Slow and selective death of spinal motor neurons in vivo by intrathecal infusion of kainic acid: implications for AMPA receptor-mediated excitotoxicity in ALS.
Excitotoxicity mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has been proposed to play a major role in the selective death of motor neurons in sporadic amyotrophic lateral sclerosis (ALS), and motor neurons are more vulnerable to AMPA receptor-mediated excitotoxicity than are other neuronal subclasses. On the basis of the above evidence, we aimed to develop a rat model of ALS by the long-term activation of AMPA receptors through continuous infusion of kainic acid (KA), an AMPA receptor agonist, into the spinal subarachnoid space. These rats displayed a progressive motor-selective behavioral deficit with delayed loss of spinal motor neurons, mimicking the clinicopathological characteristics of ALS. These changes were significantly ameliorated by co-infusion with 6-nitro-7-sulfamobenso(f)quinoxaline-2,3-dione (NBQX), but not with d(-)-2-amino-5-phosphonovaleric acid (APV), and were exacerbated by co-infusion with cyclothiazide, indicative of an AMPA receptor-mediated mechanism. Among the four AMPA receptor subunits, expression of GluR3 mRNA was selectively up-regulated in motor neurons but not in dorsal horn neurons of the KA-infused rats. The up-regulation of GluR3 mRNA in this model may cause a molecular change that induces the selective vulnerability of motor neurons to KA by increasing the proportion of GluR2-lacking (i.e. calcium-permeable) AMPA receptors. This rat model may be useful in investigating ALS etiology.
Sun
Hui
H
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Kawahara
Yukio
Y
Ito
Kyoko
K
Kanazawa
Ichiro
I
Kwak
Shin
S
D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage* / Q000633:toxicity; D007278:Injections, Spinal; D007608:Kainic Acid / Q000008:administration & dosage* / Q000633:toxicity; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
D018690:Excitatory Amino Acid Agonists; D018091:Receptors, AMPA; D007608:Kainic Acid