Additive neuroprotective effects of a histone deacetylase inhibitor and a catalytic antioxidant in a transgenic mouse model of amyotrophic lateral sclerosis.
ALS is a devastating neurodegenerative disorder for which no effective treatment exists. Multiple molecular mechanisms are involved in the pathogenesis. We tested the catalytic antioxidant AEOL 10150, the histone deacetylase inhibitor phenylbutyrate (PBA), and the combination of PBA and AEOL 10150 in the G93A transgenic mouse model, administered from disease onset. AEOL 10150 alone improved motor function and extended survival by 11%, PBA alone significantly improved motor function and extended survival by 13%. PBA and AEOL 10150 together increased survival by 19%. Increased histone acetylation was confirmed by Western blot. Quantitative real-time RT-PCR analysis revealed upregulation of compounds capable of protecting cells against oxidative stress and apoptosis. Markers of oxidative damage were reduced in the lumbar spinal cord as compared to vehicle administration. These results suggest that agents inhibiting apoptosis and blocking oxidative stress show efficacy in treating mutant-SOD1-associated ALS and that a combination of agents targeting different disease mechanisms may exert additive therapeutic effects.
Petri
Susanne
S
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021, USA. sup2010@med.cornell.edu
Kiaei
Mahmoud
M
Kipiani
Khatuna
K
Chen
Junyu
J
Calingasan
Noel Y
NY
Crow
John P
JP
Beal
M Flint
MF
D000107:Acetylation / Q000187:drug effects; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010654:Phenylbutyrates / Q000494:pharmacology / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
C472668:AEOL 10150; D000975:Antioxidants; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D008665:Metalloporphyrins; D018696:Neuroprotective Agents; D010654:Phenylbutyrates; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D006655:Histone Deacetylases