So get your doctors working on a clinical trial. Or are they the lazy type?
http://www.jci.org/articles/view/67284?key=13390aa9d60cae59e3d4
Ischemic
stroke is a devastating condition, for which there is still no
effective therapy. Acute ischemic stroke is associated with high
concentrations of glutamate in the blood and interstitial brain fluid.
The inability of the tissue to retain glutamate within the cells of the
brain ultimately provokes neuronal death. Increased concentrations of
interstitial glutamate exert further excitotoxic effects on healthy
tissue surrounding the infarct zone. We developed a strategy based on
peritoneal dialysis to reduce blood glutamate levels, thereby
accelerating brain-to-blood glutamate clearance. In a rat model of
stroke, this simple procedure reduced the transient increase in
glutamate, consequently decreasing the size of the infarct area.
Functional magnetic resonance imaging demonstrated that the rescued
brain tissue remained functional. Moreover, in patients with kidney
failure, peritoneal dialysis significantly decreased glutamate
concentrations.
Our results suggest that peritoneal dialysis may
represent a simple and effective intervention for human stroke patients.
Introduction
Stroke
is one of the leading causes of death and disability worldwide, for
which no effective neuroprotective therapy exists. Ischemic brain damage
is triggered by excessive release of the excitatory neurotransmitter
l-glutamate (
1,
2)
as a result of energy failure and ion gradient collapse, resulting in a
reversal of glutamate uptake via glutamate transporters (
3,
4). Excessive glutamate-evoked Ca
2+ entry via NMDA receptors further promotes cell death by triggering an excitotoxic cascade that involves the activation of Ca
2+-dependent enzymes, the disruption of mitochondrial function, and cell necrosis or apoptosis (
5).
Despite intense research efforts, suitable pharmacological strategies
to enhance neuroprotection of ischemic tissues remain elusive (
6),
partly because pharmacotherapy tends to target a single step of the
complex excitotoxic cascade and it does not distinguish between damaged
and healthy tissue.
After acute ischemic stroke, there is an increase in glutamate levels in the blood (
7), most likely due to enhanced brain-to-blood efflux (
8,
9) that is driven by increased interstitial glutamate concentrations (
10).
We reasoned that peritoneal dialysis could decrease the blood levels of
glutamate, thereby minimizing the interstitial glutamate in the brain
and curtailing ischemia-induced brain damage (
8,
9).
Results and Discussion
We
investigated the hypothesis that peritoneal dialysis could decrease the
blood levels of glutamate, thereby minimizing brain damage in a model
of brain ischemia in which rats were subjected to permanent middle
cerebral artery occlusion (pMCAO) (Figure
1A). The concentration of glutamate transiently increased in plasma 4.5 and 5.5 hours after ischemia (pMCAO; Figure
1B), and a corresponding cerebral infarct of 23.3% ± 1.3% (
n = 9) was observed 24 hours after pMCAO (Figure
1,
D and E). Peritoneal dialysis is a procedure used to treat patients
with severe chronic kidney disease, whereby fluids and dissolved
substances are exchanged between the blood and the dialysate across the
peritoneum (
11,
12).
In rats subjected to pMCAO, peritoneal dialysis 2.5 hours after pMCAO
significantly attenuated the increase in plasma glutamate induced by
ischemia (pMCAO plus dialysis at 2.5 hours; Figure
1B),
and, importantly, this decrease in plasma glutamate levels was
associated with a significant reduction in the volume of cerebral
infarct (12.1% ± 2.2%,
n = 5,
P < 0.001) (Figure
1,
D and E). Confirming that rat peritoneal dialysis leads to a reduction
of plasma glutamate, we found that the accumulated glutamate in the
dialysate after 1 hour of dialysis was 59.2 ± 12.2 μM (
n = 8). As
a control, we added glutamate to the dialysate infusion to cancel the
concentration gradient for glutamate, therefore preventing its clearance
from the blood. Indeed, the addition of glutamate (400 μM) to the
dialysate abolished the glutamate clearance observed following
peritoneal dialysis, resulting in a significant increase in blood
glutamate concentration after pMCAO (pMCAO plus dialysis at 2.5 hours
plus 400 μM glutamate; Figure
1C) and, importantly, abrogated the beneficial effect of peritoneal dialysis on cerebral infarct size (Figure
1D).
In sham-operated rats, in which middle cerebral arteries were exposed
but not occluded, no changes in plasma glutamate concentration were
detected (Figure
1C) and no cerebral infarct was observed (Figure
1D). The changes in plasma glutamate correlated well with the size of cerebral infarct measured 24 hours after insult (
r2 = 0.5312,
P = 0.0021; Figure
1E).
We also observed that peritoneal dialysis is equally efficient in
reducing the infarct volume when starting 5 hours after pMCAO (15.0% ±
1.2%,
n = 7,
P < 0.01; Figure
1, A and D), as plasma glutamate at 5.5 hours after pMCAO is still high and close to maximal levels (Figure
1B).
These data indicate that by decreasing the glutamate concentration in
the blood, peritoneal dialysis effectively promotes brain-to-blood
glutamate efflux (
9), minimizing the ischemic increase in extracellular glutamate and the resulting tissue damage.
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