Di-acetyl creatine ethyl ester, a new creatine derivative for the possible treatment of creatine transporter deficiency

Enrico Adriano, Maurizio Gulino, Maria Arkel, Annalisa Salis, Gianluca Damonte, Nara Liessi, Enrico Millo, Patrizia Garbati, Maurizio Balestrino

Research output: Contribution to journalArticlepeer-review


Creatine is pivotal in energy metabolism of the brain. In primary creatine deficiency syndromes, creatine is missing from the brain. Two of them (AGAT and GAMT deficiency) are due to impaired creatine synthesis, and can be treated by creatine supplementation. By contrast, creatine transporter deficiency cannot be treated by such supplementation, since creatine crossing of biological membranes (plasma membrane and blood-brain barrier) is dependent on its transporter. This problem might be overcome by modifying the creatine molecule to allow it to cross biological membranes independently of its transporter. Thus, we designed and synthesized di-acetyl creatine ethyl ester (DAC), a compound that should cross biological membranes independently of the transporter due to its very high lipophilicity. We investigated its ability to increase intracellular creatine levels even after block of creatine transporter, and to counter cell damage induced by transporter block. In our experiments after block of the creatine transporter, DAC was able both to prevent electrophysiological failure and to increase intracellular creatine. Interestingly, it did so in micromolar concentrations, at variance with all the other creatine derivatives that we know of.

Original languageEnglish
Pages (from-to)217-223
Number of pages7
JournalNeuroscience Letters
Publication statusPublished - Feb 5 2018


  • Creatine
  • Creatine derivatives
  • Creatine transporter deficiency
  • Di-acetyl creatine ethyl ester

ASJC Scopus subject areas

  • Neuroscience(all)


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