Abstract
Ischemic neuron loss contributes to brain dysfunction in patients with cardiac arrest (CA). Histidine–tryptophan–ketoglutarate (HTK) solution is a preservative used during organ transplantation. We tested the potential of HTK to protect neurons from severe hypoxia (SH) following CA. We isolated rat primary cortical neurons and induced SH with or without HTK. Changes in caspase-3, hypoxia-inducible factor 1-alpha (HIF-1α), and nicotinamide adenine dinucleotide phosphate oxidase-4 (NOX4) expression were evaluated at different time points up to 72 h. Using a rat asphyxia model, we induced CA-mediated brain damage and then completed resuscitation. HTK or sterile saline was administered into the left carotid artery. Neurological deficit scoring and mortality were evaluated for 3 days. Then the rats were sacrificed for evaluation of NOX4 and H2O2 levels in blood and brain. In the in vitro study, HTK attenuated SH- and H2O2-mediated cytotoxicity in a volume- and time-dependent manner, associated with persistent HIF-1α expression and reductions in procaspase-3 activation and NOX4 expression. The inhibition of HIF-1α abrogated HTK’s effect on NOX4. In the in vivo study, neurological scores were significantly improved by HTK. H2O2 level, NOX4 activity, and NOX4 gene expression were all decreased in the brain specimens of HTK-treated rats. Our results suggest that HTK acts as an effective neuroprotective solution by maintaining elevated HIF-1α level, which was associated with inhibited procaspase-3 activation and decreased NOX4 expression.
Highlights
We proved that extracorporeal cardiopulmonary resuscitation could improve survival rates and neurological outcomes compared with conventional cardiopulmonary resuscitation (CPR) [1,2]
Using 1/8 HTK solution in the culture medium, the percentage change of lactate dehydrogenase (LDH) decreased significantly at 24 and 48 h compared with the severe hypoxia (SH) group at the same time points (p < 0.05)
A control group of HTK usage under normoxic environment was performed, and the results show that long-term exposure (72 h) of neurons to HTK of any proportion is harmful, as in supplementary S2 Fig
Summary
We proved that extracorporeal cardiopulmonary resuscitation could improve survival rates and neurological outcomes compared with conventional cardiopulmonary resuscitation (CPR) [1,2]. Brain damage caused by hypoperfusion and reperfusion injuries remains the leading cause of death among patients who survive cardiac arrest.
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