Pathophysiology of secondary brain injury in TBI

Oxidative injury
Oxidative injury is hypothesized to cause secondary injury in TBI, by contributing to cerebral edema, breakdown of the blood-brain barrier, and direct secondary neuronal injury.

TBI is associated with the following oxidative changes
 * Increased NOX2 expression and NADPH oxidase subunit translocation in animal and human studies. This seems to occur mainly in GABAergic parvalbumin-positive interneurons.
 * Increased levels of oxidation products for:
 * Lipids: 4-HNE, and TBARS in animal studies, malondialdehyde (MDA) in both animal and human studies.
 * Histones: p-H2A.X
 * DNA: 8-OHdG in both animal and human studies. and 8-hydroxyguanine.
 * RNA: 8-hydroxyguanosine
 * Proteins: protein carbonyl
 * Increased superoxide levels
 * Decreased Na-K ATPase activity (enzyme is sensitive to oxidative changes)

NADPH oxidase NOX 2
Mitochondria are usually considered to be the source, but the NADPH oxidase NOX2 may play a role as well. In a weight-drop mouse TBI model, NOX2 expression increased to a peak within 1 hour. It subsequently declined but peaked again at 24 hours before declining further. The increase of NOX2 expression at 1 hour has been confirmed in another study, and it coincided with a rise in cortical superoxide radical. Pretreatment with a NOX2 inhibitor, apocynin, has been shown in these models to have the following effects: Importantly, apocynin seemed to prevent cell death even when given after TBI.
 * Attenuated the increase in NOX2 expression
 * Attenuated the increase in NADPH oxidase subunit translocation
 * Attenuated the increase in cortical cell death and increased neuronal density.
 * Attenuated the increase in the levels of the oxidation products for
 * Lipids: malondialdehyde (MDA) and 4-HNE, and TBARS
 * Histones: p-H2A.X
 * DNA: 8-OHdG
 * Proteins: protein carbonyl
 * Attenuated the increase in blood-brain barrier dysfunction (as measured by Evans blue extravasation or immununoglobulin leakage ).
 * Attenuated the increase in neurological deficits seen in one study when given prior to TBI. When given after in another study using fluid percussion injury, it did not reduce motor deficits but did reduce object recognition deficits.
 * Attenuated the increase in superoxide levels in hippocampus and cortex
 * Attenuated the increase in microglial activation
 * Attenuated the increase in inflammatory markers in the brain (IL-1β, TNF-α, NOx)
 * Attenuated the increase in brain levels of beta-amyloid and amyloid precursor protein (APP)
 * Attenuated the increase in Na-K ATPase activity (enzyme is sensitive to oxidative changes)
 * No clear effect on brain edema

A NOX-2 specific inhibitor, gp91ds-tat, was also shown to have neuroprotective effects.

Oxidative injury can oxidize RNA and DNA. Of all the bases in DNA and RNA, guanine has the lowest redox potential and it is therefore the most prone to oxidative injury. Serum levels of oxidized guanine species can be elevated in a variety of disease states. Serum samples from severe TBI patients showed higher levels of oxidized guanine species (8-OHdG from DNA, 8-hydroxyguanosine from RNA, and 8-hydroxyguanine from DNA or RNA) and malondialdehyde (representing lipid peroxidation) in patients who died compared with those who survived. The association with oxidized guanine species and mortality persisted in multivariable analysis (OR 1.397, 95% CI 1.137-1.716).

Inflammation
TBI is associated with the following inflammatory changes:
 * Elevated brain IL-1β
 * Elevated brain TNF-α
 * Elevated brain NOx
 * Increased microglial activity

Blood-brain barrier dysfunction
TBI is associated with increased permeability of the blood-brain barrier.

Other causes of secondary injury
TBI is associated with increased levels of beta-amyloid and amyloid precursor protein (APP).

Apocynin
This drug inhibits the NADPH oxidase NOX2 and when given in mouse models before TBI is associated with numerous beneficial effects (see above). It seemed to have a neuroprotective effect even when given after TBI.

gp91ds-tat
This drug is a NOX2 specific inhibitor that has been associated with less edema and less neuronal damage after TBI. in animal studies.