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A dual role for AMP-activated protein kinase (AMPK) during neonatal hypoxic-ischaemic brain injury in mice.
- Source :
-
Journal of neurochemistry [J Neurochem] 2015 Apr; Vol. 133 (2), pp. 242-52. Date of Electronic Publication: 2015 Feb 24. - Publication Year :
- 2015
-
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.<br /> (© 2015 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of The International Society for Neurochemistry.)
- Subjects :
- Animals
Animals, Newborn
Benzimidazoles pharmacology
Cell Death
Cells, Cultured
Disease Models, Animal
Enzyme Inhibitors pharmacology
Glucose deficiency
Hypoxia pathology
Ionomycin pharmacology
L-Lactate Dehydrogenase metabolism
Mice
Mice, Inbred C57BL
Naphthalimides pharmacology
Neurons metabolism
Signal Transduction physiology
Time Factors
AMP-Activated Protein Kinases metabolism
Brain metabolism
Gene Expression Regulation, Developmental physiology
Hypoxia-Ischemia, Brain enzymology
Hypoxia-Ischemia, Brain pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1471-4159
- Volume :
- 133
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25598140
- Full Text :
- https://doi.org/10.1111/jnc.13034