Role of NADPH Oxidase in ICH-Induced Brain Injury

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DESCRIPTION (provided by applicant): At present, there is no effective treatment for intracerebral hemorrhage (ICH), a common and often fatal stroke subtype. Early brain injury after ICH is known to involve brain edema, disruption of the blood-brain barrier (BBB) and neurological deficits. Many of these events are related to oxidative stress especially to NADPH oxidase, however, the effects of oxidative stress in ICH have not been investigated nor have strategies been developed to evaluate this superoxide-producing enzyme's promise as a therapeutic target. Our central hypothesis is that ICH elevates NADPH oxidase in the peri-hematoma area, which results in oxidative stress, leading to early brain injury (i.e., disruption of BBB, brain edema and neurological deficit). The source of the increased NADPH oxidase is circulating neutrophils and endogenous brain parenchyma. This hypothesis is derived from our preliminary observations that gp91phox subunit of NADPH oxidase in the ipsilateral hemisphere is upregulated at the transcriptional level after ICH, accompanied by enhanced lipid peroxidation, BBB disruption and brain edema. It is also supported by the recent studies of others who find that cerebral ischemia produces less brain injury in mice lacking functional NADPH oxidase in the central nervous system or in neutrophils. Our project goal is to explore the role and identify the source of elevated NADPH oxidase involved in ICH-induced brain injury. Specific Aim 1 will determine whether (a) ICH-induced brain injury is associated with upregulation in NADPH oxidase and increase in oxidative stress in brain and (b) deficiency or inhibition of NADPH oxidase reduces brain injury in response to ICH. Specific Aim 2 will establish whether the source of NADPH oxidase that contributes to ICH-induced brain injury is neuronal, blood-born (neutrophils), or both. Our long-term goal is to explore the importance and identify the source of elevated NADPH oxidase involved in ICH-induced brain injury for future evaluation as a potential therapeutic target.