Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
You also want an ePaper? Increase the reach of your titles
YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.
1170 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80<br />
oxidative damage. CK isoenzymes invariably have a highly<br />
reactive sulfhydryl group in the active site (Cys-283 of<br />
human B-CK), oxidative modification of which results in<br />
pronounced or even complete inhibition of the enzyme<br />
(see Ref. 275). Most probably by attacking this reactive<br />
sulfhydryl group, ROS like the hydroxyl radical, superoxide<br />
radical, H 2O 2, NO, or peroxynitrite inactivate CK (see<br />
sect. IXC). �-Amyloid peptide (A�), which forms the core<br />
of AD-associated senile (amyloid) plaques <strong>and</strong> is postulated<br />
to be a major determinant of AD, promotes protein<br />
oxidation <strong>and</strong> causes irreversible inhibition of CK at concentrations<br />
that are toxic to cultured neurons (355, 1139).<br />
Accordingly, CK activity is decreased in AD brain by up to<br />
86% (see Refs. 9, 154, 908). A comparable increase in<br />
protein oxidation <strong>and</strong> decrease in brain CK activity was<br />
observed in Pick’s disease <strong>and</strong> diffuse Lewy body disease<br />
(9). The mechanism of CK inhibition by A� is not yet<br />
understood. A� can fragment <strong>and</strong> generate peptide-derived<br />
free radicals that may then exert an inhibitory effect<br />
(355, 1139). Alternatively, Met-35 of A� was reported to be<br />
oxidized to methionine sulfoxide presumably via a free<br />
radical oxidation process. In vitro, methionine sulfoxide<br />
in fact inhibits CK activity irreversibly (324). In the light of<br />
the unphysiologically high methionine sulfoxide concentration<br />
of 20 mM used, the physiological relevance of this<br />
finding must, however, be questioned. David et al. (154)<br />
observed that despite an 86% decrease in CK activity, the<br />
quantity of immunodetectable CK protein is virtually unchanged<br />
in AD brain [although Aksenova et al. (9) found<br />
a decrease in BB-CK content in frontal cortex], that inactivation<br />
is due most probably to modification at the active<br />
site of the enzyme, <strong>and</strong> that the modified, inactive CK,<br />
rather than being soluble in the cytosol, is mostly associated<br />
with particulate subcellular structures from which it<br />
can be extracted in part by detergents. In cultured rat<br />
hippocampal neurons, the antioxidant vitamin E was<br />
shown to protect from A�-(25O35)-induced protein oxidation,<br />
CK inactivation, <strong>and</strong> neuronal toxicity (1139).<br />
If impairment of high-energy phosphate metabolism<br />
plays a critical role in the progression of neurodegenerative<br />
disease, then compounds that increase the cerebral<br />
energy reserve may be neuroprotective. Recently, a series<br />
of experiments were conducted where Cr <strong>and</strong> some of its<br />
analogs were evaluated in animal models of Huntington’s<br />
disease, Parkinson’s disease, <strong>and</strong> amyotrophic lateral<br />
sclerosis. In the animal models for Huntington’s disease,<br />
oral Cr or cCr supplementation produced significant protection<br />
against malonate lesions, <strong>and</strong> Cr protected against<br />
3-nitropropionic acid (3-NP) neurotoxicity, whereas cCr<br />
did not (182, 616). Cr supplementation decreased the<br />
volume of lesions produced by subacute systemic administration<br />
of 3-NP to rats by �80%. With regard to the<br />
mechanism of action by which Cr exerts its neuroprotective<br />
effect, the following findings were made: 1) decreases<br />
in the concentrations of Cr, PCr, ATP, GDP, AMP, NAD,<br />
<strong>and</strong> ADP plus GTP, which are known to be induced by<br />
3-NP, were attenuated significantly in Cr-fed animals. 2)<br />
Cr protected against 3-NP-induced increases in striatal<br />
lactate concentrations in vivo. 3) Cr protected against<br />
malonate-induced increases in the conversion of salicylate<br />
to 2,3- <strong>and</strong> 2,5-dihydroxybenzoic acid, biochemical<br />
markers of hydroxyl radical generation. 4) Cr protected<br />
against 3-NP-induced increases in 3-nitrotyrosine concentration,<br />
a marker of peroxynitrite-mediated oxidative injury.<br />
5) In cortical <strong>and</strong> striatal astrocytes in vitro, Cr<br />
pretreatment delayed increases in intracellular Ca 2� produced<br />
by 3-NP. It seems that by attenuating or delaying<br />
ATP depletion, Cr <strong>and</strong> some of its analogs prevent a<br />
pathological cascade that leads to free radical generation<br />
<strong>and</strong> eventual cell death. Alternatively, Cr <strong>and</strong> its analogs<br />
could regulate the mitochondrial permeability transition<br />
pore, a mitochondrial protein complex that was implicated<br />
with cell death (717).<br />
In the MPTP model of Parkinson’s disease, Cr or cCr<br />
supplementation produced significant protection against<br />
MPTP-induced depletion of dopamine <strong>and</strong> of its metabolites<br />
in the substantia nigra of mice (615). Both Cr <strong>and</strong> cCr<br />
also attenuated MPTP-induced degeneration of Nisslstained<br />
<strong>and</strong> tyrosine hydroxylase-immunostained neurons.<br />
In a transgenic mouse model of amyotrophic lateral<br />
sclerosis with a G93A superoxide dismutase-1 mutation,<br />
oral supplementation with Cr dose-dependently improved<br />
motor performance <strong>and</strong> extended survival even more<br />
than the approved drug riluzole or any other agent tested<br />
to date (489). Cr protected the transgenic mice from loss<br />
of both motor neurons <strong>and</strong> substantia nigra neurons <strong>and</strong><br />
from increases in biochemical indices of oxidative damage.<br />
In preliminary studies in Huntington’s disease patients,<br />
Cr seems to favorably impact brain energetics <strong>and</strong><br />
to reduce lactate production (Beal et al., unpublished<br />
data). These studies all suggest that Cr <strong>and</strong> its analogs<br />
may emerge as a new class of neuroprotective agents.<br />
Multiple sclerosis (MS) is an inflammatory disease<br />
causing multiple plaques of demyelination, predominantly<br />
in white matter. The results published so far on the disturbances<br />
of Cr metabolism in MS brain are contradictory.<br />
Although the PCr/ATP ratio was reported to be<br />
decreased in one patient with a large lesion, but unchanged<br />
in four patients without lesions (106), it was<br />
suggested to be increased in another study (647). A 35%<br />
decrease in Cr concentration in MS plaques <strong>and</strong> normalappearing<br />
white matter adjacent to plaques was observed<br />
in the postmortem MS brain (156). Total Cr was also<br />
decreased in MS plaques of children (100). On the other<br />
h<strong>and</strong>, total Cr <strong>and</strong> PCr concentration were found by Husted<br />
et al. (392) to be significantly increased in normalappearing<br />
white matter of MS patients compared with<br />
controls. In this same study, total Cr was also increased in<br />
MS lesions. In an investigation of different brain regions<br />
of patients with relapsing-remitting MS, [Cr] was found to