1. Division of Imaging Sciences and Biomedical Engineering, Centre for the Developing Brain, King's College London, King's Health Partners, St. Thomas’ Hospital, London, UK;2. Redox Metabolism Group, MRC Clinical Sciences Centre, Imperial College, London, UK;3. Cellular Stress Group, MRC Clinical Sciences Centre, Imperial College, London, UK;4. Inserm, U1141, Paris, France;5. Université Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France;6. Perinatal Centre, Institutes of Clinical Sciences & Physiology and Neuroscience, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Abstract:
Perinatal hypoxic–ischaemic encephalopathy (HIE) occurs in 1–2 in every 1000 term infants and the devastating consequences range from cerebral palsy, epilepsy and neurological deficit to death. Cellular damage post insult occurs after a delay and is mediated by a secondary neural energy failure. AMP‐activated protein kinase (AMPK) is a sensor of cellular stress resulting from ATP depletion and/or calcium dysregulation, hallmarks of the neuronal cell death observed after HIE. AMPK activation has been implicated in the models of adult ischaemic injury but, as yet, there have been no studies defining its role in neonatal asphyxia. Here, we find that in an in vivo model of neonatal hypoxia–ischaemic and in oxygen/glucose deprivation in neurons, there is pathological activation of the calcium/calmodulin‐dependent protein kinase kinase β (CaMKKβ)‐AMPKα1 signalling pathway. Pharmacological inhibition of AMPK during the insult promotes neuronal survival but, conversely, inhibiting AMPK activity prior to the insult sensitizes neurons, exacerbating cell death. Our data have pathological relevance for neonatal HIE as prior sensitization such as exposure to bacterial infection (reported to reduce AMPK activity) produces a significant increase in injury.
