Human recombinant glutamate oxaloacetate transaminase 1 (GOT1) supplemented with oxaloacetate induces a protective effect after cerebral ischemia

Abstract

Blood glutamate scavenging is a novel and attractive protecting strategy to reduce the excitotoxic effect of extracellular glutamate released during ischemic brain injury. Glutamate oxaloacetate transaminase 1 (GOT1) activation by means of oxaloacetate administration has been used to reduce the glutamate concentration in the blood. However, the protective effect of the administration of the recombinant GOT1 (rGOT1) enzyme has not been yet addressed in cerebral ischemia. The aim of this study was to analyze the protective effect of an effective dose of oxaloacetate and the human rGOT1 alone and in combination with a non-effective dose of oxaloacetate in an animal model of ischemic stroke. Sixty rats were subjected to a transient middle cerebral artery occlusion (MCAO). Infarct volumes were assessed by magnetic resonance imaging (MRI) before treatment administration, and 24 h and 7 days after MCAO. Brain glutamate levels were determined by in vivo MR spectroscopy (MRS) during artery occlusion (80 min) and reperfusion (180 min). GOT activity and serum glutamate concentration were analyzed during the occlusion and reperfusion period. Somatosensory test was performed at baseline and 7 days after MCAO. The three treatments tested induced a reduction in serum and brain glutamate levels, resulting in a reduction in infarct volume and sensorimotor deficit. Protective effect of rGOT1 supplemented with oxaloacetate at 7 days persists even when treatment was delayed until at least 2 h after onset of ischemia. In conclusion, our findings indicate that the combination of human rGOT1 with low doses of oxaloacetate seems to be a successful approach for stroke treatmentThis project has been partially supported by grants from the Spanish Ministry of Economy and Competitiveness SAF2011-30517, Xunta de Galicia (Consellería Economía Industria: 10PXIB918282PR; and Consellería Educación: CN2011/010), Instituto de Salud Carlos III (PI11/00909 and CP12/ 03121), Spanish Research Network on Cerebrovascular Diseases RETICSINVICTUS (RD12/0014), Fundación Mutua Madrileña and by the European Union program FEDER. Furthermore, T. Sobrino and P. Ramos-Cabrer are recipients of a research contract from Miguel Servet Program of Instituto de Salud Carlos III. Sponsors did not participate in study design, collection, analysis and interpretation of the data, writing the report or in the decision to submit the paper for publication. P Menendez as an ICREA Research Professor of the Generalitat of Catalunya supported by ISCIII (PI10/00449 and PI12/03112)S

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