TY - JOUR
T1 - Brain neuroprotection by scavenging blood glutamate
AU - Zlotnik, Alexander
AU - Gurevich, Boris
AU - Tkachov, Sergei
AU - Maoz, Ilana
AU - Shapira, Yoram
AU - Teichberg, Vivian I.
N1 - Funding Information:
This work was supported in part by grants to VIT from the Nella and Leon Benoziyo Center for Neurological Diseases; the Irwin Green Fund for Studying the Development of the Brain, the Yeshaya Horowitz Foundation, the Carl and Micaela Einhorn-Dominic Institute for Brain Research, the Weizmann-Negri Fund and the Israel Cancer Research Fund. The data obtained are part of A.Z.'s PhD thesis. VIT is the incumbent of the Louis and Florence Katz-Cohen Chair of Neuropharmacology.
PY - 2007/1/1
Y1 - 2007/1/1
N2 - 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.
AB - 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.
KW - Acute brain neurodegeneration
KW - Blood glutamate scavenging
KW - Brain glutamate levels
KW - Closed head injury
KW - Glutamate-oxaloacetate transaminase
KW - Neurological severity score
KW - Neuroprotection
KW - Oxaloacetate
KW - Spontaneous recovery
UR - http://www.scopus.com/inward/record.url?scp=33751417383&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2006.08.021
DO - 10.1016/j.expneurol.2006.08.021
M3 - Article
C2 - 17014847
AN - SCOPUS:33751417383
VL - 203
SP - 213
EP - 220
JO - Experimental Neurology
JF - Experimental Neurology
SN - 0014-4886
IS - 1
ER -