Selective MMP-inhibition with Ro 28-2653 in acute experimental stroke--a magnetic resonance imaging efficacy study.
Blood-brain-barrier (BBB) breakdown due to matrix metalloproteinase (MMP) activity following stroke is often associated with cerebral edema, larger infarct volumes and bad outcome. In the present study we examined a novel MMP-inhibitor (Ro 28-2653) with high selectivity for MMP2, MMP9 and membrane type 1-MMP in an acute stroke model comparing two different treatment regimens. We subjected rats to 90 min of focal cerebral ischemia followed by 3 days or 7 days of reperfusion, respectively, using the middle cerebral artery (MCA) filament occlusion technique. Ro 28-2653 was administered daily in a vehicle solution for 2 days or 6 days after ischemia, respectively. We assessed the behavior with a functional neuroscore and infarct volumes as well as blood-brain-barrier (BBB) breakdown with magnetic resonance imaging (MRI) after 3 and 7 days. Infarct edema volumes, BBB breakdown and behavior at 3 days were significantly attenuated in rats treated for 2 days with Ro 28-2653 as compared to vehicle and untreated controls. After 6 days of treatment however, infarct and BBB breakdown volumes as well as behavior did not differ significantly between the groups at 7 days. The new high selective MMP-inhibitor Ro 28-2653 significantly reduced brain injury only when administered in the first 2 days after focal cerebral ischemia. Prolonged treatment for 6 days did not show any beneficial effects possibly due to interference with protective restorative processes.
Department of Neurology, University of Heidelberg, Heidelberg, Germany.
S
S
Nagel
P V
PV
Heinemann
S
S
Heiland
J
J
Koziol
H
H
Gardner
S
S
Wagner
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology*; D004195:Disease Models, Animal; D004487:Edema / Q000188:drug therapy / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery; D008279:Magnetic Resonance Imaging; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome
D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines; D011743:Pyrimidines; C453902:Ro 28-2653