TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase.
Intracerebral hemorrhage occurs in tumors, stroke and head trauma. Proteolysis of the extracellular matrix around cerebral capillaries by naturally occurring mammalian 72-kDa type IV collagenase may initiate this pathologic event. To investigate this hypothesis adult rats underwent intracerebral injection of type IV collagenase purified from human melanoma cells. Histologically, at 4 h there was perivascular cellular infiltration with hemorrhage, and by 24 h there was infarction with necrosis, edema and hemorrhage. Ultrastructurally, the basal lamina of endothelial cells was disrupted at 2 h. Brain uptake of [14C]dextran and [3H]sucrose increased after intracerebral injection of type IV collagenase compared to controls (P less than 0.0001). Tissue inhibitor of metalloproteinase-2 (TIMP-2) reduced the tracer uptake (P less than 0.02). Metalloproteinase inhibitors reduce extracellular matrix proteolysis and protect the blood-brain barrier.
Rosenberg
G A
GA
Department of Neurology, University of New Mexico School of Medicine, Albuquerque 87131-5281.
Kornfeld
M
M
Estrada
E
E
Kelley
R O
RO
Liotta
L A
LA
Stetler-Stevenson
W G
WG
D000704:Analysis of Variance; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002196:Capillaries / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003911:Dextrans / Q000378:metabolism; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D003012:Microbial Collagenase / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013395:Sucrose / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2
D003911:Dextrans; D009363:Neoplasm Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2; D013395:Sucrose; D003012:Microbial Collagenase