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Papers In Press, published online ahead of print March 16, 2005
Department of Neurology, University of Connecticut Health Center, Farmington, CT 06030
Corresponding Author: lmccullough{at}uchc.edu
Summary 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 CNS ischemia. AMP-activated protein kinase (AMPK), a master sensor of energy balance in peripheral tissues, is phosphorylated and activated when energy balance is low. In the hypothalamus, neuronal AMPK is responsive to changes in energy balance, and in turn AMPK functions in regulating food intake. We investigated whether AMPK might also modulate neuronal energy homeostasis during ischemia. We utilized two model systems of ischemia, middle cerebral artery occlusion (MCAO) in vivo and oxygen-glucose deprivation (OGD) 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 MCAO and OGD. 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 AICAR exacerbated damage. Mice deficient in neuronal NOS demonstrated a decrease in both stroke damage and AMPK activation compared to 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 pharmacologically manipulate neuronal energy balance and thus decrease AMPK activation during ischemia represents an innovative approach to neuroprotection.
J. Biol. Chem, 10.1074/jbc.M409985200
Submitted on August 31, 2004
Revised on March 14, 2005
Accepted on March 16, 2005
Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke
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