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Delayed matrix metalloproteinase inhibition reduces intracerebral hemorrhage after embolic stroke in rats

Sugawara, Taku
Chan, Pak H.
Published in Experimental neurology. 2008, vol. 213, no. 1, p. 196-201
Abstract 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.
Keywords AnimalsBrain Edema/drug therapy/physiopathology/prevention & controlCerebral Arteries/drug effects/enzymology/physiopathologyCerebral Hemorrhage/enzymology/physiopathology/prevention & controlDrug Administration ScheduleDrug SynergismEnzyme Inhibitors/pharmacology/therapeutic useIntracranial Embolism/drug therapy/enzymology/physiopathologyMaleMatrix Metalloproteinases/antagonists & inhibitors/metabolismRatsRats Sprague-DawleyStroke/drug therapy/enzymology/physiopathologyTime FactorsTissue Plasminogen Activator/pharmacologyTreatment Outcome
PMID: 18590727
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Research group Groupe Gasche Yvan (Soins intensifs) (501)
(ISO format)
COPIN, Jean-Christophe et al. Delayed matrix metalloproteinase inhibition reduces intracerebral hemorrhage after embolic stroke in rats. In: Experimental neurology, 2008, vol. 213, n° 1, p. 196-201. doi: 10.1016/j.expneurol.2008.05.022 https://archive-ouverte.unige.ch/unige:842

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Deposited on : 2009-02-18

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