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Neurosci Lett. 2018 Feb 5;665:217-223. doi: 10.1016/j.neulet.2017.12.020. Epub 2017 Dec 8.

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

Author information

1
Department of Neuroscience, Ophthalmology, Genetics, Maternal-Infantile Sciences (DINOGMI), University of Genova, Largo Paolo Daneo 3, 16132 Genova, Italy.
2
Department of Experimental Medicine (DIMES), Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy; Center of Excellence for Biomedical Research (CEBR), University of Genova, Viale Benedetto XV 5, 16132 Genova, Italy.
3
Department of Hearth Environmental and Life Science (DISTAV), University of Genova, Corso Europa 26, 16132 Genova, Italy; Center of Excellence for Biomedical Research (CEBR), University of Genova, Viale Benedetto XV 5, 16132 Genova, Italy.
4
Center of Excellence for Biomedical Research (CEBR), University of Genova, Viale Benedetto XV 5, 16132 Genova, Italy.
5
Ospedale Policlinico San Martino, Genova, Italy.
6
Department of Neuroscience, Ophthalmology, Genetics, Maternal-Infantile Sciences (DINOGMI), University of Genova, Largo Paolo Daneo 3, 16132 Genova, Italy; Ospedale Policlinico San Martino, Genova, Italy. Electronic address: mbalestrino@neurologia.unige.it.

Abstract

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.

KEYWORDS:

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

PMID:
29229397
DOI:
10.1016/j.neulet.2017.12.020
[Indexed for MEDLINE]

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