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.