Creatine salts provide neuroprotection even after partial impairment of the creatine transporter.

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.

Searching for a therapy of creatine transporter deficiency: some effects of creatine ethyl ester in brain slices in vitro.

Creatine, an ergogenic compound essential for brain function, is very hydrophilic and needs a transporter to cross lipid-rich cells' plasma membranes. Hereditary creatine transporter deficiency is a severe incurable neurological disease where creatine is missing from the brain. Creatine esters are more lipophylic than creatine and may not need the transporter to cross plasma membranes. Thus, they may represent a useful therapy for hereditary creatine transporter deficiency. Creatine ethyl ester (CEE) is commercially available and widely used as a nutritional supplement. It was reported that it enters the cells of patients lacking the transporter but was not useful when administered in vivo, by oral route, to affected patients. In this paper we investigated the effects of CEE in in vitro brain slices before and after biochemical block of the creatine transporter. We found that CEE is rapidly degraded in the aqueous incubation medium to creatinine, however it remains in solution long enough to cause an increase in tissue content of creatine and, more prominently, phosphocreatine. Both CEE and creatine delayed the anoxia-induced failure of synaptic transmission, and there was no difference between the two compounds. Contrary to what we expected, CEE did not increase tissue creatine content after the creatine transporter was blocked. We confirm that CEE is probably not an effective treatment for hereditary creatine transporter deficiency. Two factors seem to affect the possibility for creatine esters to be exploited in the therapy of creatine transporter deficiency. First, the size of their alcohol moiety should be increased since this would increase the lipophilicity of the compound and improve its ability to diffuse through biological membranes. Second, creatine esters should be further modified to slow their degradation to creatinine and increase their half-life in aqueous solutions. Moreover, we should not forget the possibility that they are degraded in vivo by plasma esterases.