Role of Plasminogen System Components in Focal Cerebral Ischemic Infarction

Abstract

Background —The role of plasminogen system components in focal cerebral ischemic infarction (FCI) was studied in mice deficient in plasminogen (Plg −/− ), in tissue or urokinase plasminogen activator (tPA −/− or uPA −/− ), or in plasminogen activator inhibitor-1 or α 2 -antiplasmin (PAI-1 −/− or α 2 -AP −/− ). Methods and Results —FCI was produced by ligation of the left middle cerebral artery and measured after 24 hours by planimetry of stained brain slices. In control (wild-type) mice, infarct size was 7.6±1.1 mm 3 (mean±SEM), uPA −/− mice had similar infarcts (7.8±1.0 mm 3 , P =NS), tPA −/− mice smaller (2.6±0.80 mm 3 , P <0.0001), PAI-1 −/− mice larger (16±0.52 mm 3 , P <0.0001), and Plg −/− mice larger (12±1.2 mm 3 , P =0.037) infarcts. α 2 -AP −/− mice had smaller infarcts (2.2±1.1 mm 3 , P <0.0001 versus wild-type), which increased to 13±2.5 mm 3 ( P <0.005 versus α 2 -AP −/− ) after intravenous injection of human α 2 -AP. Injection into α 2 -AP −/− mice of Fab fragments of affinospecific rabbit IgG against human α 2 -AP, after injection of 200 μg human α 2 -AP, reduced FCI from 11±1.5 to 5.1±1.1 mm 3 ( P =0.004). Conclusions —Plg system components affect FCI at 2 different levels: (1) reduction of tPA activity ( tPA gene inactivation) reduces whereas its augmentation ( PAI-1 gene inactivation) increases infarct size, and (2) reduction of Plg activity ( Plg gene inactivation or α 2 -AP injection) increases whereas its augmentation (α 2 - AP gene inactivation or α 2 -AP neutralization) reduces infarct size. Inhibition of α 2 -AP may constitute a potential avenue to treatment of FCI.

Tissue-Type Plasminogen Activator has a Neuroprotective Effect in the Ischemic Brain Mediated by Neuronal TNF-α

“…Because after tPA-induced neuroprotectionits intravenous administration rtPA reaches the brain parenchyma (Benchenane et al, 2005), we propose that besides its beneficial thrombolytic properties, treatment with rtPA may also have a neuroprotective effect in the ischemic brain. Our findings are in apparent conflict with those by others indicating that genetic deficiency of tPA is associated with a better neurological outcome after experimental cerebral ischemia (Wang et al, 1998;Nagai et al, 1999). We propose that this discrepancy may be explained by a pleiotropic effect of tPA in the ischemic brain.…”

“…However, our observations agree with the existence of a narrow 'therapeutic window' for the protective effect of preconditioning (Kirino, 2002). Our findings are in discrepancy with reports by others, indicating that tPA mediates hypoxia-and ischemia-induced neuronal death (Wang et al, 1998;Nagai et al, 1999). Indeed, our data show that tPA does not induce neuronal death during neither normoxia nor hypoxia.…”

Recombinant Tissue Plasminogen Activator Enhances Microglial Cell Recruitment after Stroke in Mice

“…Cerebral ischemia studies performed with tPA-deficient animals have clearly underlined that endogenous tPA has a role in brain infarction and BBB dysfunction as well. 11,22,23 Endogenous tPA is expressed by endothelial cells, neurons, and glial cells and could therefore become a confounding factor when studying the impact of rtPA on stroke. The present animal model allowed us to distinguish deleterious effects produced by rtPA after cerebral ischemia and reperfusion independently of its thrombolytic activity because of mechanical occlusion of the MCA with an intraluminal filament and subsequent recanalization by withdrawal of the filament.…”

Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation

“…Moreover, endogenous tPA worsens infarction following both TBI and stroke. 36,37 On the basis of these commonalities, we predicted that endogenous tPA activity would be regulated in a similar manner during both stroke and TBI.…”