Effect of glutamate and blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome and pathohistology of the hippocampus after traumatic brain injury in rats.

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. Four weeks after traumatic brain injury, a histologic analysis of surviving neurons was performed. RESULTS Oxaloacetate and pyruvate treatment groups demonstrated increased neuronal survival (oxaloacetate 2,200 ± 37, pyruvate 2,108 ± 137 vs. control 1,978 ± 46, P < 0.001, mean ± SD). Glutamate treatment revealed decreased neuronal survival (1,715 ± 48, P < 0.001). Treatment groups demonstrated favorable neurologic outcomes at 24 and 48 h (Neurological Severity Score at 24 and 48 h: 5.5 (1-8.25), 5 (1.75-7.25), P = 0.02 and 3(1-6.5), 4 (1.75-4.5), P = 0.027, median ± corresponding interquartile range). Blood glutamate concentrations were decreased in the oxaloacetate and pyruvate treatment groups. Administration of oxaloacetate and pyruvate was not shown to have any adverse effects. CONCLUSIONS The authors demonstrate that the blood glutamate scavengers oxaloacetate and pyruvate provide neuroprotection after traumatic brain injury, expressed both by reduced neuronal loss in the hippocampus and improved neurologic outcomes. The findings of this study may bring about new therapeutic possibilities in a variety of clinical settings.