title: Ceftriaxone modulates uptake activity of glial glutamate transporter-1 against global brain ischemia in rats.
abstract: Ceftriaxone(Cef) selectively increases the expression of glial glutamate transporter-1 (GLT-1), which was thought to be neuroprotective in some circumstances. However, the effect of Cef on glutamate uptake of GLT-1 was mostly assayed using in vitro studies such as primary neuron/astrocyte cultures or brain slices. In addition, the effect of Cef on neurons in different ischemic models was still discrepant. Therefore, this study was undertaken to observe the effect of Cef on neurons in global brain ischemia in rats, and especially to provide direct evidence of the up-regulation of GLT-1 uptake for glutamate contributing to the neuronal protection of Cef against brain ischemia. Neuropathological evaluation indicated that administration of Cef, especially pre-treatment protocols, significantly prevented delayed neuronal death in hippocampal CA1 subregion normally induced by global brain ischemia. Simultaneously, pre-administration of Cef significantly up-regulated the expression of GLT-1. Particularly, GLT-1 uptake assay with (3) H-glutamate in living cells from adult rats showed that up-regulation in glutamate uptake accompanied up-regulated GLT-1 expression. Inhibition of GLT-1 by antisense oligodeoxynucleotides or dihydrokainate significantly inhibited the Cef-induced up-regulation in GLT-1 uptake and the neuroprotective effect against global ischemia. Thus, we may conclude that Cef protects neurons against global brain ischemia via up-regulation of the expression and glutamate uptake of GLT-1. Glutamate uptake by glial glutamate transporter-1 (GLT-1) is the principal way to regulate extracellular glutamate homeostasis in central nervous system. Over-accumulation of glutamate results in excitotoxicity and injures neurons after cerebral ischemia. Ceftriaxone up-regulates GLT-1 expression and uptake of glutamate, diminishes the excitotoxicity of glutamate and then protects neurons against global brain ischemia.
authors.affiliation: Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Yu-Yan
authors.initials: YY
authors.lastname: Hu
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Li
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002443:Ceftriaxone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000378:metabolism*; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D018696:Neuroprotective Agents; D020319:Oligodeoxyribonucleotides, Antisense; C493395:Slc1a2 protein, rat; D018698:Glutamic Acid; C020889:dihydrokainic acid; D002443:Ceftriaxone; D007608:Kainic Acid
keywords: antisense oligodeoxynucleotides; ceftriaxone; glial glutamate transporter-1; global brain ischemia; glutamate uptake; rat