Delayed matrix metalloproteinase inhibition reduces intracerebral hemorrhage after embolic stroke in rats.
Hemorrhagic transformation (HT) and brain edema are life-threatening complications of recombinant tissue plasminogen activator (rt-PA)-induced reperfusion after ischemic stroke. The risk of HT limits the therapeutic window for reperfusion to 3 h after stroke onset. Pre-treatment with matrix metalloproteinase (MMP) inhibitors reduces HT and cerebral edema in experimental stroke. However, whether a delayed therapeutic intervention would be beneficial is unknown. In this study, 215 male Sprague-Dawley rats were subjected to embolic stroke and 75 rats were included in the final analysis. The animals were treated with the MMP inhibitor p-aminobenzoyl-gly-pro-D-leu-D-ala-hydroxamate before or after 3 or 6 h of ischemia. Animals were monitored for reperfusion and received rt-PA 6 h after ischemia onset. The results at 24 h showed that MMP inhibition 3 h after ischemia significantly decreased the degree of brain edema (17% of hemispheric enlargement in the treated group versus 24% in controls, P=0.018), reduced the risk (OR=0.163; 95% CI: 0.029 to 0.953) and gravity (0.09 versus 0.19 mg of parenchymal hemoglobin, P=0.02) of intracerebral hemorrhage, and improved neurological outcome (20% of the treated animals had a slight deficit; all of the controls had a bad outcome, P<0.05). Delaying MMP inhibition to 6 h after ischemia restricted the beneficial role of the treatment to a reduction in the risk of parenchymal hemorrhage (OR=0.242; 95% CI: 0.060 to 0.989). Our results confirm the involvement of MMPs in HT and support the possibility of extending the therapeutic window for thrombolysis in stroke by administering a broad-spectrum MMP inhibitor after the onset of ischemia.
Copin
Jean-Christophe
JC
Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland. Jean-Christophe.Copin@medecine.unige.ch
Merlani
Paolo
P
Sugawara
Taku
T
Chan
Pak H
PH
Gasche
Yvan
Y
D000818:Animals; D001929:Brain Edema / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D002536:Cerebral Arteries / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020766:Intracranial Embolism / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D010959:Tissue Plasminogen Activator; D020782:Matrix Metalloproteinases