Adenosine monophosphate activated protein kinase inhibition is protective in both sexes after experimental stroke.

Abstract

Sex differences in clinical and experimental stroke are now well recognized. Adenosine monophosphate activated protein kinase (AMPK) is an important energy sensor that is activated in times of energy demand. Increasing AMPK is deleterious in experimental cerebral ischemia, at least in males. Interestingly, studies in peripheral tissues have suggested that there are sex differences in the regulation of AMPK in muscle after exercise. PolyADP ribose polymerase (PARP), a key mediator of ischemic cell death, stimulates AMPK activation, yet activation of PARP appears to be selectively detrimental in male brain. As interference with sex specific cell death pathways can determine the efficacy of experimental neuroprotective agents, and AMPK inhibition is a novel neuroprotective target, we examined the effect of AMPK inhibition in male and female mice. In this study, AMPK alpha2 gene expression (mRNA) and pAMPK protein levels were examined and found to be comparable between both sexes after transient middle cerebral artery occlusion (MCAO). Treatment with the AMPK inhibitor Compound C at stroke onset significantly reduced infarct size and neurological deficits 24h after stroke in ovariectomized female mice. Finally, genetic deletion of AMPK alpha2 in ovariectomized females was neuroprotective as assessed by smaller infarct volumes and improved neurological deficits when compared to wild type littermates. This work demonstrates that AMPK activation is deleterious in experimental stroke, and this effect is independent of sex.

• Authors: Jun Li, Sharon E Benashski, Chad Siegel, Fudong Liu, Louise D McCullough
• Journal: Neuroscience letters (Neurosci Lett) Vol. 482 Issue 1 Pg. 62-5 (Sep 20 2010) ISSN: 1872-7972 [Electronic] Ireland
• PMID: 20621158 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Enzyme Inhibitors
• RNA, Messenger
• AMPK alpha2 subunit, mouse
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Blotting, Western
• Brain (drug effects, enzymology, pathology)
• Enzyme Activation (physiology)
• Enzyme Inhibitors (pharmacology)
• Female
• Male
• Mice
• Ovariectomy
• RNA, Messenger (analysis)
• Reverse Transcriptase Polymerase Chain Reaction
• Sex Characteristics
• Stroke (enzymology, pathology)