TY - JOUR
T1 - Neuroprotective effects of adenosine monophosphate-activated protein kinase inhibition and gene deletion in stroke
AU - Li, Jun
AU - Zeng, Zhiyuan
AU - Viollet, Benoit
AU - Ronnett, Gabriele V.
AU - McCullough, Louise D.
PY - 2007/11
Y1 - 2007/11
N2 - 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 α-1 or α-2. RESULTS - AMPK inhibition was neuroprotective after focal stroke. Mice deficient in AMPK α-2 demonstrated significantly smaller infarct volumes compared with wild-type littermates, whereas deletion of AMPK α-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 α-2 contributes to the deleterious effects of AMPK activation. AMPK inhibition leads to neuroprotection even when these agents are administered poststroke.
AB - 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 α-1 or α-2. RESULTS - AMPK inhibition was neuroprotective after focal stroke. Mice deficient in AMPK α-2 demonstrated significantly smaller infarct volumes compared with wild-type littermates, whereas deletion of AMPK α-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 α-2 contributes to the deleterious effects of AMPK activation. AMPK inhibition leads to neuroprotection even when these agents are administered poststroke.
KW - AMP-activated protein kinase
KW - Animal model
KW - Neuroprotection
KW - Stroke
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U2 - 10.1161/STROKEAHA.107.490904
DO - 10.1161/STROKEAHA.107.490904
M3 - Article
C2 - 17901380
AN - SCOPUS:35649019733
SN - 0039-2499
VL - 38
SP - 2992
EP - 2999
JO - Stroke
JF - Stroke
IS - 11
ER -