Biological Effects and Mechanisms of Caspases in Early Brain Injury after Subarachnoid Hemorrhage

Figure 2

Apoptosis and necroptosis in SAH. The intrinsic pathway is activated by various stresses after SAH prompting activation of Bak and Bax and release of cytochrome c, which binds to Apaf-1 and then activates through self-cleavage of procaspase-9, further initiating the apoptotic cascade of caspase-3. The extrinsic pathway is activated through membrane receptor formation complexes, and the programmed death cascade induced through caspase-8 to caspase-3 activation. In addition, endoplasmic reticulum stress activates caspase-12 via calcium-activated calpains and ultimately acts on caspase-3 to mediate apoptosis. The natural inhibitor XIAP, the broad-spectrum inhibitor Z-VAD-FMK, the artificial inhibitors Z-IETD-FMK and Ac-DEVD-CHO, which exert inhibitory functions on caspase-8, caspase-9, and caspase-3, respectively, can effectively alleviate apoptosis in EBI. Necroptosis is triggered downstream of the death domain receptor TNFR. Upon detection of a “death signal,” RIP1 is activated and the subsequent formation of a RIP homotypic interaction motif (RHIM) begins to recruit RIP3. The RIPK1/RIP3 complex recruits and phosphorylates MLKL to form necrosomes. Ultimately, MLKL acts on the cell membrane to form pores that lead to necroptosis by allowing the uncontrolled release of intracellular substances.