Article
Combination with NMDA antagonists optimizes fibrinolytic therapy of experimental intracerebral hemorrhages
Die Kombination mit NMDA-Antagonisten zur Optimierung der fibrinolytischen Therapie experimenteller, intrazerebraler Blutungen
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Published: | May 8, 2006 |
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Objective: Tissue plasminogen activator (tPA) exerts pleiotropic actions in the brain including regulation of vasoactivity, amplification of calcium conductance by cleavage of the N-methyl-D-aspartate (NMDA) receptor subunit, and activation of metalloproteinases that increase excitotoxicity, damage the blood brain barrier, and worsen edema. We investigated whether the non-competitive NMDA antagonist MK801 can be used as adjuvant therapy in combination with rtPA to attenuate the unfavourable delayed edema formation and inflammation after rtPA-therapy in experimental porcine intracerebral hemorrhages.
Methods: In 20 pigs, MK801 was administered i.v. (0.3 mg/kg) immediately after hematoma induction, on the 1st and 3rd postoperative day. 10 of the 20 pigs were randomly assigned to fibrinolytic therapy with rtPA, whereas the hematomas of the remaining 10 control animals followed their natural course of resorption. The degree of edema formation was evaluated by MRI planimetry on days 0, 4, and 10 after hematoma induction and was correlated to the histopathological changes found at autopsy. The 9 pigs treated with rtPA only of our previous series served as a control to rtPA-induced alterations.
Results: In the animals treated both with MK801 and rtPA (n=10), the mean perihematomal edema size on FLAIR images had not significantly increased on days 4 (p<0.08) and 10 (p<0.35) after hematoma induction. In the 10 control animals, the increase in mean perifocal edema was significant after 4 days (p<0.02) and non-significant after 10 days (p<0.09).
Conclusions: MK801 reduces rtPA-induced delayed edema formation and inflammatory response. The fibrinolytic potential of rtPA can only be beneficial in the combination with agents such as MK801 that block the neurotoxic properties of rtPA.