Effects of Delivering Guanidinoacetic Acid or Its Prodrug to the Neural Tissue: Possible Relevance for Creatine Transporter Deficiency.

Enrico Adriano,Enrico Millo,Annalisa Salis,Gianluca Damonte,Maurizio Balestrino

doi:10.3390/brainsci12010085

Enrico Adriano, Enrico Millo + Show 3 more

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https://doi.org/10.3390/brainsci12010085

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Abstract

The creatine precursor guanidinoacetate (GAA) was used as a dietary supplement in humans with no adverse events. Nevertheless, it has been suggested that GAA is epileptogenic or toxic to the nervous system. However, increased GAA content in rodents affected by guanidinoacetate methyltransferase (GAMT) deficiency might be responsible for their spared muscle function. Given these conflicting data, and lacking experimental evidence, we investigated whether GAA affected synaptic transmission in brain hippocampal slices. Incubation with 11.5 μM GAA (the highest concentration in the cerebrospinal fluid of GAMT-deficient patients) did not change the postsynaptic compound action potential. Even 1 or 2 mM had no effect, while 4 mM caused a reversible decrease in the potential. Guanidinoacetate increased creatine and phosphocreatine, but not after blocking the creatine transporter (also used by GAA). In an attempt to allow the brain delivery of GAA when there was a creatine transporter deficiency, we synthesized diacetyl guanidinoacetic acid ethyl ester (diacetyl-GAAE), a lipophilic derivative. In brain slices, 0.1 mM did not cause electrophysiological changes and improved tissue viability after blockage of the creatine transporter. However, diacetyl-GAAE did not increase creatine nor phosphocreatine in brain slices after blockage of the creatine transporter. We conclude that: (1) upon acute administration, GAA is neither epileptogenic nor neurotoxic; (2) Diacetyl-GAAE improves tissue viability after blockage of the creatine transporter but not through an increase in creatine or phosphocreatine. Diacetyl-GAAE might give rise to a GAA–phosphoGAA system that vicariates the missing creatine–phosphocreatine system. Our in vitro data show that GAA supplementation may be safe in the short term, and that a lipophilic GAA prodrug may be useful in creatine transporter deficiency.

Highlights

Creatine is of paramount importance in the energetic metabolism of excitable cells, where it serves both as a “shuttle” for rapidly transferring adenosine tri-phosphate (ATP)
Hereditary conditions where creatine is missing are attended by severe neurological symptoms including mental retardation, autism, speech disturbances, extrapyramidal movements, and epilepsy [5]
Endogenous synthesis of creatine takes place in two steps [1], which Figure 1 illustrates in a simplified way

Summary

Introduction

Hereditary conditions where creatine is missing are attended by severe neurological symptoms including mental retardation, autism, speech disturbances, extrapyramidal movements, and epilepsy [5]. Creatine is both taken up from the diet and synthesized by the body, both sources contributing to creatine turnover in normal subjects [1]. Endogenous synthesis of creatine takes place in two steps [1], which Figure 1 illustrates in a simplified way Both taken up from the diet and synthesized by the body, both uting to creatine turnover in normal subjects [1]. Endogenous sy place in two steps [1], which Figure 1 illustrates in a simplified w

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