Ceftriaxone-mediated upregulation of the glutamate transporter GLT-1 contrasts neurotoxicity evoked by kainate in rat organotypic spinal cord cultures |
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| Affiliation: | 1. Institute of Pesticide and Environmental Toxicology, Zhejiang University, Hangzhou 310029, China;2. Department of Entomology, Genetics and Neuroscience Programs, Michigan State University, East Lansing, MI48824, USA;3. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada;4. Sechenov Institute of Evolutionary Physiology & Biochemistry, Russian Academy of Sciences, St. Petersburg 194223, Russia;1. The BOSCH Institute, Blackburn Building, DO6, University of Sydney, NSW 2006, Australia;2. Department of Medicine, Blackburn Building, DO6, University of Sydney, NSW 2006, Australia;3. Discipline of Pharmacology, Blackburn Building, D06, University of Sydney, NSW 2006, Australia;4. The Children’s Hospital, Westmead, Sydney, NSW 2145, Australia;1. Jiangsu Key Laboratory of Brain Disease Bioinformation and the Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, 209 Tongshan Road, Xuzhou 221004, Jiangsu, PR China;2. Department of Biochemistry and Molecular Biology, Sochoow University, 199 Ren׳ai Road, Suzhou 215002, Jiangsu, PR China;1. Developmenatl Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group CSIR – Indian Institute of Toxicology Research, Post Box 80, 31 MG Marg Lucknow – 226 001, India;2. Department of Biochemistry, Integral Institute of Medical Sciences & Research Integral University Lucknow – 226 026, India;3. Department of Biostatistics and Health Informatics Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow – 226 014, India;4. Department of Bioengineering, Faculty of Engineering Integral University, Lucknow – 226 026, India;1. Department of Entomology, Cornell University, Geneva, NY 14456, USA;2. Monsanto Company, St. Louis, MO, USA;3. College of Life Sciences, Nankai University, Tianjin 300071, China |
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| Abstract: | Excitotoxicity is a major pathological trigger of neurodegenerative diseases like amyotrophic lateral sclerosis. This process is caused by excessive release of the transmitter glutamate that overwhelms the capacity of astroglia transporters to maintain a low extracellular level of this aminoacid and strongly stimulates neurons. Using an in vitro model of rat organotypic spinal slice culture, we explored if the excitotoxicity caused by the potent glutamate analogue kainate, widely employed as a paradigm to evoke neurotoxicity in the central nervous system, was prevented by the antibiotic ceftriaxone known to enhance glutamate transporter expression. We also tested if excitotoxicity was made worse by inhibiting glutamate uptake with dl-threo-β-benzyloxyaspartate (TBOA). These experiments were aimed at clarifying the relative contribution to neurotoxicity by kainate-activation of glutamate receptors or kainate-mediated release of glutamate. Neither ceftriaxone nor TBOA alone had adverse effects. Ceftriaxone (10 μM; 3 days) significantly decreased delayed cell death induced by kainate (100 μM; 1 h) and limited neuronal damage especially to motoneurons. This effect was associated to stronger astrocytic immunostaining of the glutamate transporter GLT-1. Conversely, pharmacological inhibition of glutamate uptake with TBOA was per se unable to induce neurotoxicity, yet it intensified cell death evoked by kainate. These data indicate that kainate-mediated glutamate release was critical to damage neurons, an effect prevented by up regulating glutamate uptake. These data suggest that modulating glutamate uptake is an important strategy to preserve neuronal networks. |
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| Keywords: | Excitotoxicity Astrocyte β-lactam antibiotic Glutamate uptake blocker Neuroprotection Motoneuron |
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