Progesterone attenuates hemorrhagic transformation after delayed tPA treatment in an experimental model of stroke in rats: involvement of the VEGF-MMP pathway.

Abstract

Tissue plasminogen activator (tPA) is the only FDA-approved treatment for acute stroke, but its use remains limited. Progesterone (PROG) has shown neuroprotection in ischemia, but before clinical testing, we must determine how it affects hemorrhagic transformation in tPA-treated ischemic rats. Male Sprague-Dawley rats underwent middle cerebral artery occlusion with reperfusion at 4.5 hours and tPA treatment at 4.5 hours, or PROG treatment intraperitoneally at 2 hours followed by subcutaneous injection at 6 hours post occlusion. Rats were killed at 24 hours and brains evaluated for cerebral hemorrhage, swelling, blood-brain barrier (BBB) permeability, and levels of matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor level (VEGF), and tight junction (TJ) proteins. We also evaluated PROG's efficacy in preventing tPA-induced impairment of transendothelial electrical resistance (TEER) and TJ proteins under hypoxia/reoxygenation in the endothelial cells. Delayed tPA treatment induced significant hemorrhagic conversion and brain swelling. Treatment with PROG plus tPA ameliorated hemorrhage, hemispheric swelling, BBB permeability, MMP-9 induction, and VEGF levels compared with controls. Progesterone treatment significantly prevented tPA-induced decrease in TEER and expression of occludin and claudin-5, and attenuated VEGF levels in culture media subjected to hypoxia. The study concluded that PROG may extend the time window for tPA administration in ischemic stroke and reduce hemorrhagic conversion.

• Authors: Soonmi Won, Jin Hwan Lee, Bushra Wali, Donald G Stein, Iqbal Sayeed
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 34 Issue 1 Pg. 72-80 (Jan 2014) ISSN: 1559-7016 [Electronic] United States
• PMID: 24045404 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fibrinolytic Agents
• Tight Junction Proteins
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, rat
• Progesterone
• Tissue Plasminogen Activator
• Matrix Metalloproteinase 9

Topics

• Animals
• Blood-Brain Barrier (drug effects, pathology)
• Brain Edema (etiology, metabolism, pathology, prevention & control)
• Capillary Permeability (drug effects)
• Cell Line
• Cerebral Hemorrhage (etiology, metabolism, pathology, prevention & control)
• Disease Models, Animal
• Drug Therapy, Combination
• Endothelial Cells (drug effects, pathology)
• Fibrinolytic Agents (administration & dosage, adverse effects, therapeutic use)
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Progesterone (administration & dosage, adverse effects, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Stroke (complications, drug therapy, metabolism, pathology)
• Tight Junction Proteins (metabolism)
• Time Factors
• Tissue Plasminogen Activator (administration & dosage, adverse effects, therapeutic use)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, metabolism)