Published Online
on September 27, 2007

A more recent version of this article appeared on November 1, 2007

This Article Full Text (PDF) All Versions of this Article: 38/11/2992    most recent STROKEAHA.107.490904v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, J. Articles by McCullough, L. D. Search for Related Content PubMed PubMed Citation Articles by Li, J. Articles by McCullough, L. D. Related Collections Animal models of human disease Brain Circulation and Metabolism

Submitted on April 10, 2007
Revised on April 26, 2007
Accepted on April 30, 2007

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; and 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.

^* To whom correspondence should be addressed. 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

This article has been cited by other articles:

				M. R. Spasic, P. Callaerts, and K. K. Norga AMP-Activated Protein Kinase (AMPK) Molecular Crossroad for Metabolic Control and Survival of Neurons Neuroscientist, August 1, 2009; 15(4): 309 - 316. [Abstract] [PDF]

				G. R. Steinberg and B. E. Kemp AMPK in Health and Disease Physiol Rev, July 1, 2009; 89(3): 1025 - 1078. [Abstract] [Full Text] [PDF]

				C. D. L. Folmes, C. S. Wagg, M. Shen, A. S. Clanachan, R. Tian, and G. D. Lopaschuk Suppression of 5'-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H313 - H321. [Abstract] [Full Text] [PDF]