Creatine and Creatinine Metabolism - Physiological Reviews

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1168 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80 occur in particular between 12 and 17 days of age (see Ref. 377). Interestingly, in this same developmental interval, the proportion of Mi-CK and the flux through the CK reaction increase by a factor of 4 (377, 1018). On the other hand, both CK activity and flux through the CK reaction were shown to be decreased in aged rats and humans (see Ref. 909), and it is tempting to speculate that this may correlate with the cognitive decline in the elderly. In rats in which EEG activity was varied over a fivefold range by either bicuculline stimulation or thiopental inhibition, the forward rate constant of the CK reaction (k f) measured by 31 P-NMR saturation transfer was linearly correlated with EEG intensity (849). A linear correlation was also observed in the brain between k f and the accumulation of deoxyglucose-6-phosphate after intraperitoneal administration of deoxyglucose, which is a measure of glucose uptake and utilization in brain. In contrast, brain ATP concentration remained constant over the whole range of EEG intensities studied, and PCr concentration only decreased at high EEG intensities. These findings suggest that k f is a more sensitive and reliable indicator of brain activity than [ATP] or [PCr]. In a similar study on the rat brain, the dihydropyridine calcium antagonist isradipine slowed ATP depletion during global ischemia, which was paralleled by a decrease in the flux through the CK reaction by �25% (825). By increasing the ATP-regenerating capacity via the CK reaction before oxygen deprivation, it might be possible to delay ATP depletion and, thereby, to protect the brain from ischemic or anoxic damage. As a matter of fact, in hippocampal slices of the guinea pig brain exposed to 5–30 mM Cr for 0.5–3 h before anoxia, PCr accumulation in the slices increased with Cr concentration and incubation time, synaptic transmission measured with electrophysiological methods survived up to three times longer during anoxia, and postanoxic recovery of both high-energy phosphates and of the postsynaptic potential was considerably improved relative to control slices (see Refs. 563, 730). Similarly, preincubation of rat neocortical slices with 25 mM Cr for �2 h had a pronounced protective effect on excitatory and inhibitory synaptic transmission during brief periods of hypoxia (579), and preincubation of rat hippocampal slices with 0.03–25 mM Cr slowed ATP depletion, prevented the impairment of protein synthesis, reduced neuronal death during anoxia in a dose-dependent manner, and delayed anoxic depolarization (43, 112). In brain stem slices of Cr-pretreated neonatal mice, and in slices of nonpretreated neonatal mice incubated for 3 h with 0.2 mM Cr, ATP depletion was delayed and hypoglossal activity enhanced and stabilized relative to controls during 30 min of anoxia (1105). The susceptibility to seizures is highest in human term newborns and 10- to 12-day-old rats, and it has been suggested that the low Cr and PCr concentrations in the metabolically immature brain may critically influence susceptibility to hypoxic seizures (376). As a matter of fact, injection of Cr into rat pups for 3 days before exposing them to hypoxia on postnatal day 10 increased brain PCr-to-nucleoside triphosphate ratios, decreased hypoxia-induced seizures and deaths, and enhanced brain PCr and ATP recoveries after hypoxia. As in skeletal muscle and heart (see sects. VIIIA and IXC), long-term feeding of mice with the Cr analog cCr increased the total high-energy phosphate pool in the brain and slightly delayed ATP depletion during brain ischemia (1119), but did not improve the hypoxic survival time of the mice (30). The rate of cCr accumulation in the brain was relatively slow when the compound was supplied in the diet but could be increased by circumventing the blood-brain barrier, or when the compound was given intravenously (R. Kaddurah-Daouk, unpublished data). Feeding of mice with the Cr analog GPA resulted in the accumulation of PGPA, decreased the flux through the CK reaction in the brain in vivo by �75%, and enhanced survival during hypoxia (371, 372, 374). Recently, GAMT deficiency was identified as the first inborn error of Cr metabolism in three children presenting with neurological symptoms (276, 867, 946–949). One of the male patients exhibited an extrapyramidal movement disorder starting at the age of 5 mo. At the age of 22 mo, he displayed severe muscular hypotonia and developmental delay. The EEG showed abnormally low background activity with multifocal spikes. Another patient, a girl aged 4 yr, presented a dystonic-dyskinetic syndrome, developmental delay, and epilepsy with myoclonic and astatic seizures and grand mal. The third patient, a 5-yrold boy, displayed global developmental delay and experienced frequent tonic seizures, associated with apnea. GAMT deficiency was identified as the underlying metabolic basis of the disease by finding considerably increased brain, cerebrospinal fluid, serum, and urine concentrations of guanidinoacetate; low Cr concentrations in plasma, cerebrospinal fluid, and urine; a virtual absence of Cr and PCr in the brain (0.2–0.3 vs. 5.1–5.5 mM in controls); strongly depressed Crn concentrations in serum and urine; as well as a drastically reduced GAMT activity in liver biopsies (0.5–1.35 vs. 36.4 nmol � h �1 � g �1 in controls). In addition, oral supplementation with Arg resulted in an increase in brain guanidinoacetate concentration but did not elevate cerebral Cr levels. The nucleic acid mutations causing GAMT deficiency were characterized and include base substitutions, insertions, and deletions (948). Oral supplementation with 4–8 g Cr/day or 2 g � kg �1 � day �1 slowly normalized the concentration of Cr in the brain (276, 867, 946, 947). After 6 wk, brain Cr had reached almost 50% of its normal concentration, whereas after 25 mo on treatment, brain [Cr] was nearly normal. The slow increase in brain [Cr] is a further indication for
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
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