The neuroprotective effects of oxaloacetate in closed head injury in rats is mediated by its blood glutamate scavenging activity: evidence from the use of maleate.

Abstract

INTRODUCTION:

Treatment with oxaloacetate after traumatic brain injury has been shown to decrease blood glutamate levels and protect against the neurotoxic effects of glutamate on the brain. A number of potential mechanisms have been suggested to explain oxaloacetate-induced neuroprotection. We hypothesize that the primary mechanism by which intravenous oxaloacetate provides neuroprotection is by activation of the blood glutamate-scavenging enzyme glutamate-oxaloacetate transaminase, increasing thereby the driving force for the efflux of excess glutamate from brain interstitial fluids into blood. If so, coadministration of maleate, a glutamate-oxaloacetate transaminase-blocker is expected to prevent the neuroprotective effects of oxaloacetate.

MATERIALS AND METHODS:

A neurological severity score (NSS) was measured 1 hour after closed head injury (CHI) in rats. Then, rats received 30 microL/min/100 g infusion of saline, or 1 mmol/100 g solution of oxaloacetate, maleate, or a mixture of oxaloacetate and maleate. NSS was reassessed at 24 and 48 hour after CHI. Blood glutamate and glucose levels were measured at 0, 60, 90, and 120 minutes.

RESULTS:

NSS improved significantly at 24 hour (P<0.001) and 48 hour (P<0.001) only in the rats treated with oxaloacetate. Blood glutamate decreased significantly in the oxaloacetate-treated group at 90 minute (at the conclusion of oxaloacetate administration) (P<0.00001), but not in the control, maleate or oxaloacetate+maleate groups. A strong correlation r2=0.86 was found to exist between the percent decrease in blood glutamate levels and percent improvement in NSS.

DISCUSSION:

The results of this study demonstrate that the primary mechanism by which oxaloacetate provides neuroprotective activity after CHI is related to its blood glutamate scavenging activity. Management of blood glutamate concentration may have important implications in the treatment of acute brain conditions, including CHI and stroke.

• Authors: Alexander Zlotnik, Shaun E Gruenbaum, Alan A Artru, Irene Rozet, Michael Dubilet, Sergey Tkachov, Evgeny Brotfain, Yael Klin, Yoram Shapira, Vivian I Teichberg
• Journal: Journal of neurosurgical anesthesiology (J Neurosurg Anesthesiol) Vol. 21 Issue 3 Pg. 235-41 (Jul 2009) ISSN: 1537-1921 [Electronic] United States
• PMID: 19543002 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Maleates
• Neuroprotective Agents
• Oxaloacetic Acid
• Glutamic Acid
• maleic acid
• Aspartate Aminotransferase, Cytoplasmic

Topics

• Animals
• Aspartate Aminotransferase, Cytoplasmic (antagonists & inhibitors, metabolism)
• Behavior, Animal (drug effects)
• Blood Gas Analysis
• Enzyme Inhibitors (pharmacology)
• Glutamic Acid (blood)
• Head Injuries, Closed (drug therapy, psychology)
• Male
• Maleates (pharmacology)
• Neuroprotective Agents
• Oxaloacetic Acid (pharmacology)
• Psychomotor Performance (drug effects)
• Rats
• Rats, Sprague-Dawley