Cited by 334Neuroprotection in Cerebral IschemiaMetabolism, Diabetes, and CancerAcute Ischemic Stroke Management

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Pharmacological Inhibition of AMP-activated Protein Kinase Provides Neuroprotection in Stroke

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McCullough, Louise D., Zeng, Zhiyuan, Li, Hong, Landree, Leslie E., McFadden, Jill, Ronnett, Gabriele V.·2005·Journal of Biological Chemistry

DOI 10.1074/jbc.m409985200

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Abstract

The restoration of energy balance during ischemia is critical to cellular survival; however, relatively little is known concerning the regulation of neuronal metabolic pathways in response to central nervous system ischemia. AMP-activated protein kinase (AMPK), a master sensor of energy balance in peripheral tissues, is phosphorylated and activated when energy balance is low. We investigated whether AMPK might also modulate neuronal energy homeostasis during ischemia. We utilized two model systems of ischemia, middle cerebral artery occlusion in vivo and oxygen-glucose deprivation in vitro, to delineate changes in AMPK activity incurred from a metabolic stress. AMPK is highly expressed in cortical and hippocampal neurons under both normal and ischemic conditions. AMPK activity, as assessed by phosphorylation status, is increased following both middle cerebral artery occlusion and oxygen-glucose deprivation. Pharmacological inhibition of AMPK by either C75, a known modulator of neuronal ATP levels, or compound C reduced stroke damage. In contrast, activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside exacerbated damage. Mice deficient in neuronal nitric-oxide synthase demonstrated a decrease in both stroke damage and AMPK activation compared with wild type, suggesting a possible interaction between NO and AMPK activation in stroke. These data demonstrate a role for AMPK in the response of neurons during metabolic stress and suggest that in ischemia the activation of AMPK is deleterious. The ability to manipulate pharmacologically neuronal energy balance during ischemia represents an innovative approach to neuroprotection.

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3 retracted

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Meley, D., Bauvy, C., Houben-Weerts, J. H. P. M., Dubbelhuis, P. F., Helmond, M. T. J., Codogno, P., & Meijer, A. J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605488200 · Cited by 419
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See all 334

Authors: McCullough, L. D., Zeng, Z., Li, H., Landree, L. E., McFadden, J., & Ronnett, G. V.
Affiliations: Pediatrics and Genetics (US)
Johns Hopkins University (US)
Corresponding author: McCullough, Louise D.
Ronnett, Gabriele V.
ORCID: McCullough, Louise D.
Zeng, Zhiyuan
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2005-05
Volume: 280
Issue: 21
Pages: 20493-20502
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m409985200
OpenAlex: W2026535174
Cited by: 333
References: 81
Citations by year: 2026: 5 · 2025: 4 · 2024: 9 · 2023: 11 · 2022: 5 · 2021: 21 · 2020: 7 · 2019: 14 · 2018: 25 · 2017: 18 · 2016: 17 · 2015: 21 · 2014: 26 · 2013: 23 · 2012: 22
FWCI: 6.96
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 5647 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Neurology › Neuroprotection in Cerebral Ischemia
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Clinical Neurology › Acute Ischemic Stroke Management
Keywords: AMPK, stroke, neuroprotection, cerebral ischemia, middle cerebral artery occlusion, oxygen-glucose deprivation, C75, compound C, neuronal nitric oxide synthase, nitric oxide, AMPK phosphorylation
MeSH terms: Aminoimidazole Carboxamide, Animals, Cerebral Cortex, Brain Ischemia, Constriction, Disease Models, Animal, Energy Metabolism, Enzyme Activation, Enzyme Inhibitors, Glucose, Hippocampus, Immunohistochemistry, Male, Mice, Inbred C57BL, Multienzyme Complexes, Nerve Tissue Proteins, Neurons, Oxygen, Ribonucleotides, 4-Butyrolactone, Protein Serine-Threonine Kinases, Mice, Knockout, Neuroprotective Agents, Nitric Oxide Synthase, Stroke, Middle Cerebral Artery, Mice, Rats, Nitric Oxide Synthase Type I, AMP-Activated Protein Kinases, Fatty Acid Synthases

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Pharmacological Inhibition of AMP-activated Protein Kinase Provides Neuroprotection in Stroke

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