Abstract
Cerebral injury after cardiac arrest (CA)/cardiopulmonary resuscitation (CPR) has been implicated in the poor prognosis of CA survivors. This study was designed to evaluate the impact of melatonin on postresuscitation neurological outcomes and to explore the underlying mechanism. Sprague-Dawley rats were randomly assigned to four groups: sham group, CPR group, melatonin pretreatment group (Pre-M) and posttreatment group (Post-M). For the last 2 groups, daily melatonin gavage was performed for 12 consecutive days before or 24 hours after rat survival from CA/CPR. No statistical differences were observed in heart rate (HR), mean arterial blood pressure (MAP), and end-tidal carbon dioxide (ETCO2) at baseline and after restoration of spontaneous circulation (ROSC) among groups. However, melatonin pretreatment or posttreatment significantly improved neurological deficit score and memory and spatial learning ability after CA/CPR. Further studies demonstrated that the complex I- and complex-II supported mitochondrial respiration were greatly increased under melatonin treatment. In addition, melatonin treatment preserved the mitochondrial-binding hexokinase II (HKII) and ATP levels and suppressed the upregulated protein lysine acetylation in hippocampus after CA/CPR. In conclusion, using a rat asphyxial CA model we have demonstrated that treatment with melatonin either before or after CA/CPR provides a promising neuroprotective effect, and this protection was mediated by increasing mitochondrial HKII expression, suppressing protein acetylation and improving mitochondrial function in hippocampus.
Highlights
Cardiac arrest (CA) is a leading cause of death worldwide, claiming the lives of over 450,000 in United States, 350,000 in Europe and 544,000 in China annually [1, 2]
After achievement of restoration of spontaneous circulation (ROSC), we observed a short period of mean arterial blood pressure (MAP) elevation, which was probably caused by use of the vasoactive drug epinephrine
There were no differences in heart rate (HR), MAP and ETCO2 post-resuscitation among groups, indicating that melatonin has no direct impact on blood pressure and heart physiology
Summary
Cardiac arrest (CA) is a leading cause of death worldwide, claiming the lives of over 450,000 in United States, 350,000 in Europe and 544,000 in China annually [1, 2]. Melatonin can evoke the antioxidative molecular machinery by activating the nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2-ARE) signaling pathway, which has been demonstrated to be neuroprotective in several models of brain injury [10]. Through those mechanisms, melatonin is able to prevent the deterioration of cellular membranes and reduces lipid peroxidation [11]. Melatonin can maintain the efficiency of electron transport chain to facilitate ATP synthesis [14] Whether these beneficial effects of melatonin could alleviate post-CA brain damage and the underlying mechanism have not been fully understood. Based on rat asphyxial CA model, this study was designed to investigate the effect of melatonin administrated before or after CA/CPR and to elucidate the mitochondrial mechanism
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