Doxycycline inhibits MMPs via modulation of plasminogen activators in focal cerebral ischemia.
Tetracyclines inhibit matrix metalloproteinases (MMPs) and reduce infarction volume following cerebral ischemia. In this thesis an involvement of urokinase could be proven. Cerebral ischemia in rats was induced for 3 h followed by 24 h reperfusion (suture model). Each 6 animals received orally either doxycycline or water. Doxycycline treatment began 10 days before ischemia. MMP-2 and MMP-9 were substantially decreased. The possibility of involvement of the endogenous MMP inhibitors in the MMP inhibiting mechanisms was excluded. The plasminogen activator uPA was significantly decreased by doxycycline indicating an MMP inhibiting mechanism including the plasminogen/plasmin system. In the doxycycline group, this resulted in a decreased damage to the cerebral microvessels and less loss of the basal lamina antigen collagen type IV. Hemoglobin extravasation was also significantly reduced. Our results suggest that doxycycline may have a potential use as an anti-ischemic compound since it provides microvascular protection by inhibiting the plasminogen system.
Burggraf
Dorothe
D
Department of Neurology, Ludwig-Maximilians University, Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany.
Trinkl
Andreas
A
Dichgans
Martin
M
Hamann
Gerhard F
GF
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001485:Basement Membrane / Q000201:enzymology / Q000473:pathology; D001921:Brain / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004318:Doxycycline / Q000494:pharmacology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010960:Plasminogen Activators / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D000900:Anti-Bacterial Agents; D061965:Matrix Metalloproteinase Inhibitors; D018696:Neuroprotective Agents; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D010960:Plasminogen Activators; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline