Exploration of the optimal dose of HOE-642 for the protection of neuronal mitochondrial function after cardiac arrest in rats

Abstract

Introduction: It has been demonstrated HOE-642 ameliorates ischemic contracture, prevents post-resuscitation diastolic dysfunction, and favors the earlier return of contractile function. This study is the first report to explore the optimal dose of HOE-642 in protecting the neuronal mitochondrial function after cardiac arrest.

Methods: Cardiac arrest was induced by 8 min asphyxia in rats. There were Sham (S), Normothermic (NORM), and Hypothermic (HYPO) groups. The NORM or HYPO groups consist of four subgroups: NORM/HYPO + HOE-642 0, 1, 3, and 5 mg/kg. Survival and NDS were evaluated after 24 h of resuscitation. ΔΨm, mitochondrial swelling, ROS production, and mitochondrial complex IIV activity of the hippocampus were detected.

Results: Survival in the HYPO + 1 mg group was the best and significantly higher than in the NORM + 0 mg and NORM + 1 mg groups. NDS in the HYPO + 0 mg, HYPO + 1 mg, and HYPO + 3 mg groups was significantly lower than in the NORM + 0 mg group. ΔΨm in the NORM + 1 mg (n = 5) group was significantly higher than in the NORM + 0 mg (n = 8), NORM + 3 mg (n = 5), and NORM + 5 mg (n = 5) groups. The ROS production in the NORM + 1 mg and NORM + 3 mg groups were significantly lower than in the NORM + 0 mg and NORM + 5 mg groups. Complex I and III activities in the HYPO + 1 mg (n = 5) group were significantly higher than in the HYPO + 3 mg (n = 5), and HYPO + 5 mg (n = 5) groups. Complex II and IV activities in the NORM + 3 mg and HYPO + 3 mg groups were significantly higher than in the NORM + 0 mg, NORM + 1 mg, and HYPO + 0 mg (n = 4)groups.

Conclusions: HOE-642 1 or 3 mg/kg showed benefits compared to HOE-642 5 mg/kg used when initiating resuscitation. When combined with hypothermia after cardiac arrest, HOE-642 1 or 3 mg/kg improved survival and neurological function compared with hypothermia or HOE-642 alone, however, HOE-642 5 mg/kg plus hypothermia did not.

Keywords: CPR; Cardiac arrest; HOE-642; Ischemia-reperfusion; Mitochondria.