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J. Biol. Chem., Vol. 280, Issue 21, 20493-20502, May 27, 2005

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

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

From the Departments of Neurology and Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, FASgen, Inc., Baltimore, Maryland 21224, and Departments of ^**Neuroscience and ^||Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

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.

Received for publication, August 31, 2004 , and in revised form, March 14, 2005.

^* This work was supported by The American Heart Association and the Goddess Fund for Stroke Research in Women (to L. D. M.), NINDS and NIDDK grants from the National Institutes of Health (to G. V. R.), and NINDS F32 Fellowship from the National Institutes of Health (to L. E. L.). Under a licensing agreement between FASgen and The Johns Hopkins University, G. V. R., L. D. M., and L. E. L. are entitled to a share of the royalty received by the University on sales of products related to compounds described in this article. G. V. R. has an interest in FASgen stock, which is subject to certain restrictions under University policy. The Johns Hopkins University, in accordance with its conflict of interest policies, is managing the terms of this arrangement. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence and reprint requests may be addressed: Dept. of Neurology and Neuroscience, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030. Tel.: 860-679-3186; Fax: 860-679-4446; E-mail: lmcculllough{at}uchc.edu. To whom correspondence may be addressed: 1006B Preclinical Teaching Bldg., The Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205. Tel.: 410-614-6424; E-mail: gronnett{at}jhmi.edu.

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