Minocycline and hypothermia for reperfusion injury after focal cerebral ischemia in the rat: effects on BBB breakdown and MMP expression in the acute and subacute phase.
Reperfusion injury is a complication of recanalization therapies after focal cerebral ischemia. The disruption of the blood-brain barrier (BBB) caused by up-regulated metalloproteinases (MMPs) can lead to edema and hemorrhage. Middle cerebral artery occlusion (MCAO=90 min) and reperfusion (R=24 h vs. 5 days) was induced in male Wistar rats. Rats were randomized in four groups: (1) control (C), (2) twice daily minocycline (30 mg/kg bodyweight) every day (M), (3) hypothermia (33 degrees C) for 4 h starting 60 min after occlusion (H), (4) combination of groups 2 and 3 (MH). Serial MRI was performed regarding infarct evolution and BBB disruption, MMP-2 and MMP-9 were assessed by zymography of serum and ischemic brain tissue, and a functional neuroscore was done at 24 h and 5 days. M and H reduced both infarct sizes, volume and signal intensity of BBB breakdown and improved neuroscore at all points in time to the same extent. This was most likely due to inhibition of MMP-2 and MMP-9. The presence of MMP-9 at 24 h or MMP-2 at 5 days in brain tissue correlated with BBB breakdown whereas serum MMP-2- and -9 showed no relationship with BBB breakdown. The combination MH had a small but not significantly additional effect over the single treatments. Minocycline seems to be as neuroprotective as hypothermia in the acute and subacute phase after cerebral ischemia. One essential mechanism is the inhibition of MMPs. The combination therapy is only slightly superior. The net effect of MMPs inhibition up to 5 days after focal cerebral ischemia is still beneficial.
Nagel
Simon
S
Department of Neurology University of Heidelberg, Medical School, Heidelberg, Germany. simon_nagel@med.uni-heidelberg.de
Su
Ying
Y
Horstmann
Solveig
S
Heiland
Sabine
S
Gardner
Humphrey
H
Koziol
Jim
J
Martinez-Torres
Francisco J
FJ
Wagner
Simone
S
D000208:Acute Disease; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001929:Brain Edema / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy; D002545:Brain Ischemia / Q000201:enzymology / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D018450:Disease Progression; D007036:Hypothermia, Induced / Q000379:methods*; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology / Q000503:physiopathology / Q000628:therapy; D020300:Intracranial Hemorrhages / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy; D008279:Magnetic Resonance Imaging; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D045726:Metalloproteases / Q000378:metabolism*; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000628:therapy*; D013997:Time Factors
D000900:Anti-Bacterial Agents; D018696:Neuroprotective Agents; D045726:Metalloproteases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008911:Minocycline