Inhaled Carbon Dioxide Improves Neurological Outcomes by Downregulating Hippocampal Autophagy and Apoptosis in an Asphyxia-Induced Cardiac Arrest and Resuscitation Rat Model

Abstract

BACKGROUND: Protracted cerebral hypoperfusion following cardiac arrest (CA) may cause poor neurological recovery. We hypothesized that inhaled carbon dioxide (CO2) could augment cerebral blood flow (CBF) and improve post-CA neurological outcomes. METHODS AND RESULTS: After 6-minute asphyxia-induced CA and resuscitation, Wistar rats were randomly allocated to 4 groups (n=25/group) and administered with different inhaled CO2 concentrations, including control (0% CO2 ), 4% CO2, 8% CO2, and 12% CO2 . Invasive monitoring was maintained for 120 minutes, and neurological outcomes were evaluated with neurological function score at 24 hours post-CA. After the 120-minute experiment, CBF was 242.3% (median; interquartile range, 221.1%– 267.4%) of baseline in the 12% CO2 group while CBF fell to 45.8% (interquartile range, 41.2%– 58.1%) of baseline in the control group (P<0.001). CBF increased along with increasing inhaled CO2 concentrations with significant linear trends (P<0.001). At 24 hours post-CA, compared with the control group (neurological function score, 9 [interquartile range, 8– 9]), neurological recovery was significantly better in the 12% CO2 group (neurological function score, 10 [interquartile range, 9.8– 10]) (P<0.001) while no survival difference was observed. Brain tissue malondialdehyde (P=0.02) and serum neuron-specific enolase (P=0.002) and S100β levels (P=0.002) were significantly lower in the 12% CO2 group. TUNEL (terminal deoxynucle-otidyl transferase– mediated biotin– deoxyuridine triphosphate nick-end labeling)-positive cell densities in hippocampal CA1 (P<0.001) and CA3 (P<0.001) regions were also significantly reduced in the 12% CO2 group. Western blotting showed that beclin-1 (P=0.02), p62 (P=0.02), and LAMP2 (lysosome-associated membrane protein 2) (P=0.01) expression levels, and the LC3B-II:LC3B-I ratio (P=0.02) were significantly lower in the 12% CO2 group. CONCLUSIONS: Administering inhaled CO2 augmented post-CA CBF, mitigated oxidative brain injuries, ameliorated neuronal injury, and downregulated apoptosis and autophagy, thereby improving neurological outcomes.