title: The protective effects of riluzole on manganese-induced disruption of glutamate transporters and glutamine synthetase in the cultured astrocytes.
abstract: Chronic exposure to excessive manganese (Mn) can lead to manganism, a type of neurotoxicity accomplished with extracellular glutamate (Glu) accumulation. To investigate this accumulation, this study focused on the role of astrocyte glutamate transporters (GluTs) and glutamine synthetase (GS), which have roles in Glu transport and metabolism, respectively. And the possible protective effects of riluzole (a glutamatergic modulator) were studied in relation to Mn exposure. At first, the astrocytes were exposed to 0, 125, 250, and 500 μM MnCl(2) for 24 h, and 100 μM riluzole was pretreated to astrocytes for 6 h before 500 μM MnCl(2) exposure. Then, [(3)H]-glutamate uptake was measured by liquid scintillation counting; Na(+)-K(+) ATPase and GS activities were determined by a colorimetric method; glutamate/aspartate transporter (GLAST), glutamate transporter-1 (GLT-1), and GS mRNA expression were determined by RT-PCR and protein levels were measured by western blotting. The results showed that Mn inhibited Glu uptake, Na(+)-K(+) ATPase and GS activities, GLAST, GLT-1, and GS mRNA, and protein in a concentration-dependent manner. And they were significantly higher for astrocytes pretreated with 100 μM riluzole than the group exposed to 500 μM MnCl(2). The results suggested that Mn disrupted Glu transport and metabolism by inhibiting GluTs and GS. Riluzole activated protective effects on enhancing GluTs and GS to reverse Glu accumulation. In conclusion, Mn exposure results in the disruption of GLAST, GLT-1, and GS expression and function. Furthermore, riluzole attenuates this Mn toxicity.
authors.affiliation: Department of Environmental Health, School of Public Health, China Medical University, Shenyang, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Deng
authors.forename: Zhaofa
authors.initials: Z
authors.lastname: Xu
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Donghui
authors.initials: D
authors.lastname: Xu
authors.forename: Yawen
authors.initials: Y
authors.lastname: Tian
authors.forename: Wanyu
authors.initials: W
authors.lastname: Feng
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D001692:Biological Transport; D015153:Blotting, Western; D002478:Cells, Cultured; D002712:Chlorides / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D008345:Manganese / Q000633:toxicity*; D017895:Manganese Compounds; D020149:Manganese Poisoning; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019782:Riluzole / Q000494:pharmacology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D036401:Toxicity Tests, Chronic
chemical_list: D027322:Amino Acid Transport System X-AG; D002712:Chlorides; D017895:Manganese Compounds; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D018698:Glutamic Acid; D008345:Manganese; D019782:Riluzole; D005974:Glutamate-Ammonia Ligase; D000254:Sodium-Potassium-Exchanging ATPase; C025340:manganese chloride