ERK 1/2 mediates the TWEAK-induced hypoxic and/or ischemic tolerance. (A) Representative western blot analysis for pERK 1/2 in Wt cerebral cortical neurons incubated for 0 to 180 minutes with TWEAK 100 ng/mL alone or in combination with SL327 10 μM. (B) Mean neuronal survival in Wt cerebral cortical neurons exposed to 55 minutes of oxygen-glucose deprivation conditions 24 hours after 60 minutes of incubation with TWEAK 100 ng/mL alone (white bar) or in combination with either wortmannin 100 nM (dark gray bar) or the ERK 1/2 inhibitor SL327 (light gray bar). n = 16 per group, *P < 0.05 compared to neurons maintained under normoxic conditions, **P < 0.05 compared to neurons preconditioned with TWEAK alone. Lines denote SD. (C) Volume of the ischemic lesion in Wt mice treated with vehicle (control, black bar) or TWEAK 0.2 mg alone (white bar) or in combination with the ERK 1/2 inhibitor SL327 10 uM (gray bar) 24 hours before tMCAO. *P < 0.05 compared to non-preconditioned mice and with mice preconditioned with TWEAK alone. n = 8 per experimental group. Lines denote SD. Ns: non-significant; OGD: oxygen-glucose deprivation; pERK: ERK 1/2 phosphorylated at Thr202/Tyr204; tERK: total ERK; tMCAO: transient middle cerebral artery occlusion; TWEAK: tumor necrosis factor-like weak inducer of apoptosis; Wort: wortmannin; Wt: wild-type.