Neuronal Survival, As Easy as APC

Abstract

Activated protein C (APC) is best known for its abilities to reduce inflammation and increase blood flow but also has antiapoptotic activity in brain endothelial cells, which may help protect the brain from ischemic injury. Guo et al. report that the naturally occurring compound also protects mouse cortical neurons from apoptosis. Exposure of cultured neurons to APC blocked apoptosis induced by two modes of injury—overstimulation of N -methyl-D-aspartate (NMDA) receptors and exposure to the chemical agent staurosporin. APC treatment blocked injury-induced activation of caspases, the nuclear translocation of mitochondrial protein apoptosis-inducing factor, and the expression of proapoptotic factors p53 and Bax. These effects required the expression of protease-activated receptors (PARs), whose activation in brain endothelial cells depends on activation of the APC receptor. Both antibody blockage of PAR proteins and lack of PAR expression in neurons of PAR-null mice thwarted APC's protective effect against apoptosis. Intracerebral injection of APC reduced NMDA-induced lesions in mice by 70%, which suggests a possible new avenue for treating neurodegenerative disorders and brain injury. H. Guo, D. Liu, H. Gelbard, T. Cheng, R. Insalaco, J. A. Fernández, J. H. Griffin, B. V. Zlokovic, Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron 41 , 563-572 (2004). [Online Journal]