Therapeutic hypothermia achieves neuroprotection via a decrease in acetylcholine with a concurrent increase in carnitine in the neonatal hypoxia-ischemia

Toshiki Takenouchi, Yuki Sugiura, Takayuki Morikawa, Tsuyoshi Nakanishi, Yoshiko Nagahata, Tadao Sugioka, Kurara Honda, Akiko Kubo, Takako Hishiki, Tomomi Matsuura, Takao Hoshino, Takao Takahashi, Makoto Suematsu, Mayumi Kajimura

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)


Although therapeutic hypothermia is known to improve neurologic outcomes after perinatal cerebral hypoxia-ischemia, etiology remains unknown. To decipher the mechanisms whereby hypothermia regulates metabolic dynamics in different brain regions, we used a two-step approach: a metabolomics to target metabolic pathways responding to cooling, and a quantitative imaging mass spectrometry to reveal spatial alterations in targeted metabolites in the brain. Seven-day postnatal rats underwent the permanent ligation of the left common carotid artery followed by exposure to 8% O 2 for 2.5 hours. The pups were returned to normoxic conditions at either 38°C or 30°C for 3 hours. The brain metabolic states were rapidly fixed using in situ freezing. The profiling of 107 metabolites 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. Quantitative imaging mass spectrometry demarcated that hypothermia diminishes the acetylcholine contents specifically in hippocampus and amygdala. Such decreases were associated with an inverse increase in carnitine in the same anatomic regions. These findings imply that hypothermia achieves its neuroprotective effects by mediating the cellular acetylation status through a coordinated suppression of acetyl-CoA, which resides in metabolic junctions of glycolysis, amino-acid catabolism, and ketolysis.

Original languageEnglish
Pages (from-to)794-805
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number5
Publication statusPublished - 2015 May 5


  • acetylcholine (ACh)
  • carnitine
  • cerebral metabolism
  • hypoxia-ischemia (H-I)
  • neonate
  • quantitative imaging mass spectrometry (Q-IMS)
  • therapeutic hypothermia

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine


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