Aldehyde dehydrogenase 2 (ALDH2) has been proven to protect the heart and brain against regional
ischemia/reperfusion injury, in which the protective role is related to the inhibition of pyroptosis. In the present study, we investigated whether an ALDH2 activator N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichloro-benzamide (Alda-1) would improve postresuscitation cardiac and neurological outcomes in a clinically relevant swine model of
cardiac arrest (CA) and
resuscitation. The animal model was established by 8 min of untreated
ventricular fibrillation and then 8 min of
cardiopulmonary resuscitation (
CPR). After restoring spontaneous circulation, the animals were randomly divided to receive either Alda-1 (0.88 mg/kg, n = 6) or saline (n = 5). Postresuscitation hemodynamic parameters, cardiac function, and cardiac and cerebral
injuries were periodically measured for a total of 24 h. At 24 h postresuscitation, neurological function was evaluated, and then the animals were sacrificed, and cardiac and cerebral tissue samples were obtained for the measurements of oxidative stress,
inflammation and pyroptosis. Consequently, postresuscitation cardiac and neurological dysfunction were significantly improved accompanied with significantly milder cardiac and cerebral
injuries in the Alda-1 group compared with the
CPR group. In addition, the increase in NLR family pyrin domain-containing 3
inflammasome expression and proinflammatory
cytokine production, which indicated the occurrence of inflammatory response, were significantly less in the Alda1 group than in the
CPR group. The expression level of gasdermin D used as a
protein marker of pyroptosis was also significantly reduced in all resuscitated animals receiving Alda1 treatment. Moreover, the severity of oxidative stress indicated by the changes of
4-hydroxy-2-nonenal and
malondialdehyde was significantly decreased in the heart and brain in all animals treated with Alda-1 compared to the
CPR group. Thus, Alda-1 mitigated postresuscitation cardiac and neurological dysfunction and
injuries possibly by inhibiting oxidative stress-mediated NLRP3
inflammasome activation and pyroptosis in a swine model of CA and
resuscitation.