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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

Zlotnik, Alexander MD*; Gruenbaum, Shaun E. BS*; Artru, Alan A. MD; Rozet, Irene MD; Dubilet, Michael MD*; Tkachov, Sergey MD*; Brotfain, Evgeny MD*; Klin, Yael MSc; Shapira, Yoram MD, PhD*; Teichberg, Vivian I. PhD

Journal of Neurosurgical Anesthesiology: July 2009 - Volume 21 - Issue 3 - p 235-241
doi: 10.1097/ANA.0b013e3181a2bf0b
Laboratory Investigations

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 μL/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 r 2=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.

*Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben Gurion University, Beer Sheva

Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel

Department of Anesthesiology, University of Washington, Seattle, WA

Reprints: Alan A. Artru, MD, Department of Anesthesiology, University of Washington, Seattle, WA (e-mail: artruaa@u.washington.edu).

Received for publication July 21, 2008; accepted February 25, 2009

© 2009 Lippincott Williams & Wilkins, Inc.