This is an article sharing from Oscar, a follower of this page in which he has co-authored (see link to the study below). It is a peer-reviewed article recently published in Blood (a fairly good and robust journal, the official journal of the American Society of Hematology) that focused on the effect of the overexpression of tissue plasminogen activator (tPA) on the BBB integrity.
tPA is the drug of choice for ischemic stroke (80% of total stroke), as it acts as a clot buster (it basically breaks down any clots blocking small brain vessels into pieces). tPA is also until now the only FDA-approved drug. However, tPA has severe downsides. First it has a very limited time-window efficacy that places it uses only for stroke events that have initiated less than 5 hours. Usually this time period is often passed, between the onset of the stroke outcome (the FAST signs), the arrival of 911 and drive to the appropriate stroke center and the differential diagnosis between ischemic and hemorrhagic stroke. After that time-window, tPA becomes pretty useless.
The second issue with tPA is that although it may help reperfuse the ischemic brain tissue and save the neurons inside it during the first hours, it is accompanied by a risk of hemorrhagic transformation within the first 72 hours after stroke by increasing the risk of brain bleeding. Hemorrhagic stroke is even more noxious than ischemic stroke as we have several issues to deal with: a massive entrance of water and ions resulting in brain swelling but foremost the release of hemoglobin (due to the rupture of red blood cells) inside the brain. The heme inside such hemoglobin is a very reactive and aggressive chemical. It is normally inactivated as it transformed into bilirubin and excreted via the bile. But when you have an important release of heme, you have an accumulation of bilirubin (responsible of the jaundice) that has still a toxicity. Therefore, it is important to find a protection mechanism against tPA-induced hemorrhagic stroke injury.
This paper elegantly describe the effect of overexpression of tPA in mice and what does it means in terms of increased plasmin production and its mechanism on action at the BBB. It suggest that plasmin production induced by tPA induces the production of bradykinin (BK), which in turn induces the BBB disruption. Such hypothesis is further supported by the presence of some data obtained from human patients following tPA administration after ischemic stroke injury, in which the authors have measured an elevation of BK levels.
I would say the only drawback of this paper is the absence of in vitro data that directly demonstrate the direct impact of BK on the BBB function and the mechanism by which BK impact the BBB integrity (tight junctions remodeling? destruction of tight junctions by matrix metalloproteinases?).
If you are interested to learn more about this study, you can find the full-text below (behind paywall): http://www.bloodjournal.org/content/early/2016/08/16/blood-2016-03-705384