The role of endogenous versus exogenous tPA on edema formation in murine ICH.
To minimize the neurotoxic injury by clot-derived substances after intracerebral hemorrhage (ICH) on the surrounding brain tissue, minimally invasive neurosurgical protocols have evolved evacuating the hematoma by stereotaxic injection of a fibrinolytic agent such as recombinant tissue plasminogen activator (rtPA), followed by aspiration of the lysed clot. However, the possible contribution of the presence of exogenous tPA itself to the toxic effects of hematoma-derived factors complicates the rationale and efficacy of this therapeutic approach. To clarify the role of exogenous rtPA on edema development, we examined the extent of edema formation in a murine model of collagenase-induced ICH, which included tPA-deficient (tPA-/-) and wild-type (wt) mice. In 16 (7 tPA-/- and 9 wt mice) out of 32 mice, 1 mg/kg rtPA was injected into the hematoma 5 h after ICH induction followed by aspiration of the liquefied clot 20 min later. In the control group (8 tPA-/- and 8 wt mice), only collagenase was injected. The edema volume was quantified using SPOT software on Luxol Fast Blue and Cresyl violet-stained cross-sections 24 h, 3, and 7 days post surgery. Twenty-four hours after ICH induction, tPA-/- mice had a significantly smaller edema volume (P< 0.01), even when rtPA was administered. Between days 3 and 7 after ICH, exogenous rtPA exerts its edema-promoting effect irrespective of the underlying genotype and exhibits an extensive microglial activation adjacent to the clot. In conclusion, the role of the endogenous tPA appears to be limited to the early phase of edema formation, whereas exogenous rtPA is edema-promoting between days 3 and 7 after ICH.
Thiex
Ruth
R
Department of Neurosurgery, Aachen University, Aachen, Germany. ruth.thiex@post.rwth-aachen.de
Mayfrank
Lothar
L
Rohde
Veit
V
Gilsbach
J Michael
JM
Tsirka
Styliani-Anna E
SA
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D017364:Collagenases; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique / Q000379:methods; D007211:Indoles; D007632:Keratan Sulfate / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D013194:Staining and Labeling; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000502:physiology*
D001798:Blood Proteins; D007211:Indoles; D011994:Recombinant Proteins; C018588:Luxol Fast Blue MBS; D007632:Keratan Sulfate; D010959:Tissue Plasminogen Activator; D017364:Collagenases