title: Moderate modulation of disease in the G93A model of ALS by the compound 2-(2-hydroxyphenyl)-benzoxazole (HBX).
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disease characterized by degeneration and death of motor neurons. Aberrant protein aggregation and oxidative stress are implicated in the etiology of ALS; thus preventing propagation of early aggregation events and oxidative damage could be an effective therapy. We tested the effect of dietary supplementation (initiated 40 days of age) with 2-(2-hydroxyphenyl)-benzoxazole (HBX), a compound with metal chelator and anti-aggregation properties, on disease onset, progression and lifespan in the G93A mouse model of ALS. Tests were not sufficiently powerful to detect any change to survival distribution of mice treated with HBX. However, the disease onset was delayed and max lifespan was increased in the treatment group. Additionally, disease progression was moderated as shown by reduced neuromuscular denervation measured by repetitive nerve stimulation. F2-isoprostanes, a marker of oxidative damage, are elevated in skeletal muscle from G93A mice at onset and this increase is prevented in HBX fed G93A mice. Furthermore, HBX treatment reduced mutant SOD1 protein aggregation in whole spinal cord of G93A mice at disease onset. Overall, our data suggests that HBX may be able to improve the degenerative symptoms of ALS through the prevention of oxidative damage and protein aggregation. Further studies are needed to uncover the mechanistic effects of HBX in ameliorating ALS pathology.
authors.affiliation: Departments of Pharmacology, UT Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Evans
authors.affiliation: Departments of Cellular and Structural Biology, UT Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Arunabh
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.affiliation: South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Qi
authors.affiliation: Department of Comprehensive Dentistry, UT Health Science Center San Antonio, San Antonio, TX, USA.
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Block
authors.affiliation: Department of Biochemistry, UT Southwestern, Dallas, TX, USA.
authors.forename: Asish
authors.initials: A
authors.lastname: Chaudhuri
authors.affiliation: Department of Chemistry, University of the Incarnate Word, San Antonio, TX, USA.
authors.forename: Alakananda Ray
authors.initials: AR
authors.lastname: Chaudhuri
authors.affiliation: Department of Chemistry, University of the Incarnate Word, San Antonio, TX, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Hawker
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Oklahoma City VA Medical Center, Oklahoma City, OK, USA. Electronic address: Holly-VanRemmen@omrf.org.
authors.forename: Holly
authors.initials: H
authors.lastname: Van Remmen
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000517:prevention & control*; D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage*; D001823:Body Composition / Q000187:drug effects; D002614:Chelating Agents / Q000008:administration & dosage*; D003300:Copper / Q000378:metabolism; D015891:Cystatins / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D007501:Iron / Q000378:metabolism; D028421:Isoprostanes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010636:Phenols / Q000008:administration & dosage*; D013116:Spinal Cord / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D052160:Benzothiazoles; D002614:Chelating Agents; D015891:Cystatins; D028421:Isoprostanes; D010636:Phenols; C000606290:SOD1 protein, human; C550521:cystatin F, mouse; C070846:2-(2-hydroxyphenyl)benzothiazole; D003300:Copper; D007501:Iron; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis; Chelation; Denervation; Mouse model; Protein aggregation; Treatment