Altered expression of glutamate transporters in experimental autoimmune encephalomyelitis.
Amelioration of experimental autoimmune encephalomyelitis (EAE) by blockade of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), has been recently demonstrated [Nat. Med. 6 (2000) 67; Nat. Med. 6 (2000) 62]. However, the mechanisms underlying regulation of the extracellular glutamate concentration in EAE are unclear. To address this, we examined the expression of three distinct Na(+)-dependent glutamate transporters (GLT-1, GLAST and EAAC1) in the spinal cord of the Lewis rat EAE. EAE induced a dramatic increase in EAAC1 protein and mRNA levels, which corresponded closely with the course of neurological symptoms. In contrast, the levels of GLT-1 and GLAST protein were down-regulated in the spinal cord at the peak of disease symptoms, and no recovery was observed after remission. Furthermore, these changes in GLT-1, GLAST and EAAC1 expression were suppressed by treatment with NBQX. These results suggest that AMPA receptor activation precedes the altered expression of glutamate transporters, and that the dysregulation of extracellular glutamate concentration might play a critical role in pathological changes and neuronal dysfunction in EAE.
Ohgoh
Makoto
M
Discovery Research Laboratories 1, Eisai Co. Ltd., 1-3 Tokodai 5-Chome, Tsukuba, Ibaraki 300-2635, Japan. m-ogo@hhc.eisai.co.jp
Hanada
Takahisa
T
Smith
Terence
T
Hashimoto
Toshihide
T
Ueno
Masataka
M
Yamanishi
Yoshiharu
Y
Watanabe
Masahiko
M
Nishizawa
Yukio
Y
D027322:Amino Acid Transport System X-AG / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D050580:Excitatory Amino Acid Transporter 3; D015870:Gene Expression / Q000502:physiology; D050491:Glutamate Plasma Membrane Transport Proteins; D018698:Glutamic Acid / Q000493:pharmacokinetics; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000737:chemistry / Q000378:metabolism*; D027981:Symporters; D014316:Tritium
D027322:Amino Acid Transport System X-AG; D002352:Carrier Proteins; D018691:Excitatory Amino Acid Antagonists; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D011810:Quinoxalines; D012333:RNA, Messenger; D018091:Receptors, AMPA; C493398:Slc1a1 protein, rat; C493392:Slc1a3 protein, rat; D027981:Symporters; D014316:Tritium; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D018698:Glutamic Acid