Recombinant tissue plasminogen activator attenuates basal lamina antigen loss after experimental focal cerebral ischemia.
OBJECTIVE
The use of recombinant tissue plasminogen activator (rt-PA) is a proven therapy in acute stroke. Main concerns are based on hemorrhagic complications, which are connected with microvascular integrity loss. The aim of this study was to evaluate microvascular changes after various doses of rt-PA.


RESULTS
Focal cerebral ischemia for 3 hours was induced using the suture model in rats and followed by 24 hours of reperfusion. Six rats received either saline, 0.9, 9, or 18 mg rtPA/kg body weight at the end of ischemia. By immunostaining of collagen type IV the density of microvessels and the total stained area in the basal ganglia and cortex was measured. Comparison of the ischemic with the non-ischemic hemisphere showed significantly less reduction of the number of microvessels in rats treated with low-dose rt-PA than in the other groups: controls 17 +/- 3% (basal ganglia), 12 +/- 7% (cortex); 0.9 mg rt-PA, 18 +/- 3%, 10 +/- 4%; 9 mg, 21 +/- 4%, 13 +/- 7%; 18 mg, 22 +/- 4%, 15 +/- 8%. A similar effect was observed on the total stained area: control 25 +/- 4% (basal ganglia), 14 +/- 7% (cortex); 0.9 mg rt-PA, 23 +/- 2%, 7 +/- 4%; 9 mg, 28 +/- 4%, 15 +/- 4%; 18 mg, 29 +/- 4%, 17 +/- 5%, p<0.001. The significant reduction of the area of infarction after low and moderate doses of rt-PA was visualized with an MAP2-antibody, and the volume was calculated by 3-D reconstruction: control, 165.2 mm 3 +/- 21%; 0.9 mg rt-PA, 102.6 mm 3 +/- 16%; 9 mg, 101.2 mm 3 +/- 17%; 18 mg, 133.0 mm 3 +/- 24%; p < 0.001.


CONCLUSIONS
Rats exposed to low-dose rt-PA preserved basal lamina structures, and showed smaller infarct sizes. The protective effect of low-dose rt-PA might be due to an increased microvascular patency rate.
Grobholz
Katharina
K
Department of Neurology Ludwig-Maximilians-University Munich Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany.
Burggraf
Dorothe
D
Martens
K Helge
KH
Wunderlich
Nathalie
N
Pichler
Matthias
M
Hamann
F Gerhard
FG
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D024141:Collagen Type IV / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008833:Microcirculation / Q000378:metabolism; D018715:Microscopy, Video / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis / Q000627:therapeutic use*
D024141:Collagen Type IV; D005343:Fibrinolytic Agents; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator