title: Ceftriaxone alleviates early brain injury after subarachnoid hemorrhage by increasing excitatory amino acid transporter 2 expression via the PI3K/Akt/NF-κB signaling pathway.
abstract: Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is characterized by a reduction in excitatory amino acid transporter 2 (EAAT2) expression and severe amino acid excitotoxicity. The aim of this study was to explore the neuroprotective effect of ceftriaxone (CEF), a potent compound that up-regulates EAAT2, against EBI and the potential mechanisms using in vitro experiments and a rat model of SAH. Intracisternal treatment with CEF significantly improved neurological outcomes and alleviated extracellular glutamate accumulation after SAH. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining and Western blot analysis of cleaved caspase 3 showed that CEF decreased hippocampal neuronal apoptosis following SAH. Immunofluorescent staining and Western blotting revealed that CEF significantly reversed the down-regulation of EAAT2 expression following SAH. In Morris water maze (MWM) tests, CEF remarkably ameliorated the SAH-induced cognitive dysfunction in spatial learning memory and reference memory. CEF promoted the nuclear translocation of p65 as well as the activation of Akt in hippocampal astrocytes in vitro and in vivo. These findings suggest that CEF may exert significant protective effects against EBI following SAH by modulating the PI3K/Akt/NF-κB signaling pathway.
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors.forename: D
authors.initials: D
authors.lastname: Feng
authors.affiliation: Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China; Department of Neurosurgery, 463rd Hospital of PLA, Shenyang 110042, Liaoning Province, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Anatomy, Histology and Embryology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors.forename: S
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China. Electronic address: guodonggao2013@163.com.
authors.forename: G
authors.initials: G
authors.lastname: Gao
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China. Electronic address: huaizhouqin@163.com.
authors.forename: H
authors.initials: H
authors.lastname: Qin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D002443:Ceftriaxone / Q000494:pharmacology*; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D016328:NF-kappa B; D009363:Neoplasm Proteins; D018696:Neuroprotective Agents; D029543:Nucleocytoplasmic Transport Proteins; C493395:Slc1a2 protein, rat; C063447:p65 oncofetal mRNA transport protein, rat; D018698:Glutamic Acid; D002443:Ceftriaxone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: apoptosis; ceftriaxone; early brain injury; excitatory amino acid transporter 2; subarachnoid hemorrhage