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.
BACKGROUND
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.


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.


CONCLUSIONS
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.
Zlotnik
Alexander
A
Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben Gurion University, Beer Sheva, Israel.
Gruenbaum
Shaun E
SE
Artru
Alan A
AA
Rozet
Irene
I
Dubilet
Michael
M
Tkachov
Sergey
S
Brotfain
Evgeny
E
Klin
Yael
Y
Shapira
Yoram
Y
Teichberg
Vivian I
VI
D000818:Animals; D024443:Aspartate Aminotransferase, Cytoplasmic / Q000037:antagonists & inhibitors / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001784:Blood Gas Analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018698:Glutamic Acid / Q000097:blood*; D016489:Head Injuries, Closed / Q000188:drug therapy* / Q000523:psychology; D008297:Male; D008298:Maleates / Q000494:pharmacology*; D018696:Neuroprotective Agents; D062907:Oxaloacetic Acid / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D008298:Maleates; D018696:Neuroprotective Agents; D062907:Oxaloacetic Acid; D018698:Glutamic Acid; C030272:maleic acid; D024443:Aspartate Aminotransferase, Cytoplasmic