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.
Highlights
IntroductionThrombolytic therapy with tissue plasminogen activator (tPA) is currently the only FDA-approved treatment for acute ischemic stroke, but its use is limited to patients who can be treated within 4.5 hours of ischemic onset.[1] Beyond this window, Tissue plasminogen activator (tPA) treatment has a high risk-to-benefit ratio due to its deleterious effects in the ischemic brain, including neurovascular cell death, blood–brain barrier (BBB) disruption, and hemorrhagic complications
Thrombolytic therapy with tissue plasminogen activator is currently the only FDA-approved treatment for acute ischemic stroke, but its use is limited to patients who can be treated within 4.5 hours of ischemic onset.[1]
The ischemic hemisphere of rats treated with delayed Tissue plasminogen activator (tPA) showed significantly increased brain swelling compared with saline-treated rats, whereas tPA combined with PROG treatment significantly reduced hemispheric swelling (Figure 1C) compared with tPA alone
Summary
Thrombolytic therapy with tissue plasminogen activator (tPA) is currently the only FDA-approved treatment for acute ischemic stroke, but its use is limited to patients who can be treated within 4.5 hours of ischemic onset.[1] Beyond this window, tPA treatment has a high risk-to-benefit ratio due to its deleterious effects in the ischemic brain, including neurovascular cell death, blood–brain barrier (BBB) disruption, and hemorrhagic complications. Cerebral hemorrhage is the greatest hazard with tPA treatment and occurs in 5% to 10% of patients.[2] Emerging data show that the development of hemorrhagic transformation is associated with tPA’s signaling action in the neurovascular unit[3] and subsequent BBB disruption.[4] Preventing endothelial cell injury and BBB breakdown associated with tPA treatment may contribute to better neuroprotection and increased overall efficacy for tPA reperfusion therapy. A growing literature shows that the steroid hormone progesterone (PROG) has neuroprotective effects in several stroke models.[5,6,7,8] In addition to animal studies and two positive phase II clinical trials,[9,10] an NIH-sponsored, phase III, 31 þ center clinical trial for traumatic brain injury is underway across the United States and a second phase III trial is taking place in the United States and 21 other countries
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