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, 31 (6), 1378-86

Neuroprotection by Glutamate Oxaloacetate Transaminase in Ischemic Stroke: An Experimental Study

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Neuroprotection by Glutamate Oxaloacetate Transaminase in Ischemic Stroke: An Experimental Study

Francisco Campos et al. J Cereb Blood Flow Metab.

Abstract

As ischemic stroke is associated with an excessive release of glutamate into the neuronal extracellular space, a decrease in blood glutamate levels could provide a mechanism to remove it from the brain tissue, by increasing the brain-blood gradient. In this regard, the ability of glutamate oxaloacetate transaminase (GOT) to metabolize glutamate in blood could represent a potential neuroprotective tool for ischemic stroke. This study aimed to determine the neuroprotective effects of GOT in an animal model of cerebral ischemia by means of a middle cerebral arterial occlusion (MCAO) following the Stroke Therapy Academic Industry Roundtable (STAIR) group guidelines. In this animal model, oxaloacetate-mediated GOT activation inhibited the increase of blood and cerebral glutamate after MCAO. This effect is reflected in a reduction of infarct size, smaller edema volume, and lower sensorimotor deficits with respect to controls. Magnetic resonance spectroscopy confirmed that the increase of glutamate levels in the brain parenchyma after MCAO is inhibited after oxaloacetate-mediated GOT activation. These findings show the capacity of the GOT to remove glutamate from the brain by means of blood glutamate degradation, and suggest the applicability of this enzyme as an efficient and novel neuroprotective tool against ischemic stroke.

Figures

Figure 1
Figure 1
Coculture of astrocytes and endothelial cells used in the study. (A) Schematic drawing of the noncontact coculture of rat endothelial cells with rat astrocytes. Astrocytes were grown on the top of the well and the endothelial cells in transwell. (B) Immunocytochemistry of endothelial cells stained with von Willebrand factor. Nuclei were counterstained with Hoechst. (C) Western blot analysis of the expression of occludin and ZO-1 proteins, in the endothelial cells (E), and rat brain cortex (C). Rat brain cortex was used as positive control. ZO-1, Zonula occludens protein-1.
Figure 2
Figure 2
Excitatory amino-acid transporters (EAATs) protein expresion in rat endothelial cells. Western blot analysis shows the expression of EAAT1 and EAAT3, but not EAAT2, in endothelial cells (E). Tissue from the brain cortex (C) was used as positive control of EAATS.
Figure 3
Figure 3
Doses–reponse effect of oxaloacetate on blood glutamate (A) and aspartate (B) levels. The treatment with oxaloacetate 3.5 mg/100 g (intravenously) (n=4) induces a greater reduction in blood glutamate levels and increase in aspartate than the dose of 1.5 mg/100 g (intravenously) (n=3). Glutamate and aspartate data are shown as mean±s.e.m. of percentage with respect to basal levels (considered as 100%).
Figure 4
Figure 4
Time course of blood glutamate levels in control (n=10) and treated (n=10) middle cerebral arterial occlusion (MCAO) animals. The treatment with oxaloacetate 3.5 mg/100 g (intravenously) induces a reduction in blood glutamate levels. Glutamate levels are presented as mean±s.e.m.
Figure 5
Figure 5
Infarct size and edema development were assessed by means of magnetic resonance image (MRI). Diffusion-weighted images (DWI) were acquired immediately after removing the suture from the animal (90 minutes after the occlusion); T2-weighted (T2-W) images were acquired at 24 hours, 3 days, and 7 days after ischemia onset (A). (B) The time course of infarct volumes. Treated middle cerebral arterial occlusion (MCAO) animals (n=10) had smaller infarct volumes than control animals (n=10). (C) The time course of the edema volumes decreases in control and treated groups after MCAO. Edema volume decrease in the MCAO-treated animals during the first 7 days. Infarct volumes (% of ipsilesional hemispheric volume) and edema (% ipsilesional versus contralesional hemispheric volumes) are shown as mean±s.e.m.
Figure 6
Figure 6
Magnetic resonance spectroscopy (MRS) studies. (A) The brain region where the cubic voxel of 3 × 3 × 3 mm3 (27 μL) was located. (B) The spectra that corresponded to control and treated animals at 3 hours after occlusion. The quantitative analysis of glutamate signals were normalized to creatine peaks for each single expectrum. Brain glutamate levels were lower in treated middle cerebral arterial occlusion (MCAO) animals. (C) The time course of brain glutamate levels in control (n=10) and treated (n=10) MCAO animals. Treated animals showed lower brain glutamate levels. Glutamate is shown as mean±s.e.m. of percentage with respect to basal levels (considered as 100%).

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