No abstract

Background: Decreasing blood glutamate concentrations after traumatic brain injury accelerates brain-to-blood glutamate efflux, leading to improved neurologic outcomes. The authors hypothesize that treatment with blood glutamate scavengers should reduce neuronal cell loss, whereas administration of glutamate should worsen outcomes. The authors performed histologic studies of neuronal survival in the rat hippocampus after traumatic brain injury and treatment with blood glutamate scavengers. Methods: Traumatic brain injury was induced on anesthetized male Sprague-Dawley rats by a standardized weight drop. Intravenous treatment groups included saline (control), oxaloacetate, pyruvate, and glutamate. Neurologic outcome was assessed using a Neurological Severity Score at 1 h, and 1, 2, 7, 14, 21, 28 days. Blood glutamate was determined at baseline and 90 min.

Introduction Traumatic brain injury (TBI) is a major cause of death and disability worldwide. The deleterious effects of secondary brain injury may be attenuated by early pharmacological therapy in the emergency room and intensive care unit (ICU). Current medical management of acute TBI is primarily supportive, aimed at reducing intracranial pressure (ICP) and optimizing cerebral perfusion. There are no pharmacological therapies to date that have been unequivocally demonstrated to improve neurological outcomes after TBI. Objectives The purpose of this systematic review was to evaluate the recent clinical studies from January 2013 through November 2015 that investigated neuroprotective functional outcomes of pharmacological agents after TBI. Methods The following databases were searched for relevant studies: MEDLINE (OvidSP January Week 1, 2013–November Week 2 2015), Embase (OvidSP 2013 January 1–2015 November 24), and the unindexed material in PubMed (National Library of Medicine/National Institutes of Health [NLM/NIH]). This systematic review included only full-length clinical studies and case series that included at least five patients and were published in the English language. Only studies that examined functional clinical outcomes were included. Results Twenty-five of 527 studies met our inclusion criteria, which investigated 15 independent pharmacological therapies. Eight of these therapies demonstrated possible neuroprotective properties and improved functional outcomes, of which five were investigated with randomized clinical trials: statins, N-acetyl cysteine (NAC), Enzogenol, Cerebrolysin, and nitric oxide synthase inhibitor (VAS203). Three pharmacological agents did not demonstrate neuroprotective effects, and four agents had mixed results. Conclusions While there is currently no single pharmacological therapy that will unequivocally improve clinical outcomes after TBI, several agents have demonstrated promising clinical benefits for specific TBI patients and should be investigated further.

In previous studies, we have shown that by increasing the brain-to-blood glutamate efflux upon scavenging blood glutamate with either oxaloacetate or pyruvate, one achieves highly significant neuroprotection particularly in the context of traumatic brain injury. The current study examines, for the first time, how the blood glutamate scavenging properties of glutamate-pyruvate transaminase (GPT), alone or in combination with pyruvate, may contribute to the spectrum of its neuroprotective mechanisms and improve the outcome of rats exposed to brain ischemia, as they do after head trauma. Rats that were exposed to permanent middle cerebral artery occlusion (MCAO) and treated with intravenous 250 mg/kg pyruvate had a smaller volume of infarction and reduced brain edema, resulting in an improved neurological outcome and reduced mortality compared to control rats treated with saline. Intravenous pyruvate at the low dose of 31.3 mg/kg did not demonstrate any neuroprotection. However, when combined with 0.6 mg/kg of GPT there was a similar neuroprotection observed as seen with pyruvate at 250 mg/kg. Animals treated with 1.69 g/kg glutamate had a worse neurological outcome and a larger extent of brain edema. The decrease in mortality, infarcted brain volume and edema, as well as the improved neurological outcome following MCAO, was correlated with a decrease in blood glutamate levels. We therefore suggest that the blood glutamate scavenging activity of GPT and pyruvate contributes to the spectrum of their neuroprotective mechanisms and may serve as a new neuroprotective strategy for the treatment of ischemic stroke.