Effects of tissue plasminogen activator on cerebral microvessels of rats during focal cerebral ischemia and reperfusion.
The time window in the treatment of ischemic stroke with tissue plasminogen activator (tPA) is narrow, arbitrarily within 3 hours after the onset of symptom. Hemorrhagic transformation resulting from cerebral ischemia may be related to damage of the microvascular basal lamina of the brain, which may in turn cause microvascular fibrin deposition and aggravate cerebral ischemia. Here, we investigated the effect of tPA on the microvascular tissue changes during cerebral ischemia/reperfusion. Sprague-Dawley rats were subjected to focal cerebral ischemia by ligation of the right middle cerebral artery and bilateral common carotid arteries for 90 minutes. Sixty minutes after the onset of ischemia, escalated dosages of tPA from 2.5 to 10 mg/kg or saline were intravenously infused for 60 minutes. Twenty-four hours after reperfusion, the animals were allowed to be killed for examination. Low dosage of tPA (2.5-7.5 mg/kg) reduced post-ischemic brain infarction, suppressed metalloproteinase 2 (MMP-2) activity and restored blood-brain barrier (BBB) integrity. In contrast, high dose of tPA (10 mg/kg) aggravated brain infarction, increased MMP-2 activity and exacerbated BBB disruption. Cerebral ischemia/reperfusion decreased the immunoreactivity of both collagen type IV- and laminin-positive microvessels, whereas the low dosage of tPA (2.5-7.5 mg/kg) attenuated the reduction. When these molecules in whole cortical tissues were analysed, tPA dosage-dependently decreased the total content of collagen type IV, laminin and fibronectin. Although the detailed mechanisms regarding the action of tPA are yet to be investigated, our findings demonstrate that the detrimental effect of tPA was mediated, at least in part, through the destruction of the basal lamina in the cerebral microvessels by activating MMP-2.
Yang
Dar-Yu
DY
Department of Emergency Medicine, Taichung Veterans General Hospital, Taiwan.
Pan
Hung-Chuan
HC
Chen
Chun-Jung
CJ
Cheng
Fu-Chou
FC
Wang
Yeou-Chih
YC
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy; D002544:Cerebral Infarction / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D007839:Functional Laterality; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D010959:Tissue Plasminogen Activator / Q000494:pharmacology* / Q000627:therapeutic use
D016326:Extracellular Matrix Proteins; D010959:Tissue Plasminogen Activator