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

Rousset, C. I., Leiper, F. C. , Kichev, A., Gressens, P., Carling, D., Hagberg, H. and Thornton, C. (2015) A dual role for AMP-activated protein kinase (AMPK) during neonatal hypoxic-ischaemic brain injury in mice. Journal of Neurochemistry, 133(2), pp. 242-252. (doi: 10.1111/jnc.13034) (PMID:25598140) (PMCID:PMC4855681)

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.

• Item Type: Articles
• Additional Information: We gratefully acknowledge the help of Phillip Muckett forassistance with the animal experiments. We gratefully acknowledgethe support of the Department of Perinatal Imaging and Health andfinancial support from Wellcome Trust (WT094823), the MedicalResearch Council, Action Medical Research, Swedish MedicalResearch Council (VR 2012-3500), ERA-net (EU;VR 529-2014-7551), Wilhelm and Martina Lundgren Foundation, the�Ahl�enFoundation, the Frimurare Barnhus Foundation, the Byggm€astareOlle Engqvist Foundation, the Brain Foundation (2013-0035),Governmental Grants for University Hospitals in Sweden (AL-FGBG-426401) and the Leducq Foundation (DSRRP34404) toenable this study to be completed. In addition, the authorsacknowledgefinancial support from the Department of Health viathe National Institute for Health Research (NIHR) comprehensiveBiomedical Research Centre award to Guy’s & St Thomas’NHSFoundation Trust in partnership with King’s College London andKing’s College Hospital NHS Foundation Trust. The experimentaldesign, data acquisition and analysis were performed by CIR, FCLand CT and all authors contributed to the preparation of themanuscrip
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Leiper, Dr Fiona
• Authors: Rousset, C. I., Leiper, F. C., Kichev, A., Gressens, P., Carling, D., Hagberg, H., and Thornton, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Journal of Neurochemistry
• Publisher: Wiley
• ISSN: 0022-3042
• ISSN (Online): 1471-4159
• Published Online: 17 January 2015
• Copyright Holders: Copyright © 2015 The Authors
• First Published: First published in Journal of Neurochemistry 133(2):242-252
• Publisher Policy: Reproduced under a Creative Commons License