Role of osteopontin in early brain injury after subarachnoid hemorrhage in rats.
BACKGROUND
Subarachnoid hemorrhage (SAH)-induced early brain injury (EBI) contributes to delayed ischemic neurological deficits, one of whose key pathologic manifestation is the blood-brain barrier (BBB) disruption. Although post-SAH BBB breakdown is a self-repairable phenomenon, the molecular pathways are unknown. We determined the role of osteopontin (OPN), a pleiotropic extracellular matrix glycoprotein, in the post-SAH BBB disruption in rats.


METHODS
First, we produced the endovascular perforation model of SAH and studied if OPN is induced in the brain after SAH. Secondly, we examined the effects of blockage of endogenous OPN induction on neurological impairments and BBB disruption. Thirdly, we evaluated the effects of exogenous OPN on neurological impairments, brain edema and BBB disruption, and the related protein expression levels.


RESULTS
OPN was significantly induced and peaked at 72 h after SAH, in the recovery phase of EBI. OPN small interfering RNA significantly aggravated neurological impairment and BBB disruption 72 h after SAH. Exogenous OPN significantly prevented neurological impairment, brain edema and BBB disruption associated with the deactivation of nuclear factor-κB activity, the inhibition of matrix metalloproteinase (MMP)-9 induction and tissue inhibitor of MMP-1 reduction, and the consequent preservation of cerebral microvessel basal lamina protein laminin and tight junction protein zona occludens-1.


CONCLUSIONS
These findings suggest the protective effects of OPN against BBB disruption after SAH, a finding which should provide a novel therapeutic approach for post-SAH EBI.
Department of Physiology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
Hidenori
H
Suzuki
Robert
R
Ayer
Takashi
T
Sugawara
Wanqiu
W
Chen
Takumi
T
Sozen
Yu
Y
Hasegawa
Kenji
K
Kanamaru
John H
JH
Zhang
D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001930:Brain Injuries / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D008954:Models, Biological; D053495:Osteopontin / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D013997:Time Factors
D034741:RNA, Small Interfering; D053495:Osteopontin