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(Stroke. 2007;38:2992.)
© 2007 American Heart Association, Inc.

Original Contributions

Neuroprotective Effects of Adenosine Monophosphate- Activated Protein Kinase Inhibition and Gene Deletion in Stroke

Jun Li, PhD; Zhiyuan Zeng, BS; Benoit Viollet, PhD; Gabriele V. Ronnett, MD, PhD Louise D. McCullough, MD, PhD

From the Departments of Neurology and Neuroscience (J.L., Z.Z., L.D.M.), University of Connecticut Health Center, Farmington, Conn; Institut Cochin (B.V.), Département Endocrinologie Métabolisme et Cancer, Paris, France; Inserm, U567 (B.V.), Paris, France; CNRS (B.V.), UMR 8104, Paris, France; Université Paris 5 (B.V.), Faculté de Médecine René Descartes, UM 3, Paris, France; and the Departments of Neuroscience and Neurology (G.V.R.), The Johns Hopkins University School of Medicine, Baltimore, Md.

Correspondence to Louise D. McCullough, MD, PhD, Director of Stroke Research and Education, MC-1840, Department of Neurology, 263 Farmington Avenue, Farmington, CT 06030. E-mail lmccullough{at}uchc.edu

Background and Purpose— 5' adenosine monophosphate-dependent protein kinase (AMPK) acts as a metabolic sensor. AMPK is elevated under ischemic conditions, but the role of AMPK in ischemic brain remains controversial. In this study, we examined the effects of AMPK inhibition using both pharmacological and genetic approaches in an in vivo stroke model.

Methods— Focal stroke was induced by reversible middle cerebral artery occlusion in male wild-type mice as well as mice deficient in one of the isoforms of the catalytic subunit of AMPK, AMPK -1 or -2.

Results— AMPK inhibition was neuroprotective after focal stroke. Mice deficient in AMPK -2 demonstrated significantly smaller infarct volumes compared with wild-type littermates, whereas deletion of AMPK -1 had no effect. Phosphorylation of a major upstream regulator of AMPK, LKB1, was also induced in stroke brain.

Conclusions— AMPK activation is detrimental in a model of focal stroke. The AMPK catalytic isoform -2 contributes to the deleterious effects of AMPK activation. AMPK inhibition leads to neuroprotection even when these agents are administered poststroke.

Key Words: AMP-activated protein kinase • animal model • neuroprotection • stroke