Carbon monoxide-releasing molecule-3 exerts neuroprotection effects after cardiac arrest in mice: A randomized controlled study

Background: Post-cardiac arrest brain injury (PCABI) is the leading cause of death in survivors of cardiac arrest (CA). Carbon monoxide-releasing molecule (CORM-3) is a water-soluble exogenous carbon monoxide that has been shown to have neuroprotection benefits in several Neurological Disease models. However, the effects of CORM-3 on PCABI is still unclear.

Methods: A mice model combined asystole with hemorrhage was used. Mice were anesthetized and randomized into 4 groups (n = 12/group) and underwent either 9.5 min CA followed by cardiopulmonary resuscitation (CPR) or sham surgery. CORM-3 (30 mg/kg) or vehicle (normal saline) were administered at 1 h after return of spontaneous circulation or sham surgery. Survival, neurologic deficits, alterations in the permeability of the brain-blood barrier and cerebral blood flow, changes of oxidative stress level, level of neuroinflammation and neuronal degeneration, and the activation of Nrf2/HO-1 signaling pathway were measured.

Results: In CORM-3 treated mice that underwent CA/CPR, significantly improved survival (75.00% vs. 58.33%, P = 0.0146 (24 h) and 66.67% vs. 16.67%, P < 0.0001 (72 h)) and neurological function were observed at 24 h and 72 h after ROSC (P < 0.05 for each). Additionally, increased cerebral blood flow, expression of tight junctions, and reduced Reactive Oxygen Species generation at 24 h after ROSC were observed (P < 0.05 for each). CORM-3 treated mice had less neuron death and alleviated neuroinflammation at 72 h after ROSC (P < 0.05 for each). Notably, the Nrf2/HO-1 signaling pathway was significantly activated in mice subjected to CA/CPR with CORM-3 treatment.

Conclusions: CORM-3 could improve survival and exert neuroprotection after CA/CPR in mice. CORM-3 may be a novel and promising pharmacological therapy for PCABI.

Carbon monoxide; Carbon monoxide-releasing molecule-3; Cardiac arrest; Neuroprotection; Post-cardiac arrest brain injury.