Down-regulation of the glial glutamate transporter GLT-1 in rat hippocampus and striatum and its modulation by a group III metabotropic glutamate receptor antagonist following transient global forebrain ischemia.
Our goals were to identify biochemical markers for transient global ischemia-induced delayed neuronal death and test possible drug therapies against this neuronal damage. Four-vessel occlusion (4-VO) for 20 min was used as a rat model. The temporal expression profiles of three glutamate transporters (GLT-1, GLAST and EAAC1) were evaluated in the CA1 region of the hippocampus and the striatum. The protein levels of the GLT-1 were significantly down-regulated between 3 and 6 h after ischemia-reperfusion in the CA1 region and striatum, returned to the control (2-VO) levels 24 h after reperfusion and remained unchanged for up to 7 days. The levels of GLAST in the CA1 region and striatum, and EAAC1 in the CA1 region did not change after ischemia from 1 h to 7 days. Pretreatment with group III metabotropic glutamate receptor antagonist s-alpha-MCPA (20 microg/5 microl) 30 min prior to 4-VO significantly restored the GLT-1 levels in the CA1 region caused by global ischemia at both 3 and 6 h after reperfusion. The loss of pyramidal neurons in the CA1 region due to ischemia-reperfusion could also be prevented by intraventricular pretreatment with s-alpha-MCPA. The current findings pinpoint the significance of GLT-1 during ischemia/reperfusion and suggest a potential application of group III metabotropic glutamate receptor antagonist against ischemic/hypoxic neuronal damage.
Chen
Jin-Chung
JC
Department of Pharmacology, Chang-Gung University, 259 Wen-Hwa 1st Road, Tao-Yuan, Kwei-Shan, Taiwan, ROC. jinchen@mail.cgu.edu.tw
Hsu-Chou
Hong
H
Lu
Jin-Lan
JL
Chiang
Yao-Chang
YC
Huang
Hwa-Ming
HM
Wang
Hung-Li
HL
Wu
Tony
T
Liao
Jui-Jung
JJ
Yeh
Tu-Shai
TS
D008456:2-Methyl-4-chlorophenoxyacetic Acid / Q000494:pharmacology; D027322:Amino Acid Transport System X-AG / Q000096:biosynthesis; D000818:Animals; D015153:Blotting, Western; D015536:Down-Regulation / Q000187:drug effects; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis*; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007276:Injections, Intraventricular; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D027981:Symporters / Q000096:biosynthesis
D027322:Amino Acid Transport System X-AG; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D018094:Receptors, Metabotropic Glutamate; C493398:Slc1a1 protein, rat; C493392:Slc1a3 protein, rat; D027981:Symporters; D008456:2-Methyl-4-chlorophenoxyacetic Acid