Abstract Body: Introduction:
We previously demonstrated that mitochondrial transplantation (MTx) administered immediately after resuscitation improved 72-hour survival and neurological outcomes in a rat model of 10-minute asphyxial cardiac arrest (CA). However, the therapeutic efficacy of MTx when its administration is delayed—a scenario more reflective of clinical reality—remains unclear.
Objective:
To evaluate the effects of delayed MTx administration on neurological outcomes following cardiac arrest and resuscitation.
Methods:
Adult male Sprague-Dawley rats were anesthetized, intubated, and mechanically ventilated. Microcatheters were inserted into the left femoral artery and vein for blood pressure monitoring and drug delivery, respectively. After 10 minutes of asphyxial CA, the rats were resuscitated using mechanical ventilation, manual chest compressions, and intravenous epinephrine. Rats achieving ROSC were randomized to receive MTx or vehicle via a venous catheter at 30 and 60 minutes post-ROSC. Neurological function was assessed at 24, 48, and 72 hours using the Neurological Function Score (NFS; 0 = worst, 500 = normal). At 72 hours, brain tissue was harvested from surviving animals. Neuronal degeneration was assessed via Fluoro-Jade B (FJB) staining, and neuroinflammatory responses were evaluated by immunohistochemistry for Iba-1 and CD86.
Results:
At 48 hours post-resuscitation, the NFS was significantly higher in the MTx group compared to the vehicle group (mean ± SEM: 284 ± 15 vs. 174 ± 27, p < 0.05). This trend persisted at 72 hours, with MTx-treated rats showing notably better neurological function (Fig 1). FJB staining demonstrated reduced neuronal degeneration in the cerebral cortex of MTx-treated rats (Fig 2). Iba-1–positive cells were significantly lower in the cortex and hippocampus of MTx-treated rats, indicating attenuated neuroinflammatory responses (Fig 3). In contrast, no significant differences were detected in Iba-1 expression in the caudoputamen, or in CD86 expression across the cortex, hippocampus and caudoputamen between the two groups.
Conclusion:
These findings indicate that MTx retains its neuroprotective efficacy even when administration is delayed post-resuscitation. Delayed MTx may therefore represent a viable therapeutic strategy in clinical settings where immediate delivery is not feasible, supporting further translational investigation.