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. We show that in an in vivo model of neonatal hypoxia–ischaemic and in oxygen/glucose deprivation in neurons, there is a pathological activation of the CaMKKβ‐AMPKα1 signalling pathway. Inhibiting AMPK during OGD promotes neuronal survival; conversely, inhibiting AMPK prior to OGD exacerbates cell death. Our data have clinical relevance as prior sensitization (e.g. exposure to bacterial infection reducing AMPK activity) increases injury. AMPK, AMP‐activated protein kinase; HI, hypoxia–ischaemia; OGD, oxygen–glucose deprivation.
Highlights
Both brain region and time had a significant effect on the variation in AMPactivated protein kinase (AMPK) activity and in addition, post-hoc analysis revealed a significant difference in AMPK activity between hippocampus and cortex at P5 (Fig. 1a)
AMPK is activated in vivo in response to hypoxic–ischaemic insult To test our hypothesis that, considering the large energy failures associated with HI, AMPK should be activated, we measured AMPK activity on HI injured and uninjured mice
This activation quickly returned to baseline levels once the animals were returned to normoxia (Fig. 1b). These data provide in vivo confirmation that up-regulation of AMPK activity is involved in neonatal HI
Summary
We examine the contribution of AMPK activation to the development of hypoxic–ischaemic brain injury in neonatal mouse brain. In an in vitro model of hypoxia–ischaemia (HI) in primary neurons, activation of AMPK during the injury results in increased cell death, whereas inhibition of AMPK during the insult protects the cells, implicating AMPK in the injury process. We find that inhibition of AMPK prior to injury sensitizes neurons to subsequent insult. Taken together, these data show a dual role of AMPK in HI brain injury in neonates depending on whether it is modulated prior or during the insult
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