Creatine and Creatinine Metabolism - Physiological Reviews

July 2000 CREATINE AND CREATININE METABOLISM 1169
the limited permeability of the blood-brain barrier for Cr.
Oral Cr supplementation also improved serum and urinary
Crn concentrations, brain guanidinoacetate concentration,
as well as EEG activity. Most importantly, Cr
supplementation resulted in substantial clinical improvement,
both with regard to muscle tone and extrapyramidal
symptoms. Although the plasma concentration of Cr
increased to supranormal levels (270–763 �M), the
plasma concentrations of guanidinoacetate and homoarginine
remained elevated even after 22 mo of Cr
supplementation (949). This is noteworthy for two reasons:
1) it cannot yet be excluded that guanidinoacetate
at the still elevated concentrations is neurotoxic and is
responsible, instead of Cr deficiency, for the neurological
symptoms associated with GAMT deficiency. 2) Increased
serum concentrations of Cr due to supplementation
should downregulate AGAT activity in kidney and pancreas
and therefore result in subnormal guanidinoacetate
concentrations. The opposite finding in a patient with
GAMT deficiency suggests that the serum concentration
of Cr may not be the sole signal for the downregulation of
AGAT activity (see sect. IV).
Four points deserve further consideration. 1) Despite
sharing the same primary defect, the three patients with
GAMT deficiency, for unknown reasons, displayed strikingly
different clinical symptoms. 2) Arginine restriction
of the diet for 15 days while maintaining Cr supplementation
tended to increase rather than decrease the plasma
concentration and urinary excretion of guanidinoacetate
(868). Therefore, early institution of Cr supplementation
is so far the only successful therapeutic strategy in GAMT
deficiency. 3) GAMT knock-out animals may become a
valuable model for studying the relevance of the CK system
at different developmental stages. Cr can be supplied
through the diet during both pregnancy and postnatal
development. At any developmental stage, Cr can be withdrawn
from the diet and the accompanying changes in
brain and muscle function studied. That Cr is in fact
provided to the fetus in utero is supported by the lack of
neurological symptoms in patients with GAMT deficiency
during the first few months of life and by the demonstration
of maternofetal transport of Cr in the rat (157). 4) Cr
supplementation may prove beneficial in other diseases
presenting with both neurological symptoms and reduced
tissue concentrations of Cr. For example, Cr excretion
was reported to be lowered in the hyperornithinemiahyperammonemia-homocitrullinuria
syndrome, which is
characterized by clinical symptoms such as vomiting,
lethargy, coma, seizures, ataxia, and various degrees of
mental retardation (189). Arg or citrulline supplementation
normalized Cr excretion and seemed to have favorable
clinical effects.
After these lines of evidence for a close correlation
between the functional capacity of the CK/PCr/Cr system
and brain function, let us now turn to (human) brain
diseases where the relationships between the derangements
of Cr metabolism and the pathological process are
less clear. Glutamate is the major excitatory neurotransmitter
in the vertebrate CNS. Whereas ATP-dependent
uptake of glutamate into synaptic vesicles is well documented,
it was only recently that glutamate uptake was
found to be stimulated also by PCr (1127). PCr stimulated
glutamate uptake into synaptic vesicles even in the absence
of added ATP, with an EC 50 of �10 mM. A series of
control experiments demonstrated that the effect of PCr
is CK independent and, thus, not due to local regeneration
of ATP. At a glutamate concentration of 50 �M, maximal
PCr-stimulated glutamate uptake was significantly higher
than that maximally stimulated by ATP. Mg 2� and Cl � ,
which potentiate the stimulation of glutamate uptake by
ATP, as well as inhibitors of ATP-dependent uptake had
little effect on PCr-dependent uptake activity. In conclusion,
ATP and PCr seem to stimulate glutamate uptake
into synaptic vesicles via two different, albeit unknown,
mechanisms, and both pathways are likely to contribute
additively to total glutamate uptake.
Glutamate neurotoxicity has been proposed as a
cause of neuronal death in a variety of diseases including
Alzheimer’s disease (AD). Although not in line with another
study (85), an in vivo 31 P-magnetic resonance spectroscopy
investigation of AD patients showed that PCr
levels are low in mildly demented AD patients and then
become increased as the dementia worsens (764; see also
Ref. 767). Significant correlations were also seen in AD
patients between [PCr]/[P i] and different neuropsychological
test results (910). Brown et al. (98) found a decreased
[PCr]/[P i] in both temporoparietal and frontal regions of
the AD brain relative to controls, but an increased [PCr]/
[P i] in the same brain regions of patients with multiple
subcortical cerebral infarction dementia (MSID). AD and
MSID are the two most common causes of cognitive
decline in the elderly. It remains to be seen whether and
how the CK system and the recently discovered role of
PCr in glutamate uptake would impact dementia.
In recent years, it has been realized that oxidative
stress may be a critical determinant of metabolic deterioration
in a variety of neurodegenerative diseases, e.g.,
Alzheimer’s disease, Parkinson’s disease, Huntington’s
disease, or amyotrophic lateral sclerosis (see, e.g., Refs.
76, 210, 230, 428, 471, 785, 866, 912, 915, 957, 1023, 1139).
The production of reactive oxygen species (ROS) and NO
as well as the brain concentrations of malondialdehyde,
protein carbonyls, and mitochondrial 8-hydroxydeoxyguanosine
are increased in these diseases, suggesting
stimulation of lipid peroxidation as well as oxidative protein
and DNA damage. Among other effects, oxidative
stress may compromise energy metabolism, which may
lead to activation of excitatory amino acid receptors and
to an increase in intracellular Ca 2� concentration. There
is evidence that CK may be one of the main targets of