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Thromb Haemost 2010; 103(05): 891-900
DOI: 10.1160/TH09-07-0500
Theme Issue Article
Schattauer GmbH

Different therapy options protecting microvasculature after experimental cerebral ischaemia and reperfusion

Dorothe Burggraf
1   Department of Neurology, Ludwig-Maximilians University, Klinikum Großhadern, Munich, Germany
,
Milan R. Vosko
2   Department of Neurology and Psychiatry, Linz, Austria
,
Marion Schubert
1   Department of Neurology, Ludwig-Maximilians University, Klinikum Großhadern, Munich, Germany
,
Jean-Marie Stassen
3   Thrombogenics NV, Leuven, Belgium
,
Gerhard F. Hamann
4   Department of Neurology, HSK Dr. Horst-Schmidt-Klinik, Wiesbaden, Germany
› Author Affiliations Financial support: This study was supported by Thrombogenics NV, a Belgian Biopharmaceutical Development Company. ThrombogenicsNV is the license holder of the use of microplasmin for the treatment of ischaemic stroke. The study was supported by a Marie-Curie individual fellowship of the European Community (QLRI-CT-2001–51077; M.R.V.).
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Publication History

Received: 31 July 2009

Accepted after major revision: 11 March 2009

Publication Date:
22 November 2017 (online)

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Summary

Recombinant tissue plasminogen activator (rt-PA) is successfully used in human stroke, but often shows serious drawbacks. To find an alternative, we hypothesised that the novel thrombolytic microplasmin would have fewer adverse effects on haemoglobin extravasation and microvascular damage compared with the effects of rt-PA and tenecteplase (TNK). A constant period of ischaemia (3 hours) was induced in a rat suture model followed by reperfusion (24 hours). Mikroplasmin (10 mg/kg), TNK (5 mg/kg), rt-PA (9 mg/kg) and saline (control), were administered. The volume of the ischaemic lesion was calculated, the loss of collagen type IV and the extravasation of haemoglobin were quantified by Western blotting. The matrix-metalloproteinases 2 and 9 (MMP-2/-9) were quantified by zymography and their endogenous tissue inhibitors (TIMPs) were analysed by reverse zymography. Microplasmin treatment caused the lowest volume of the ischaemic lesion (51.0 ± 22.6 mm3) compared with control (167.3 ± 13.1 mm3; p<0.05). The content of col-lagen type IV was significantly increased and haemoglobin extravasation reduced (154 ± 24%; p<0.05) compared with control (442 ± 124%); MMP-2/-9 and the corresponding TIMPs remained unchanged. In comparison, TNK did not significantly reduce basal lamina damage and caused the highest extravasation. MMP-2/-9 were severely increased after TNK treatment (p<0.05). Thus, the balance between MMPs and TIMPs was shifted toward the inhibitory side with TNK. Microplasmin had a protective effect on the microvascular basal lamina and blood-brain barrier, whereas TNK was significantly disadvantageous from the viewpoint of ischaemic damage. Microplasmin also appears to be safer than other PAs in terms of damage to the microvasculature associated with thrombolytic therapy of ischaemic stroke.

Keywords

Cerebral ischaemia - microplasmin - MMPs - plasminogen activator - rat - rt-PA - tenecteplase
 

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