SHPS‐1 deficiency induces robust neuroprotection against experimental stroke by attenuating oxidative stress

J. Neurochem. (2012) 122 , 834–843. Abstract Src homology 2 domain–containing protein tyrosine phosphatase substrate–1 (SHPS‐1), also known as Signal‐regulatory protein alpha (SIRPα) or SIRPA is a transmembrane protein that is predominantly expressed in neurons, dendritic cells, and macrophages. This study was conducted to investigate the role of SHPS‐1 in the oxidative stress and brain damage induced by acute focal cerebral ischemia. Wild‐type (WT) and SHPS‐1 mutant (MT) mice were subjected to middle cerebral artery occlusion (60 min) followed by reperfusion. SHPS‐1 MT mice had significantly reduced infarct volumes and improved neurological function after brain ischemia. In addition, neural injury and oxidative stress were inhibited in SHPS‐1 MT mice. The mRNA and protein levels of the antioxidant genes nuclear factor‐E2‐related factor 2 (Nrf2) and heme oxygenase 1 were up‐regulated in SHPS‐1 MT mice. The SHPS‐1 mutation suppressed the phosphorylation of SHP‐1 and SHP‐2 and increased the phosphorylation of Akt and GSK3β. These results provide the first demonstration that SHPS‐1 plays an important role in the oxidative stress and brain injury induced by acute cerebral ischemia. The activation of Akt signaling and the up‐regulation of Nrf2 and heme oxygenase 1 likely account for the protective effects that were observed in the SHPS‐1 MT mice.