CYR119, a central nervous system-penetrant stimulator of soluble guanylyl cyclase, improves survival in a mouse model of resuscitation after cardiac arrest

Abstract

Background

Treatment with inhaled nitric oxide (NO) improves rates of survival and neurologic outcomes in a mouse model of resuscitation after cardiac arrest. The effect of NO is dependent on the soluble guanylyl cyclase/cyclic guanosine monophosphate (NO-sGC-cGMP) pathway. NO-sGC is a potential target for drugs to modulate NO-dependent signaling in conditions that include ischemia-associated inflammation. The objective of this study was to determine whether CYR119, a stimulator of NO-sGC that can penetrate the central nervous system, improves outcomes after resuscitation from cardiac arrest.

Methods

Adult C57BL/6J wild-type mice of both sexes were subjected to potassium chloride-induced cardiac arrest and cardiopulmonary resuscitation. Fifteen minutes after the return of spontaneous circulation, mice were randomized to receive subcutaneous injections of either CYR119 or vehicle alone. The length of survival after the procedure and degree of neurological dysfunction were assessed. A composite outcome measure was used to define a good outcome as survival with good neurological function, while a poor outcome was defined as either death or exhibiting poor neurologic function. In addition, mRNA levels of inflammatory cytokines in the brain and a plasma marker of kidney injury were measured.

Results

CYR119 significantly improved 10-day survival (35 % in CYR119-treated mice; 15 % in vehicle-treated mice) and the likelihood of achieving a good outcome, demonstrating an association between treatment and both survival and neurological recovery. CYR119-treated mice also exhibited reduced transcript levels of TNF⍺ and IL-1β in the hippocampus and cortex, respectively, and lower plasma creatinine levels.

Conclusion

The current study revealed that CYR119 substantially improved the likelihood of survival with good neurologic function in mice resuscitated from cardiac arrest. The beneficial effects of post-arrest treatment with CYR119 were associated with decreased mRNA expression of inflammatory cytokines in the brain and decreased plasma creatinine levels, suggestive of renal protection. These findings support the potential of CYR119 as a therapeutic strategy for post-cardiac arrest recovery.