Comments for:

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Response to Diez-Tejedor et al.

Submitter: José Sánchez-Prieto | jsprieto@vet.ucm.es

Authors: Ignacio Lizasoain, Maria Angeles Moro and Magdalena Torres

Universidad Complutense de Madrid

Published February 10, 2014

We welcome the criticism raised by Dr E Diez-Tejedor in a recent e-letter on our article in J Clin Invest 2013, 123 (10) 4359-4363 doi:10.1172/JCI67284 by Godino MC et al., on the neuroprotective effect of peritoneal dialysis on ischemic brain damage in rats, by accelerating brain-to-blood glutamate clearance  

In response to the comments raised, we point out the following:

1. First, it is stated that our results “suggest” that the treatment described could decrease the size of the infarct area in a rat model of stroke.  We have to point out that our article does suggest the utility of peritoneal dialysis in human stroke patients. The effect on infarct size in the rats stroke model, however, is clearly demonstrated.

2. In relation to the fact that glutamate levels are increased in various systemic acute pathologies such as pancreatitis, the rats used in our study were, to the best of our knowledge, healthy and they did not suffer from pancreatitis; therefore the increased  glutamate plasma levels observed were, in our study, directly associated to the occlusion of the middle cerebral artery (MCAO). Basal plasma levels of glutamate where 51.8 ± 2.6 μM (n = 21).

3.  Indeed,  PD can potentially clear from blood any permeable molecule due to the large concentration gradient existing between blood and the peritoneal cavity, particularly at time 0. However, the finding that the presence of glutamate in the peritoneal solution suffices to abolish the protection provided by PD strongly points to this amino-acid as the blood player related to the PD-induced protection from brain damage.

4. Related to point (iii), we used 400 mM glutamate in the peritoneum as a concentration large enough to counteract the maximal recorded glutamate concentration attained in the blood (around 120 mM). It should be kept in mind that this blood concentration could be even larger if, for example, the sampling did not coincide with the peak of glutamate in blood. For the aim of our study, the concentration used (400 mM), which is used during PD and not after PD as stated by the author of this e-letter, should be large enough to change the direction of the gradient and prevent the removal of glutamate –and ONLY glutamate- from blood. 

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Peritoneal dialysis in acute ischemic stroke

Submitter: Exuperio Díez-Tejedor | patrindalo@hotmail.com

Authors: María Gutiérrez-Fernández and Patricia Martínez-Sánchez

La Paz University Hospital

Published December 16, 2013

We have read with great interest the paper by Godino et al. published recently (1) in The Journal of Clinical Investigation. The authors developed a strategy based on peritoneal dialysis to reduce blood glutamate levels, suggesting that this treatment could decrease the size of the infarct area in a rat model of stroke.

Glutamate plasma concentrations are associated with stroke severity, as well as with early neurological worsening (2), infarct growth and volume of tissue at risk of infarction (3). However, glutamate plasma levels are not specific to brain ischemia, since glutamate is released after several stressful systemic stimuli in animals (4). Furthermore, glutamate levels are increased in various systemic acute pathologies such as acute pancreatitis (5). This may indicate that glutamate does not play a pathogenic role in brain ischemia, but rather is an unspecific marker of brain damage that is released in other non-neurological pathologies.

There are many other unspecific inflammation biomarkers that have been related to cerebral infarct severity and prognosis both in humans and rodents. IL-6 is associated with early neurological deterioration, greater infarct volumes and poor outcomes (6). Moreover, TNF-a, together with IL-1b, induces a secondary inflammatory response mediated by IL-6 and IL-8, which appears to exacerbate cerebral ischemic injury (6).

Taking into account the above, the study by Godino et al (1) has two limitations. First, peritoneal dialysis in a rat model of stroke could decrease not only blood levels of glutamate but the levels of many other inflammation biomarkers, such as cytokines and other neurotransmitters, which could be related to the reduction in cerebral infarct volume. It would be interesting to specifically analyze the blood levels of other biomarkers that are related with stroke size and prognosis. Second, the authors demonstrated that the addition of 400 µM of glutamate, which is almost ten times more than the amount accumulated in the dialysate after 1 hour of dialysis (59.2 ± 12.2 µM), abrogated the beneficial effect of peritoneal dialysis on cerebral infarct size. However, the authors did not explain why they chose that amount of glutamate to add after the dialysis. Perhaps it would be more appropriate to select an amount similar to that dialyzed. Moreover, the vehicle used to infuse the glutamate is not specified in the method section. The vehicle volume and composition could exert some effect on the size of the brain infarction, thus a control group of rats receiving only vehicle is mandatory.

Peritoneal dialysis could be related to a reduction in the size to the ischemic lesion in a rat model of stroke; however, the mechanism implicated in this effect, specifically the role of glutamate, needs to be clarified.

 

REFERENCES

1. Godino Mdel C, Romera VG, Sánchez-Tomero JA, Pacheco J, Canals S, Lerma J, Vivancos J, Moro MA, Torres M, Lizasoain I, Sánchez-Prieto J. Amelioration of ischemic brain damage by peritoneal dialysis. et al. ShowJ Clin Invest. 2013;123(10):4359-63.
2. Castillo J, Dávalos A, Noya M (1997) Progression of ischaemic stroke and excitotoxic amino acids. Lancet 349: 79–83.
3. Castellanos M, Sobrino T, Pedraza S, Moldes O, Pumar JM et al. (2008) High plasma glutamate concentrations are associated with infarct growth in acute ischemic stroke. Neurology 71:1862-8.
4. Singewald N, Zou GY, Schneider C. Release of excitatory and inhibitory amino acids from the locus coeruleus of conscious rats by cardiovascular stimuli and various forms of acute stress. Brain Res 1995;704, 42-50.
5. Zaporozchenko BS, Shilov VI. Changes in free amino acid plasma levels in patients with acute pancreatitis and their correction with early parenteral feeding. Klin Khir 2000; 1, 13-5.
6. Rodríguez-Yáñez M, Castillo J. Role of inflammatory markers in brain ischemia. Curr Opin Neurol 2008;21(3):353-7.