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Thromb Haemost 2003; 89(06): 1072-1080
DOI: 10.1055/s-0037-1613410
Vascular Development and Vessel Remodelling
Schattauer GmbH

Recombinant human tissue plasminogen activator protects the basal lamina in experimental focal cerebral ischemia

Dorothe Burggraf
1   Department of Neurology, Ludwig-Maximilians-University Munich, Klinikum Großhadern, Munich, Germany
,
Helge K. Martens
1   Department of Neurology, Ludwig-Maximilians-University Munich, Klinikum Großhadern, Munich, Germany
,
Gabriele Jäger
1   Department of Neurology, Ludwig-Maximilians-University Munich, Klinikum Großhadern, Munich, Germany
,
Gerhard F. Hamann
1   Department of Neurology, Ludwig-Maximilians-University Munich, Klinikum Großhadern, Munich, Germany
› Author AffiliationsFinancial support: Support for this study was provided by the Kompetenznetzwerk Schlaganfall of the BMBF (Project Number B3).
Further Information

Publication History

Received 16 September 2002

Accepted after revision 15 February 2003

Publication Date:
08 December 2017 (online)

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Summary

While recombinant tissue plasminogen activator (rt-PA) is successfully used in human ischemic stroke, it may also cause hemorrhagic complications. Animal experiments have shown that hemorrhages are related to microvascular basal lamina damage. We investigated the effects of different doses of rt-PA on the brain microvasculature. Experimental cerebral ischemia in rats was induced for 3 h and followed by 24 h reperfusion (suture model). Each group of rats (n = 6) received either treatment (0.9, 9, or 18 mg rt-PA/kg body weight) or saline (control group) at the end of ischemia. The loss of microvascular basal lamina antigen collagen type IV was measured by Western blot of the ischemic and non-ischemic basal ganglia and cortex. Compared with the contralateral non-ischemic area, collagen type IV was significantly reduced in the ischemic area: (basal ganglia/cortex) 43% +/- 9% / 64% +/- 4 %. Low/moderate doses of rt-PA had a protective effect: 0.9 mg 79% +/- 3% / 89% +/-6%, 9 mg 72% +/- 9%/ 81% +/- 12% (p < 0.05). Higher doses of rt-PA (18 mg) had a similar effect as seen in untreated controls: 57% +/- 11% / 59% +/- 9% (p < 0.05, Anova). MMP-9 and MMP-2, measured by gelatine zymography, steadily increased over higher doses of rt-PA: MMP-9 (basal ganglia/cortex): control 115% +/- 4% / 123% +/- 3% compared with 18 mg rt-PA 146% +/- 5%/ 162% +/- 6% (p < 0.05) and MMP-2: control 109% +/-4%/ 116% +/- 5% and 18 mg rt-PA 222% +/- 15%/ 252% +/- 2% (p < 0.05). Low to moderate doses of rt-PA protect the microvascular basal lamina, whereas high doses of rt-PA have the opposite effect, probably due to increased coactivation of MMP-2 and MMP-9.

Keywords

Cerebral ischemia - basal lamina - collagen type IV - microvasculature - matrix metalloproteinases
 

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