Abstract
The role of nitric oxide synthases (NOSs) in early blood-brain barrier (BBB) disruption was determined using a new mouse model of transient focal cerebral ischemia. Ischemia was induced by ligating the middle cerebral artery (MCA) at its M2 segment and reperfusion was induced by releasing the ligation. The diameter alteration of the MCA, arterial anastomoses and collateral arteries were imaged and measured in real time. BBB disruption was assessed by Evans Blue (EB) and sodium fluorescein (Na-F) extravasation at 3 hours of reperfusion. The reperfusion produced an extensive vasodilation and a sustained hyperemia. Although expression of NOSs was not altered at 3 hours of reperfusion, L-NAME (a non-specific NOS inhibitor) abolished reperfusion-induced vasodilation/hyperemia and significantly reduced EB and Na-F extravasation. L-NIO (an endothelial NOS (eNOS) inhibitor) significantly attenuated cerebral vasodilation but not BBB disruption, whereas L-NPA and 7-NI (neuronal NOS (nNOS) inhibitors) significantly reduced BBB disruption but not cerebral vasodilation. In contrast, aminoguanidine (AG) (an inducible NOS (iNOS) inhibitor) had less effect on either cerebral vasodilation or BBB disruption. On the other hand, papaverine (PV) not only increased the vasodilation/hyperemia but also significantly reduced BBB disruption. Combined treatment with L-NAME and PV preserved the vasodilation/hyperemia and significantly reduced BBB disruption. Our findings suggest that nNOS may play a major role in early BBB disruption following transient focal cerebral ischemia via a hyperemia-independent mechanism.
Highlights
Stroke continues to be a leading cause of death and permanent disability worldwide [1]
We examined the influences of nitric oxide synthases (NOSs) inhibitors (non-specific NOS inhibitor: L-nitroarginine methyl ester (L-NAME); selective neuronal NOS (nNOS) inhibitors: N(omega)-propyl-L-arginine (L-NPA) and 7-nitroindazole (7-NI); relatively selective endothelial NOS (eNOS) inhibitor: L-N(5)-(1-iminoethyl)ornithine (L-NIO); selective inducible NOS (iNOS) inhibitor: aminoguanidine (AG)) and Nitric oxide (NO)-independent vasodilator (papaverine (PV)) on middle cerebral artery (MCA) ligation (MCAL)/reperfusion-induced regional vasodilation, hyperemia and early blood-brain barrier (BBB) disruption
MCAL/reperfusion-induced cerebral vasodilation Cerebral vasodilation occurred in most branches of MCA, arterial anastomoses, and terminal branches of anterior cerebral artery (ACA)/posterior cerebral artery (PCA) during both ischemia and reperfusion
Summary
Stroke continues to be a leading cause of death and permanent disability worldwide [1]. Due to the use of thrombolytic therapy, transient focal cerebral ischemia has become one of the most common types of ischemic stroke. Establishment of reperfusion is important for the cells in the penumbral zone, reperfusion is the most powerful independent predictor of BBB disruption [2]. BBB disruption occurs in early and late phases following ischemic stroke [3]. BBB disruption can be found as early as within first hour of reperfusion [4], whereas late BBB disruption occurs between 24 hours to 72 hours of reperfusion [3]. The mechanism remains poorly delineated, activation of matrix metalloproteinases (MMPs) 2 and 9 has been implicated in the pathogenesis of early BBB disruption following transient focal cerebral ischemia [3]
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