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