Therapeutic hypothermia achieves neuroprotection via a decrease in acetylcholine with a concurrent increase in carnitine in the neonatal hypoxia‐ischemia (877.2)

Abstract

Although therapeutic hypothermia has been shown to improve neurologic outcomes after the perinatal cerebral hypoxia‐ischemia, etiology remains unknown. To decipher mechanisms whereby hypothermia regulates metabolism in different regions of the brain, we took a two‐step approach; metabolomics to target metabolic pathways responding to lowering temperature, and quantitative imaging mass spectrometry (Q‐IMS) to reveal spatial alterations in targeted metabolites at specific regions of the brain. 7‐day postnatal rats underwent permanent ligation of left common carotid artery followed by exposure to 8% O2 for 2.5 hrs. Pups were returned to normoxia at either 38 °C or 30 °C for 3 hrs. Brain metabolism was rapidly fixed by in‐situ freezing. Profiling of 107metabolites showed that hypothermia diminishes the carbon biomass related to acetyl‐moieties such as pyruvate and acetyl CoA; conversely, it increases deacetylated metabolites such as carnitine and choline. Q‐IMS indicated that hypothermia diminishes ACh contents specifically in hippocampus and amygdala. The decrease is associated with an inverse increase in carnitine in the same anatomical regions. These findings imply that therapeutic hypothermia achieves neuroprotective effects by mediating acetylation status with coordinated suppression of acetyl CoA which resides in metabolic crossroads of glycolysis, amino acid catabolism and ketolysis.Grant Funding Source: Grant‐in‐Aid for Scientific Research 24791121 and 24500448 from the Japan Society for the Promotion