Alda-1, an Activator of ALDH2, Protects Cardiac and Neurological Function Postresuscitation by Inhibiting Pyroptosis in Swine

Abstract PurposeThe enzyme aldehyde dehydrogenase 2 (ALDH2) has been shown to protect the heart and brain from oxidative stress injury, and this effect is related to the inhibition of pyroptosis. In the present study, we hypothesised that the ALDH2 activator N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichloro-benzamide (Alda-1) would mitigate cardiac and neurological injury postresuscitation in a preclinical swine model of CA.MethodsFollowing 8 minutes of untreated ventricular fibrillation, and another 8 minutes of cardiopulmonary resuscitation (CPR), the swine randomly received either Alda-1 (0.88 mg/kg, n = 6) or saline (n=5) after restoration of spontaneous circulation (ROSC). Hemodynamic parameters and cardiac function were monitored, and serial blood samples were collected postresuscitation to detect biomarkers of cardiac and neurological injury. At 24 hours postresuscitation, first, neurological scores were evaluated, and then, the swine were sacrificed and pyroptosis-related proteins, proinflammatory cytokines, and oxidative stress were assessed in heart and brain samples.ResultsCardiac and neurological injury were significantly improved in the Alda-1 group compared with the CPR group postresuscitation. In addition, after treatment with Alda-1, the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, Gasdermin D (GSDMD), and proinflammatory cytokine levels were markedly suppressed. Moreover, 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA), indicators of oxidative stress, were also significantly inhibited after Alda-1 administration, which was accompanied by increased ALDH2 activity and protein expression.ConclusionAlda-1 improves cardiac and neurological dysfunction postresuscitation in a swine model of CA, at least partly by inhibiting oxidative stress-mediated NLRP3 inflammasome activation and pyroptosis.