A dual role for AMP-activated protein kinase (AMPK) during neonatal hypoxic-ischaemic brain injury in mice

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 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 (CaMKK)β-AMPKα1 signalling pathway. Pharmacological inhibition of AMPK during the insult promotes neuronal survival but, conversely, inhibiting AMPK activity prior to the insult sensitises neurons, exacerbating cell death. Our data have pathological relevance for neonatal HIE as prior sensitisation such as exposure to bacterial infection (reported to reduce AMPK activity) produces a significant increase in injury.