title: Creatine salts provide neuroprotection even after partial impairment of the creatine transporter.
abstract: Creatine, a compound that is critical for energy metabolism of nervous cells, crosses the blood-brain barrier (BBB) and the neuronal plasma membrane with difficulty, and only using its specific transporter. In the hereditary condition where the creatine transporter is defective (creatine transporter deficiency) there is no creatine in the brain, and administration of creatine is useless lacking the transporter. The disease is severe and incurable. Creatine-derived molecules that could cross BBB and plasma membrane independently of the transporter might be useful to cure this condition. Moreover, such molecules could be useful also in stroke and other brain ischemic conditions. In this paper, we investigated three creatine salts, creatine ascorbate, creatine gluconate and creatine glucose. Of these, creatine glucose was ineffective after transporter block with guanidine acetic acid (GPA) administration. Creatine ascorbate was not superior to creatine in increasing tissue creatine and phosphocreatine content after transporter impairment, however even after such impairment it delayed synaptic failure during anoxia. Finally, creatine gluconate was superior to creatine in increasing tissue content of creatine after transporter block and slowed down PS disappearance during anoxia, an effect that creatine did not have. These findings suggest that coupling creatine to molecules having a specific transporter may be a useful strategy in creatine transporter deficiency. In particular, creatine ascorbate has effects comparable to those of creatine in normal conditions, while being superior to it under conditions of missing or impaired creatine transporter.
authors.affiliation: Department of Neuroscience, Ophthalmology, Genetics, Maternal-Infantile Sciences, University of Genova, Largo Paolo Daneo 3, 16132 Genova, Italy. Electronic address: adriano@neurologia.unige.it.
authors.forename: E
authors.initials: E
authors.lastname: Adriano
authors.affiliation: Department of Neuroscience, Ophthalmology, Genetics, Maternal-Infantile Sciences, University of Genova, Largo Paolo Daneo 3, 16132 Genova, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Garbati
authors.affiliation: Department of Hearth Environmental and Life Science (DISTAV), University of Genova, Corso Europa 26, 16132 Genova, Italy; Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 5, 16132 Genova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Salis
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy; Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 5, 16132 Genova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Damonte
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy; Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 5, 16132 Genova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Millo
authors.affiliation: Department of Neuroscience, Ophthalmology, Genetics, Maternal-Infantile Sciences, University of Genova, Largo Paolo Daneo 3, 16132 Genova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Balestrino
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000737:chemistry / Q000494:pharmacology*; D003401:Creatine / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D005942:Gluconates / Q000737:chemistry / Q000494:pharmacology*; D005947:Glucose / Q000737:chemistry / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D002534:Hypoxia, Brain / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D046509:Tissue Culture Techniques
chemical_list: D005942:Gluconates; D026901:Membrane Transport Proteins; D018696:Neuroprotective Agents; C080679:creatine transporter; D005947:Glucose; D003401:Creatine; D001205:Ascorbic Acid
keywords: creatine; creatine ascorbate; creatine gluconate; creatine glucose; creatine transporter deficiency; neuroprotection