Role of NADPH oxidase in the brain injury of intracerebral hemorrhage

The major risk factors for intracerebral hemorrhage (ICH) are hypertension and aging. A fundamental mechanism for hypertension- and aging-induced vascular injury is oxidative stress. We hypothesize that oxidative stress has a crucial role in ICH. To test our hypothesis, we used bacterial collagenase to produce ICH in wild-type C57BL/6 and gp91(phox) knockout (gp91(phox) KO) mice (deficient in gp91(phox) subunit of the superoxide-producing enzyme NADPH oxidase). All animals were studied at 20-35 weeks of age, resembling an older patient population. We found that collagenase produced less bleeding in gp91(phox) KO mice than wild-type mice. Total oxidative product was lower in gp91(phox) KO mice than in wild-type mice, both under basal conditions and after ICH. Consistent with the ICH volume, brain edema formation, neurological deficit and a high mortality rate was noted in wild-type but not in gp91(phox) KO mice. This ICH-induced brain injury in wild-type mice is associated with enhanced expression of the gp91(phox) subunit of NADPH oxidase. In conclusion, the oxidative stress resulting from activation of NADPH oxidase contributes to ICH induced by collagenase and promotes brain injury.