title: Brain neuroprotection by scavenging blood glutamate.
abstract: Excess glutamate in brain fluids characterizes acute brain insults such as traumatic brain injury and stroke. Its removal could prevent the glutamate excitotoxicity that causes long-lasting neurological deficits. As blood glutamate scavenging has been demonstrated to increase the efflux of excess glutamate from brain into blood, we tested the prediction that oxaloacetate-mediated blood glutamate scavenging causes neuroprotection in a pathological situation such as closed head injury (CHI), in which there is a well established deleterious increase of glutamate in brain fluids. We observed highly significant improvements of the neurological status of rats submitted to CHI following an intravenous treatment with 1 mmol oxaloacetate/100 g rat weight which decreases blood glutamate levels by 40%. No detectable therapeutic effect was obtained when rats were treated IV with 1 mmol oxaloacetate together with 1 mmol glutamate/100 g rat. The treatment with 0.005 mmol/100 g rat oxaloacetate was no more effective than saline but when it was combined with the intravenous administration of 0.14 nmol/100 g of recombinant glutamate-oxaloacetate transaminase, recovery was almost complete. Oxaloacetate provided neuroprotection when administered before CHI or at 60 min post CHI but not at 120 min post CHI. Since neurological recovery from CHI was highly correlated with the decrease of blood glutamate levels (r=0.89, P=0.001), we conclude that blood glutamate scavenging affords brain neuroprotection Blood glutamate scavenging may open now new therapeutic options.
authors.affiliation: Division of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zlotnik
authors.forename: Boris
authors.initials: B
authors.lastname: Gurevich
authors.forename: Sergei
authors.initials: S
authors.lastname: Tkachov
authors.forename: Ilana
authors.initials: I
authors.lastname: Maoz
authors.forename: Yoram
authors.initials: Y
authors.lastname: Shapira
authors.forename: Vivian I
authors.initials: VI
authors.lastname: Teichberg
mesh_terms: D000818:Animals; D024443:Aspartate Aminotransferase, Cytoplasmic / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001930:Brain Injuries / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004357:Drug Synergism; D018698:Glutamic Acid / Q000097:blood*; D007275:Injections, Intravenous; D008297:Male; D009410:Nerve Degeneration / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000378:metabolism; D062907:Oxaloacetic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D009498:Neurotoxins; D062907:Oxaloacetic Acid; D018698:Glutamic Acid; D024443:Aspartate Aminotransferase, Cytoplasmic