title: A dual role for AMP-activated protein kinase (AMPK) during neonatal hypoxic-ischaemic brain injury in mice.
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.
authors.affiliation: 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.
authors.forename: Catherine I
authors.initials: CI
authors.lastname: Rousset
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Leiper
authors.forename: Anton
authors.initials: A
authors.lastname: Kichev
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.forename: David
authors.initials: D
authors.lastname: Carling
authors.forename: Henrik
authors.initials: H
authors.lastname: Hagberg
authors.forename: Claire
authors.initials: C
authors.lastname: Thornton
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D016923:Cell Death; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology* / Q000473:pathology*; D015759:Ionomycin / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053644:Naphthalimides / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D053644:Naphthalimides; C458525:STO 609; D015759:Ionomycin; D007770:L-Lactate Dehydrogenase; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMPK; hypoxia; ischaemia; neonatal; oxygen-glucose deprivation