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A dual role for AMP ‐activated protein kinase (AMPK) during neonatal hypoxic–ischaemic brain injury in mice
Author(s) -
Rousset Catherine I.,
Leiper Fiona C.,
Kichev Anton,
Gressens Pierre,
Carling David,
Hagberg Henrik,
Thornton Claire
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13034
Subject(s) - ampk , protein kinase a , hypoxia (environmental) , medicine , amp activated protein kinase , ischemia , kinase , programmed cell death , endocrinology , biology , microbiology and biotechnology , chemistry , biochemistry , apoptosis , organic chemistry , oxygen
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)‐ AMPK α1 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.