Amelioration of ischemic brain damage by peritoneal dialysis

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 Ca²⁺ entry via NMDA receptors further promotes cell death by triggering an excitotoxic cascade that involves the activation of Ca²⁺-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.