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 treatment
Highlights
After ischemic stroke, there is a rapid but transient elevation of glutamate into the extracellular space followed by a marked increase in intracellular calcium, which provokes a neuronal death through an excitotoxicity mechanism.[2]
The efficacy of this strategy has been demonstrated in different types of ischemic animal models, and it has been tested in other pathologies associated with an increase in brain glutamate levels, such as traumatic brain injury (TBI)[4] or glioma[12] with successful results
We found that the i.v. administration of recombinant GOT1 (rGOT1) was able to induce a reduction in serum and brain glutamate levels, which resulted in a significant reduction in the infarct volume and improvement in the sensorimotor deficit after ischemia
Summary
There is a rapid but transient elevation of glutamate into the extracellular space followed by a marked increase in intracellular calcium, which provokes a neuronal death through an excitotoxicity mechanism.[2] calcium and glutamate antagonists have been widely studied as protective agents in experimental models of cerebral ischemia with encouraging results They failed or displayed severe adverse effects when they were tested in clinical trials.[3] because of the central role of glutamate in the ischemic cascade, the mitigation of glutamate excitotoxicity remains one of the most promising strategies for the development of effective treatments to minimize neurological damage following an acute ischemic stroke. In a previous retrospective study with 4400 human patients, we have found that ischemic patients with good outcome at 3 months after stroke, showed lower glutamate concentration and higher GOT activity (418 U/l) in serum.[8,9] it is tentative to postulate that treatments based on the administration of recombinant GOT1 (rGOT1) alone or supplemented with low doses of oxaloacetate could improve the protective effects of oxaloacetate administered on its own
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