title: Concurrent administration of Neu2000 and lithium produces marked improvement of motor neuron survival, motor function, and mortality in a mouse model of amyotrophic lateral sclerosis.
abstract: The Fas pathway and oxidative stress mediate neuronal death in stroke and may contribute to neurodegenerative disease. We tested the hypothesis that these two factors synergistically produce spinal motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Levels of reactive oxygen species were increased in motor neurons from ALS mice compared with wild-type mice at age 10 weeks, before symptom onset. The proapoptotic proteins Fas, Fas-associated death domain, caspase 8, and caspase 3 were also elevated. Oral administration of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid (Neu2000), a potent antioxidant, blocked the increase in reactive oxygen species but only slightly reduced activation of proapoptotic proteins. Administration of lithium carbonate (Li(+)), a mood stabilizer that prevents apoptosis, blocked the apoptosis machinery without preventing oxidative stress. Neu2000 or Li(+) alone significantly enhanced survival time and motor function and together had an additive effect. These findings provide evidence that jointly targeting oxidative stress and Fas-mediated apoptosis can prevent neuronal loss and motor dysfunction in ALS.
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, Sawon, Korea 442-749.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Shin
authors.forename: Sung Ig
authors.initials: SI
authors.lastname: Cho
authors.forename: Hyang Ran
authors.initials: HR
authors.lastname: Lim
authors.forename: Jae Keun
authors.initials: JK
authors.lastname: Lee
authors.forename: Young Ae
authors.initials: YA
authors.lastname: Lee
authors.forename: Jai Sung
authors.initials: JS
authors.lastname: Noh
authors.forename: In Soo
authors.initials: IS
authors.lastname: Joo
authors.forename: Kee-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Byoung Joo
authors.initials: BJ
authors.lastname: Gwag
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000401:mortality; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000008:administration & dosage* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005464:Fluorobenzenes; D016651:Lithium Carbonate / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D009026:Mortality; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D012459:Salicylates; D019014:fas Receptor / Q000378:metabolism; D062368:meta-Aminobenzoates
chemical_list: C519903:2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)benzoic acid; D000975:Antioxidants; D001565:Benzoates; D005464:Fluorobenzenes; D012459:Salicylates; D019014:fas Receptor; D062368:meta-Aminobenzoates; D016651:Lithium Carbonate