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

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. 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.

• Authors: Alexander Zlotnik, Igor Sinelnikov, Benjamin F Gruenbaum, Shaun E Gruenbaum, Michael Dubilet, Elena Dubilet, Akiva Leibowitz, Sharon Ohayon, Adi Regev, Matthew Boyko, Yoram Shapira, Vivian I Teichberg
• Journal: Anesthesiology (Anesthesiology) Vol. 116 Issue 1 Pg. 73-83 (Jan 2012) ISSN: 1528-1175 [Electronic] United States
• PMID: 22129535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Hemoglobins
• Oxaloacetic Acid
• Glutamic Acid
• Pyruvic Acid

Topics

• Animals
• Behavior, Animal (physiology)
• Blood Gas Analysis
• Blood Glucose (metabolism)
• Brain (pathology)
• Brain Injuries (pathology)
• Cell Survival (drug effects)
• Glutamic Acid (blood, pharmacology)
• Hemodynamics (physiology)
• Hemoglobins (metabolism)
• Hippocampus (injuries, pathology)
• Linear Models
• Male
• Neurologic Examination
• Neurons (drug effects, pathology)
• Oxaloacetic Acid (pharmacology)
• Pyruvic Acid (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Spectrometry, Fluorescence
• Treatment Outcome