Dissociation and protection of the neurovascular unit after thrombolysis and reperfusion in ischemic rat brain.
In the ischemic brain, reperfusion with tissue plasminogen activator (tPA) sometimes causes catastrophic hemorrhagic transformation (HT); however, the mechanism remains elusive. Here, we show that the basement membrane, and not the endothelial cells, is vulnerable to ischemic/reperfusion injury with tPA treatment. We treated a spontaneously hypertensive rat model of middle cerebral artery occlusion (MCAO) with vehicle alone, tPA alone, or a free radical scavenger, edaravone, plus tPA. Light and electron microscopic analyses of each microvascular component revealed that the basement membrane disintegrated and became detached from the astrocyte endfeet in tPA-treated animals that showed HT. On the other hand, edaravone prevented the dissociation of the neurovascular unit, dramatically decreased the HT, and improved the neurologic score and survival rate of the tPA-treated rats. These results suggest that the basement membrane that underlies the endothelial cells is a key structure for maintaining the integrity of the neurovascular unit, and a free-radical scavenger can be a viable agent for inhibiting tPA-induced HT.
Yamashita
Toru
T
Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Kamiya
Tatsushi
T
Deguchi
Kentaro
K
Inaba
Toshiki
T
Zhang
Hanzhe
H
Shang
Jingwei
J
Miyazaki
Kazunori
K
Ohtsuka
Aiji
A
Katayama
Yasuo
Y
Abe
Koji
K
D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D001485:Basement Membrane / Q000473:pathology*; D002545:Brain Ischemia / Q000150:complications* / Q000628:therapy; D002543:Cerebral Hemorrhage / Q000139:chemically induced*; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery; D051381:Rats; D011918:Rats, Inbred SHR; D015424:Reperfusion; D015912:Thrombolytic Therapy / Q000009:adverse effects* / Q000379:methods; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000627:therapeutic use
D016166:Free Radical Scavengers; D010959:Tissue Plasminogen Activator; D000077553:Edaravone; D000983:Antipyrine