transition pore opening) and transcriptional regulation (both genetic and epigenetic modulation) in the nucleus. (C) Following remote ischaemic stimulus after HI, the effects of these neuroprotective mechanisms are to decrease energy consumption; to increase substrate delivery and offset cerebral secondary energy failure; to protect against cell death and to augment long-term recovery and repair. HI, hypoxia-ischaemia; I/R, ischaemia/reperfusion; RIPostC, remote ischaemic postconditioning.