Individuals who suffer from post-CA (
cardiac arrest)
brain injury experience higher mortality and more severe functional disability.
Neuroinflammation has been identified as a vital factor in
cerebral ischemia-
reperfusion injury (CIRI) following CA. Pyroptosis induces neuronal death by triggering an excessive inflammatory injury.
Chrysophanol possesses robust anti-inflammatory features, and it is protective against CIRI. The purpose of this research was to assess the effect of
Chrysophanol postconditioning on CIRI-induced pyroptotic cell death, and to explore its underlying mechanisms. CIRI was induced in rats by CA and subsequent
cardiopulmonary resuscitation, and PC12 cells were exposed to
oxygen-
glucose deprivation/reoxygenation (OGD/R) to imitate CIRI in vitro. It was found that post-CA
brain injury led to a notable cerebral damage revealed by histopathological changes and neurological outcomes. The existence of pyroptosis was also confirmed in in vivo and in vitro CIRI models. Moreover, we further confirmed that
Chrysophanol, the main bioactive ingredient of Rhubarb, significantly suppressed expressions of pyroptosis-associated
proteins, e.g., NLRP3, ASC, cleaved-caspase-1 and N-terminal GSDMD, and inhibited the expression of
tumor necrosis factor receptor-associated factor 6 (
TRAF6). Furthermore, NLRP3 overexpression neutralized the neuroprotection of
Chrysophanol postconditioning, suggesting that pyroptosis was the major neuronal death pathway modulated by
Chrysophanol postconditioning in OGD/R. Additionally, the neuroprotection of
Chrysophanol postconditioning was also abolished by gain-of-function analyses of
TRAF6. Finally, the results demonstrated that
Chrysophanol postconditioning suppressed the interaction between
TRAF6 and NLRP3. Taken together, our findings revealed that
Chrysophanol postconditioning was protective against CIRI by inhibiting NLRP3-related pyroptosis in a TRAF6-dependent manner.