Creatine and Creatinine Metabolism - Physiological Reviews

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