MEK-inhibitor U0126 in hyperglycaemic focal ischaemic brain injury in the rat.
BACKGROUND
Hyperglycaemia aggravates ischaemic brain injury, possibly due to activation of signalling pathways involving mitogen-activated protein kinases (MAPK). In this study, the activation of MAPK/ERK was inhibited using the upstream inhibitor of MAPK-ERK-kinase (MEK) U0126, and the effects on focal brain ischaemia were evaluated during normo- and hyperglycaemia.


METHODS
Temporary (90 min) middle cerebral artery occlusion (MCAO) was induced in five groups of rats. U0126 (400 microg kg(-1)) or vehicle was given as 60-min intravenous infusions starting either 30 min prior to MCAO or 30 min prior to reperfusion. The infarct size was determined by perfusion with tetrazolium red after 24 h of survival, and the neurology was tested with the 4-level scale of Bederson and performance on an inclined plane. The inhibitory effect on the targeted MEK enzyme was investigated by analysing the phosphorylation of the downstream target ERK with western immunoblotting. Two subgroups were investigated with magnetic resonance imaging (MRI), including diffusion-weighted (DWI) and perfusion-weighted imaging (PWI).


RESULTS
U0126 effectively reduced the infarct size and improved neurology in hyperglycaemic rats both when given before and after ischemic onset. This effect was not accompanied by any detectable changes in cerebral blood flow on MRI. Normoglycaemic rats had generally milder injuries compared with the hyperglycaemic and there was a nonsignificant trend for U0126 to reduce damage also in the nonhyperglycaemic groups.


CONCLUSIONS
In conclusion, U0126 appears to be neuroprotective in this model of hyperglycaemic ischaemic brain injury. The findings support the pathogenic importance of the MEK-ERK pathway in hyperglycaemic-ischaemic brain injury.
Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden. nasim.farrokhnia@medsci.uu.se
N
N
Farrokhnia
A
A
Ericsson
A
A
Terént
F
F
Lennmyr
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply*; D002545:Brain Ischemia / Q000201:enzymology*; D002070:Butadienes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006943:Hyperglycemia / Q000150:complications; D008279:Magnetic Resonance Imaging; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000502:physiology; D016896:Treatment Outcome
D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; D020929:Mitogen-Activated Protein Kinase Kinases