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Free Radic Res. 2017 Mar;51(3):316-328. doi: 10.1080/10715762.2017.1311015. Epub 2017 Apr 9.

Involvement of Nox2 and Nox4 NADPH oxidases in early brain injury after subarachnoid hemorrhage.

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a Department of Neurosurgery & Brain and Nerve Research Laboratory , The First Affiliated Hospital of Soochow University , Suzhou , Jiangsu Province , China.
b Department of Neurosurgery , Jingjiang People's Hospital , Jiangsu , Jiangsu Province , China.
c Scott & White Clinic-Temple , Temple , TX , USA.


Oxidative stress is responsible for a poor prognosis of subarachnoid hemorrhage (SAH) patients. Nox2 has been shown to participate in SAH-induced early brain injury (EBI). Nox4 is another major subtype of Nox family widely expressed in central nervous system (CNS). Here, we investigated the role of Nox4 and whether there was a synergistic effect of Nox2 and Nox4 in SAH-induced EBI. Clinical brain biopsies of four patients with traumatic brain injury (TBI) and perihematomal brain tissue from six subjects with SAH were examined. Gp91ds-tat (a specific inhibitor of Nox2), GKT137831 (a specific inhibitor of Nox4), and apocynin (a non-specific Nox inhibitor) were used to test the role of Nox2 and Nox4. The protein levels of Nox2 and Nox4 were elevated in rat neurons and astrocytes at 12 h after SAH, and in cultured brain microvascular endothelial cells at 24 h after exposure to OxyHb. Similarly, there were higher Nox2 and Nox4 protein levels in perihematomal neurons and astrocytes in SAH patients than that in brain tissue from subjects with TBI. In SAH rat model, gp91ds-tat and GKT137831 could reduce SAH-induced neuronal death and degeneration, whereas apocynin did not induce a more intense neuroprotection. Consistently, in in vitro SAH model, siRNA-mediated silencing of Nox2 and Nox4 suppressed the OxyHb-induced neuronal apoptosis, whereas Nox2 and Nox4 co-knockdown also did not show a remarkable overlay effect. In conclusion, Nox4 should contribute to the pathological processes in SAH-induced EBI, and there was not an overlay effect of Nox2 inhibition and Nox4 inhibition on preventing SAH-induced EBI.


GKT137831; Nox2; Nox4; Subarachnoid hemorrhage; apoptosis; early brain injury; gp91ds-tat; rat

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