FIGURE 8.

Proposed mechanism for the neuroprotective effect of AA147 against post-cardiac arrest (CA) cerebral ischemia/reperfusion injury (IRI). ER stress and oxidative stress induced by post-CA cerebral IRI results in numerous neuronal death. AA147 elevates ATF6 and Nrf2 levels in the neurons and increases their nuclear translocation by covalently modifying PDIs (restraining ATF6 within ER by regulating ATF6 disulfide) and Keap1 (keeping Nrf2 in low levels outside the nucleus by promoting its ubiquitination). AA147-induced activation of ATF6 could upregulate the expression of ER chaperones (e.g., GRP78) and ER-associated protein degradation (ERAD) components to restore ER proteostasis, also activating several antioxidant genes, including catalase, to scavenge overproduced ROS. At the same time, Nrf2 could induce the expression of HO-1, NQO1, and other antioxidant proteins to inhibit oxidative stress. The AA147-induced synergistic effect of two signaling pathways reduces neuronal death caused by post-CA cerebral IRI.