Role of Cranial Temperature in Neuroprotection by Sodium Hydrogen Sulfide After Cardiac Arrest in Mice.

Abstract

The hydrogen sulfide donor sodium hydrogen sulfide (NaHS) is recognized as a neuroprotective agent, which induces a hibernation-like metabolic state and hypothermia. However, it remains unclear whether it is the sulfide itself or the hypothermia induced by the sulfide that mediates treatment outcomes following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). We therefore tested whether NaHS improved outcomes following CA/CPR in mice maintained at 35.0°C by active warming during recovery. Adult male mice were subjected to 8 minutes CA/CPR and randomly treated intraperitoneally with either implantation of miniosmotic pump with NaHS (50 μmol/kg/day) for 3 days or vehicle 30 minutes after CPR. A normothermia group had cranial temperatures kept >35.0°C for 6 hours with a heat pad, and a hypothermia group was allowed to spontaneous hypothermia at room temperature (26.0°C). Behavioral testing and histological evaluation of neurons in the CA1 hippocampal region and striatum were performed on days 4 and 12 after CA/CPR. Both cranial and body temperature decreased following CA/CPR in the hypothermia group, and this was enhanced by NaHS treatment. In the active warming (normothermia) group, NaHS protected striatal neurons and improved long-term survival, which was comparable to the hypothermia groups. No differences were found in the CA1 region. Following CA/CPR, NaHS treatment decreased the heart rate, but not the mean arterial pressure. Our study demonstrated that post-CPR treatment with NaHS exerted neuroprotection in mice while maintaining a normal cranial temperature, indicating that NaHS-related neuroprotection is independent of the known protective effect of spontaneous hypothermia.