Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
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1172 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80<br />
nal injection into rabbits (433). Crn also had convulsive<br />
activity after intracerebroventricular administration in<br />
mice (164). The relevance of these findings is questionable<br />
since intracisternal or intracerebroventricular injection<br />
cannot be compared directly with oral or intravenous<br />
administration of these compounds.<br />
In mouse spinal cord neurons in primary dissociated<br />
cell culture, Crn, MG, guanidine, GSA, <strong>and</strong> some other<br />
guanidino compounds depressed GABA <strong>and</strong> Gly responses<br />
in a concentration-dependent manner, possibly<br />
by blocking the chloride channel (164, 167). The accompanying<br />
reduction in GABA- <strong>and</strong> Gly-dependent inhibition<br />
may lead to epilepsy. GSA, in contrast to Crn, MG, <strong>and</strong><br />
guanidine, displayed significant effects at concentrations<br />
similar to those in cerebrospinal fluid <strong>and</strong> brain of uremic<br />
patients. The relative potencies with which the studied<br />
guanidino compounds depressed inhibitory amino acid<br />
responses corresponded with the relative potencies of the<br />
same compounds to induce epileptic symptomatology in<br />
behavioral experiments. MG, which is increased in uremia,<br />
may contribute to the neurological symptoms also by<br />
inhibiting acetylcholinesterase <strong>and</strong>/or Na � -K � -ATPase<br />
(609, 610).<br />
Some evidence suggests that guanidino compounds<br />
may exert their effects by influencing membrane fluidity.<br />
The lipid composition, including cholesterol concentration,<br />
is abnormal in epileptogenic whole brain tissue from<br />
cobalt lesions in animals, <strong>and</strong> dietary cholesterol appears<br />
to be inversely related to seizure susceptibility in animal<br />
models (see Ref. 696). Cholesterol administration normally<br />
is associated with a decrease in membrane fluidity<br />
(552, 705). Membranes from epileptogenic freeze-lesioned<br />
cat brain cortex displayed a lower order parameter (i.e.,<br />
slightly higher fluidity) than control membranes (696). In<br />
contradiction to these results, guanidino compounds including<br />
MG, GSA, guanidine, <strong>and</strong> GPA decrease synaptosomal<br />
membrane fluidity of rat cerebral cortex, whereas<br />
anticonvulsant drugs, including diazepam, valproic acid,<br />
<strong>and</strong> phenobarbital, increase the fluidity of synaptosomal<br />
membranes in hippocampus <strong>and</strong> whole brain (see Ref.<br />
361).<br />
Guanidino compounds may not only be a trigger of<br />
epileptic seizures, but may also change in concentration<br />
during <strong>and</strong> after convulsions. Already in 1940, Murray <strong>and</strong><br />
Hoffmann (680) noted that “in the instances of essential<br />
epilepsy studied, the basal content of ‘guanidine’ in the<br />
blood was found significantly high. All who presented<br />
convulsions of the gr<strong>and</strong> mal variety showed a blood<br />
guanidine rise during the aura reaching a high point during<br />
convulsion.” The levels of guanidinoacetate <strong>and</strong> Crn in<br />
cerebrospinal fluid increased at the onset of pentylenetetrazol-induced<br />
convulsion in the rabbit, while Arg started<br />
to decrease 2 h after the convulsion (360). Similarly, MG<br />
<strong>and</strong> guanidinoacetate levels in the rat brain were elevated<br />
for up to 3 mo after amygdala or hippocampal kindling,<br />
whereas Cr <strong>and</strong> Arg showed no significant change (362,<br />
885). In rodent, piglet, or dog brain, upon single <strong>and</strong><br />
repeated seizures induced by either electroshock, flurothyl,<br />
or pentylenetetrazol, or in bicuculline-induced status<br />
epilepticus, PCr concentration in the brain decreased<br />
with seizure activity (see Refs. 198, 373–375, 849). The<br />
change in PCr was associated with a corresponding increase<br />
in Cr content so that total Cr concentration remained<br />
constant. Although it is widely accepted that the<br />
Cr-to-N-acetylaspartate ratio is significantly elevated in<br />
patients with temporal lobe epilepsy (e.g., Refs. 136, 146,<br />
385, 761), it is not yet clear whether total Cr concentration<br />
in the brain is also increased (146) or unchanged (2, 761,<br />
1034). In conclusion, the evidence for relationships between<br />
alterations in Cr metabolism <strong>and</strong> neurological<br />
symptoms in uremia is indirect <strong>and</strong> incomplete at present<br />
<strong>and</strong>, thus, needs further substantiation in the future.<br />
Although guanidino compounds may have adverse<br />
effects on the nervous system in uremia, oral Cr (or cCr)<br />
supplementation is very unlikely to induce neurological<br />
complications in normal individuals, since only slight alterations<br />
in cerebrospinal fluid <strong>and</strong> brain concentrations<br />
of guanidino compounds may be expected. Cr <strong>and</strong> its<br />
analogs have been given to animals in high amounts <strong>and</strong><br />
over several weeks <strong>and</strong> months with no neurological side<br />
effects. Likewise, oral Cr supplementation in humans<br />
with up to 30 g/day for several days as well as cCr administration<br />
in a phase I/II clinical study in gram amounts per<br />
day over an extended period of time also had no adverse<br />
neurological effects.<br />
Finally, disturbances in Cr or guanidino compound<br />
metabolism were also seen in AIDS dementia (86); in<br />
patients with affective disorders, where, for example, Crn<br />
concentration in the cerebrospinal fluid was suggested to<br />
be negatively correlated with suicidal ideation <strong>and</strong> appetite<br />
(467, 704, 880); in hyperargininemic patients (595,<br />
596); in the human brain after acute stroke (284); in brain<br />
tumors such as gliomas, astrocytomas, <strong>and</strong> meningiomas<br />
(488, 594); in the brain of dystrophin-deficient mdx mice<br />
(1014); in audiogenic sensitive rats (1103); or in rats intoxicated<br />
with the neurotoxins ethylene oxide or acrylamide<br />
(612).<br />
In summary, brain function seems to be linked in a<br />
number of different ways with the CK system <strong>and</strong> with Cr<br />
metabolism, although the causal relationships in many<br />
cases are not yet known. Preliminary data suggest that<br />
both Cr <strong>and</strong> Cr analogs may have a therapeutic potential<br />
in brain disease. Cr supplementation, despite relatively<br />
slow uptake of Cr into the brain, may be indicated in<br />
diseases characterized by decreased brain concentrations<br />
of Cr or slowed PCr recovery. Cr <strong>and</strong> its analogs may also<br />
turn out to have therapeutic effects in neurodegenerative<br />
diseases associated with oxidative stress, such as Alzheimer’s<br />
disease, Parkinson’s disease, or amyotrophic lateral<br />
sclerosis.