Biochemical and pharmacological evidence of a functional role of AMPA receptors in motor neuron dysfunction in mnd mice.
We studied ionotropic glutamate receptor subtypes and the effect of chronic treatment with NBQX [6-nitro-7-sulphamoyl-benzo(F)quinoxaline-2,3-dione], a selective (rs)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, in the spinal cord of mnd mice. NBQX (8 mg/kg daily i.p. for 3 weeks starting from 24 weeks old) significantly improved the behavioural scores (hind leg extension reflex, cage rung grasping and gait) in mnd mice, measured after the last drug injection, and increased the number of mice with 'normal' gait (from 50% to 90%, P < 0.05). Receptor binding autoradiography of the competitive N-methyl-D-aspartate (NMDA) antagonist, [3H]CGP 39653, of [3H]AMPA and [3H]kainic acid in spinal cord sections, measured after 1 week of drug washout, were not significantly different in control and mnd mice, and were not modified by NBQX. GluR2/3 immunoreactivity, assessed using Western blotting, was significantly enhanced (by 59%, P < 0.01) in the spinal cord but not in the brain of 28-week-old mnd mice compared to age-matched control mice. NBQX treatment increased GluR2/3 immunoreactivity in the spinal cord of control mice and mnd mice by 327 +/- 74% (P < 0.01) and 212 +/- 52% (P < 0.01), respectively. The changes in GluR2/3 subunits may involve adaptive mechanisms of the receptor and play some role in the protective effect of NBQX. These findings suggest that selective antagonism of ionotropic non-NMDA receptors may be of value in the treatment of motor neuron disease.
Mennini
T
T
Istituto di ricerche Farmacologiche Mario Negri, Milan, Italy. tiziana@irfmn.mnegri.it
Cagnotto
A
A
Carvelli
L
L
Comoletti
D
D
Manzoni
C
C
Muzio
V
V
Rizzi
M
M
Vezzani
A
A
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D000818:Animals; D000906:Antibodies; D001345:Autoradiography; D015153:Blotting, Western; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009046:Motor Neurons / Q000737:chemistry / Q000473:pathology* / Q000502:physiology; D009410:Nerve Degeneration / Q000503:physiopathology*; D009498:Neurotoxins / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000032:analysis / Q000276:immunology / Q000502:physiology*; D013116:Spinal Cord / Q000737:chemistry / Q000166:cytology; D014316:Tritium; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D000906:Antibodies; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D011810:Quinoxalines; D018091:Receptors, AMPA; C104723:glutamate receptor ionotropic, AMPA 3; D014316:Tritium; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C069052:CGP 39653; D015763:2-Amino-5-phosphonovalerate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C104722:glutamate receptor ionotropic, AMPA 2