Abstract TMP33: Progesterone Prevents Hemorrhagic Transformation after tPA Treatment in Experimental Stroke

Abstract

BACKGROUND: Tissue plasminogen activator (tPA) is the only FDA-approved treatment for acute stroke. Unfortunately, because of its narrow time window and high risk-to-benefit ratio it is used in less than 3.0% of stroke patients. Our group and others have shown progesterone (PROG) to be beneficial in several ischemic brain injury models. However, before PROG can be tested in stroke patients, how it will interact with tPA, and whether combination with PROG will increase or decrease the risk of bleeding and hemorrhagic conversion, should be determined. In the present study we examined whether PROG would prevent tPA associated hemorrhagic transformation in an experimental stroke model. PROG’s efficacy in preventing tPA-induced impairment of transendothelial electrical resistance (TEER) under hypoxia/reoxygenation (H/R) conditions was evaluated in a mouse brain endothelial cell line. METHODS: Male SD rats were subjected to right middle cerebral artery occlusion (MCAO), reperfused at 4.5 hours and then treated with tPA (5 mg/kg b.wt; via femoral vein) at 4.5 hours or PROG (intraperitoneally) at 2 hours plus tPA at 4.5 hours. Rats were killed at 24 hours post-ischemia and brains perfused for evaluation of cerebral hemorrhage, brain swelling, blood-brain barrier (BBB) permeability, MMP-9 activity and cerebral infarction. TEER across the endothelial cell membrane was measured using an EVOM resistance meter. RESULTS: Delayed tPA treatment induced significant (p<0.05) hemorrhagic conversion and brain swelling. Combining PROG with delayed tPA administration significantly ameliorated brain hemorrhage, hemispheric swelling, BBB permeability and MMP-9 induction compared to the saline-treated injured group. The reduction in hemorrhagic injury in PROG+tPA-treated rats was 59.0% compared to tPA-treated rats without PROG. PROG treatment also significantly prevented the decrease in TEER induced by tPA under H/R conditions in vitro . CONCLUSIONS: Our data can be taken to suggest that PROG administration may extend the therapeutic time window for tPA administration in ischemic stroke, while at the same time reducing the risk of hemorrhagic conversion.