Attenuation of ischemia-induced mouse brain injury by SAG, a redox-inducible antioxidant protein

Cerebral ischemia resulting from a disruption of blood flow to the brain in itiates a cascade of events that causes neuron death and leads to neurologi c dysfunction. Reactive oxygen species are thought, at least in part, to me diate this disease process. The authors recently cloned and characterized a n antioxidant protein, SAG (sensitive to apoptosis gene), that is redox ind ucible and protects cells from apoptosis induced by redox agents in a numbe r of in vitro cell model systems. This study reports a neuroprotective role of SAG in ischemia/reperfusion-induced brain injury in an in vivo mouse mo del. SAG was expressed at a low level in brain tissue and was inducible aft er middle cerebral artery occlusion with peak expression at 6 to 12 hours. At the cellular level, SAG was mainly expressed in the cytoplasm of neurons and astrocytes, revealed by double immunofluorescence. An injection of rec ombinant adenoviral vector carrying human SAG into mouse brain produced an overexpression of SAG protein in the injected areas. Transduction of AdCMVS AG (wild-type), but not AdCMVmSAG (mutant), nor the AdCMVlacZ control, prot ected brain cells from ischemic brain injury, as evidenced by significant r eduction of the infarct areas where SAG was highly expressed. The result su ggests a rather specific protective role of SAG in the current in vivo mode l. Mechanistically, SAG overexpression decreased reactive oxygen species pr oduction and reduced the number of apoptotic cells in the ischemic areas. T hus, antioxidant SAG appears to protect against reactive oxygen species-ind uced brain damage in mice. Identification of SAG as a neuroprotective molec ule could lead to potential stroke therapies.