Abstract

Introduction: Mitochondrial dysfunction is associated with poor neurological outcomes after resuscitation. Over the past decade, identification of the mitochondrial outer membrane voltage-dependent anion channel 1 (VDAC1) and inner membrane mitochondrial calcium uniporter (MCU) has provided insight into the roles that mitochondrial Ca2+ regulation plays in neuronal function after cardiac arrest (CA). Hypothesis: The neuroprotective effects of 4,4'-Diisothiocyanostilbene-2,2'-disulfonic Acid (DIDS) inhibition on VDAC1 or Ruthenium red (RUR) inhibition on MCU after asphyxial CA in rats were investigated. Methods: Male SD rats, 240-340 g, were subjected to 8 min asphyxial CA and followed by manual cardiopulmonary resuscitation. Sham, Control, DIDS, RUR, DIDS+RUR groups were included. The rats in the DIDS, RUR, DIDS+RUR groups received 7 mg/kg DIDS, 3 mg/kg RUR or 7 mg/kg DIDS combined with 3 mg/kg RUR immediately after return of spontaneous circulation (ROSC). Survival and Neurologic Deficit Score were assessed at 24 h after ROSC. Neurological outcome was assessed. Hippocampal mitochondrial apoptosis was measured. Results: Survival was significantly higher in the RUR group compared to the Control group (85% vs. 40%, P < 0.05). NDS in the DIDS and RUR groups were significantly better than in the Control group (P < 0.05). Neurons were less damaged in the DIDS, RUR, DIDS+RUR groups than in the Control group (Figure). Cyt.C was lower in the DIDS, RUR, DIDS+RUR groups than in the Control group (P < 0.05). Bax was lower in the RUR, DIDS+RUR groups than in the Control group (P < 0.05). Bcl-2 was highly expressed in the RUR group than in the Control group (P < 0.05). Cleaved caspase-3 was lower in the DIDS+RUR group (P < 0.05). AIF was higher in the DIDS and RUR groups compared to the Control group (P < 0.05). Conclusions: Inhibiting VDAC1 or MCU significantly improved survival, neurological outcome and inhibited hippocampal mitochondrial apoptosis after CA.

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