Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke

Louise D. McCullough, Zhiyuan Zeng, Hong Li, Leslie E. Landree, Jill McFadden, Gabriele V. Ronnett

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)20493-20502
Number of pages10
JournalJournal of Biological Chemistry
Volume280
Issue number21
DOIs
StatePublished - May 27 2005

ASJC Scopus subject areas

  • Biochemistry

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    McCullough, L. D., Zeng, Z., Li, H., Landree, L. E., McFadden, J., & Ronnett, G. V. (2005). Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke. Journal of Biological Chemistry, 280(21), 20493-20502. https://doi.org/10.1074/jbc.M409985200