New Strategy That Delays Progression of Amyotrophic Lateral Sclerosis in G1H-G93A Transgenic Mice: Oral Administration of Xanthine Oxidoreductase Inhibitors That Are Not Substrates for the Purine Salvage Pathway.
Amyotrophic lateral sclerosis (ALS), Lou Gehrig's disease, is a progressive fatal neurodegenerative disease that involves both upper and lower motor neurons. We orally administered 4 xanthine oxidoreductase (XOR) inhibitors to G1H-G93A mice carrying 25 transgene copy numbers of human mutant G93A superoxide dismutase 1, from 80 days of age. Three nonpurine-analogue inhibitors (TEI-6720: Febuxostat, Y-700 and FYX-051), but not allopurinol with a purine analogue ring (pyrazolo pyrimidine ring), significantly delayed disease onset, prolonged survival and the duration of disease stages, improved clinical signs, and alleviated weight loss. Exercise testing (extension reflex, inclined plane, footprint, rotarod, and beam balance tests) showed significantly improved motor function in the G1H-G93A mice treated with these 3 inhibitors. Significant amelioration of disease was seen even when TEI-6720 or Y-700 was administered after the appearance of early signs. Histopathological evaluation in the late stage revealed that G1H-G93A mice treated with TEI-6720 had well-preserved motor neurons and fewer inclusion bodies, compared with mice treated with placebo or with allopurinol. Our results indicate that these 3 nonpurine-analogue XOR inhibitors might increase the supply of high-energy compounds via the purine salvage pathway, thereby protecting motor neurons against death. This strategy may be applicable for oral therapy of ALS patients.
From the Division of Neuropathology (SK) and the Division of Molecular Pathology (MK), Department of Pathology, Tottori University Faculty of Medicine, Yonago, Japan; and the Department of Biochemistry and Molecular Biology (TK, TN), Nippon Medical School, Tokyo, Japan.
Shinsuke
S
Kato
From the Division of Neuropathology (SK) and the Division of Molecular Pathology (MK), Department of Pathology, Tottori University Faculty of Medicine, Yonago, Japan; and the Department of Biochemistry and Molecular Biology (TK, TN), Nippon Medical School, Tokyo, Japan.
Masako
M
Kato
From the Division of Neuropathology (SK) and the Division of Molecular Pathology (MK), Department of Pathology, Tottori University Faculty of Medicine, Yonago, Japan; and the Department of Biochemistry and Molecular Biology (TK, TN), Nippon Medical School, Tokyo, Japan.
Teruo
T
Kusano
From the Division of Neuropathology (SK) and the Division of Molecular Pathology (MK), Department of Pathology, Tottori University Faculty of Medicine, Yonago, Japan; and the Department of Biochemistry and Molecular Biology (TK, TN), Nippon Medical School, Tokyo, Japan.
Takeshi
T
Nishino
D000284:Administration, Oral; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011687:Purines / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D011687:Purines; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D014968:Xanthine Dehydrogenase; C030985:purine
Amyotrophic lateral sclerosis; Motor neuron; Nonpurine-analogue; Oral administration; Purine salvage pathway; Therapy; Xanthine oxidoreductase inhibitor