The Histone Deacetylase Activator ITSA-1 Improves the Prognosis of Cardiac Arrest Rats by Alleviating Systemic Inflammatory Responses Following Cardiopulmonary Resuscitation.

Abstract

Objective: To investigate whether the histone deacetylase (HDAC) activator ITSA-1 can ameliorate systemic inflammation after cardiac arrest (CA), thereby enhancing cardiac function and neurological outcomes in rats. Materials and Methods: Sixty-nine healthy adult male Wistar rats were subjected to 12 min of CA induced by Vecuronium bromide. The rats were randomly assigned to five groups: normal control, sham operation, control, suberoylanilide hydroxamic acid (SAHA), and ITSA-1. The study evaluated the effects of ITSA-1 on cardiac function, survival, and neurological functions, including the neurological deficit score (NDS) at 24-, 48-, and 72-h post-return of spontaneous circulation (ROSC) and Morris water maze performance at 72 h. Additionally, levels of TNF-α, IL-1β, glial fibrillary acidic protein (GFAP), S100β in plasma, and TNF-α, IL-1β in the hippocampus were measured 4 h post-ROSC. Western blot analysis was used to assess HDACs, nuclear factor kappa B (NF-κB), p-NF-κB, caspase-3, cleaved caspase-3, Bcl-2, and Bax protein expressions. Results: ITSA-1 reduced basic life support (BLS) duration and adrenaline dosage during cardiopulmonary resuscitation (CPR) and improved cardiac and neural functions, enhancing survival compared to the control and SAHA groups. ITSA-1 decreased serum levels of IL-1β, TNF-α, GFAP, S100β, and hippocampal TNF-α, IL-1β, promoting neuronal survival in the CA1 region. It also inhibited glial cell activation and reduced histone acetylation, blocking the NF-κB pathway and neuronal apoptosis. Conclusion: ITSA-1 enhances the recovery and survival of post-ROSC rats by diminishing histone acetylation and mitigating systemic inflammation. This effect is possibly due to the inhibition of glial cell activation, increased neuronal survival in the brain, and improved cardiac output (CO) and ejection fraction (EF).