Ac2-26 Alleviates Brain Injury after Cardiac Arrest and Cardiopulmonary Resuscitation in Rats via the eNOS Pathway

Brain injury is the leading cause of death following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Ac2-26 and endothelial nitric oxide synthase (eNOS) have been shown to reduce neuroinflammation. This study is aimed at determining the mechanism by which Ac2-26 protects against inflammation during brain injury following CA and CPR.

Sixty-four rats were randomized into sham, saline, Ac2-26, and Ac2-26+L-NIO (endothelial nitric oxide synthase (eNOS) inhibitor) groups. Rats received Ac2-26, Ac2-26+L-NIO, or saline after CPR. Neurologic function was assessed at baseline, 24, and 72 hours after CPR. At 72 hours after resuscitation, serum and brain tissues were collected.

Blood-brain barrier (BBB) permeability increased, and the number of surviving neurons and neurological function decreased in the saline group compared to the sham group. Anti-inflammatory and proinflammatory factors, neuron-specific enolase (NSE) levels, and the expression of eNOS, phosphorylated (p)-eNOS, inducible nitric oxide synthase (iNOS), and oxidative stress-related factors in the three CA groups significantly increased (P < 0.05). BBB permeability decreased, and the number of surviving neurons and neurological function increased in the Ac2-26 group compared to the saline group (P < 0.05). Ac2-26 increased anti-inflammatory and reduced proinflammatory markers, raised NSE levels, increased the expression of eNOS and p-eNOS, and reduced the expression of iNOS and oxidative stress-related factors compared to the saline group (P < 0.05). The effect of Ac2-26 on brain injury was reversed by L-NIO (P < 0.05).

Ac2-26 reduced brain injury after CPR by inhibiting oxidative stress and neuroinflammation and protecting the BBB. The therapeutic effect of Ac2-26 on brain injury was largely dependent on the eNOS pathway.