Neuroprotective effects of adenosine monophosphate-activated protein kinase inhibition and gene deletion in stroke.
OBJECTIVE
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 alpha-1 or alpha-2.


RESULTS
AMPK inhibition was neuroprotective after focal stroke. Mice deficient in AMPK alpha-2 demonstrated significantly smaller infarct volumes compared with wild-type littermates, whereas deletion of AMPK alpha-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 alpha-2 contributes to the deleterious effects of AMPK activation. AMPK inhibition leads to neuroprotection even when these agents are administered poststroke.
Li
Jun
J
Department of Neurology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Zeng
Zhiyuan
Z
Viollet
Benoit
B
Ronnett
Gabriele V
GV
McCullough
Louise D
LD
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D018696:Neuroprotective Agents; D021122:Protein Subunits; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases