Neuroprotective effects of APC in the neurovascular space and in neurons. (A) APC can provide multiple neuroprotective effects in the neurovascular unit of the brain after ischemic stroke. APC inhibits the breakdown of the BBB, preventing extravasation of inflammatory cells. EPCR-mediated transfer of APC across the BBB permits APC to engage PAR1, PAR3, and EPCR directly on neurons, glia, and other cells in the brain to convey multiple cytoprotective activities and dampen neuronal damage. APC attenuates neuroinflammatory responses. Furthermore, APC promotes neurogenesis and vascular regeneration in the brain that directly contribute to repair and regeneration of the affected brain tissue after ischemic stroke (see Figure 4). Studies showing the requirement for PAR1 for APC’s neuroprotection are seen in panels B-D that show an assessment of brain damage after a 1-hour transient MCAO in wt (PAR1^+/+) and knockout (PAR1^−/−) mice treated with recombinant murine (rm)-tPA and recombinant murine wt-APC (0.2 mg/kg). Damage quantified at 24 hours after onset of ischemia was based on brain infarct volume (B), hemorrhage (C), and altered levels of NF-ĸB (D). Values are mean ± standard error of the mean (SEM), and n = 3-6 mice per group; * designates data for mice receiving both APC and rm-tPA (for details regarding panels B-D, see Cheng et al⁸⁸ ). (E) Studies using cultured neuronal cells from wt mice (PAR1^+/+, PAR3^+/+) and PAR1^−/− and PAR3^−/− knockout mice treated with 3K3A-APC showed the requirement for both PAR1 and PAR3 for 3K3A-APC’s direct neuronal protection against N-methyl-d-aspartate–induced excitotoxic injury of neurons (E). Values are mean ± SEM, n = 5 mice per group. (For details regarding panel E, see Guo et al⁹⁰ ).