Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat.
Clinical worsening often occurs 1 to 2 days after an intracerebral hemorrhage. Extracellular matrix proteolysis by metalloproteinases, which attack the basal lamina and open the blood-brain barrier, may be one contributing factor. Matrix metalloproteinases and plasminogen activators are increased 16 to 24 hours after a bacterial collagenase-induced intracerebral hemorrhage, suggesting that agents that block metalloproteinases may reduce the brain swelling after hemorrhage. Therefore, we injected 0.2, 0.3, 0.4, or 0.5 units bacterial collagenase intracerebrally in rats to produce an intracerebral hemorrhage. Twenty-four hours later, brain tissue was removed for measurement of brain water and electrolytes. Proteases were assayed by zymography. Treatment with a matrix metalloproteinase inhibitor, BB-1101, was begun 6 hours after the collagenase lesion, when the hematomas were formed and the secondary edema was increasing. Bacterial collagenase caused a dose-dependent hematoma at the injection site with secondary brain edema in both posterior regions. The lower bacterial collagenase doses (0.2 and 0.3 units) mainly caused brain edema in the tissue around the injection site, whereas the higher doses (0.4 and 0.5 units) also affected the opposite hemisphere. Administration of BB-1101 significantly reduced the brain water and sodium contents in regions away from the injection site in rats with 0.4 unit lesions (p < 0.05). Zymography showed an increase in 92-kDa type IV collagenase and urokinase-type plasminogen activator at 24 hours. Inhibitors of proteolytic cascade enzymes may be useful in treatment of secondary brain edema in intracerebral hemorrhage.
Rosenberg
G A
GA
Department of Neurology, University of New Mexico School of Medicine, Albuquerque 87131, USA.
Navratil
M
M
D000818:Animals; D001593:Benzyl Compounds; D001921:Brain / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology*; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000150:complications*; D017364:Collagenases; D003907:Dexamethasone / Q000627:therapeutic use*; D004338:Drug Combinations; D018093:Gelatinases / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D010431:Pentoxifylline / Q000627:therapeutic use*; D010960:Plasminogen Activators / Q000378:metabolism; D011480:Protease Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013386:Succinates
C101468:BB 1101; D001593:Benzyl Compounds; D004338:Drug Combinations; D011480:Protease Inhibitors; D013386:Succinates; D003907:Dexamethasone; D010960:Plasminogen Activators; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D010431:Pentoxifylline