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.
María del Carmen Godino, Victor G. Romera, José Antonio Sánchez-Tomero, Jesus Pacheco, Santiago Canals, Juan Lerma, José Vivancos, María Angeles Moro, Magdalena Torres, Ignacio Lizasoain, José Sánchez-Prieto
Submitter: José Sánchez-Prieto | email@example.com
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:
Submitter: Exuperio Díez-Tejedor | firstname.lastname@example.org
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.