title: Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis.
abstract: Telomerase is expressed in the neonatal brain, in distinct regions of adult brain, and was shown to protect developing neurons from apoptosis. Telomerase reactivation by gene manipulation reverses neurodegeneration in aged telomerase-deficient mice. Hence, we and others hypothesized that increasing telomerase expression by pharmaceutical compounds may protect brain cells from death caused by damaging agents. In this study, we demonstrate for the first time that the novel compound AGS-499 increases telomerase activity and expression in the mouse brain and spinal cord (SC). It exerts neuroprotective effects in NMDA-injected CD-1 mice, delays the onset and progression of the amyotrophic lateral sclerosis (ALS) disease in SOD1 transgenic mice, and, after the onset of ALS, it increases the survival of motor neurons in the SC by 60%. The survival of telomerase-expressing cells (i.e. motor neurons), but not telomerase-deficient cells, exposed to oxidative stress was increased by AGS-499 treatment, suggesting that the AGS-499 effects are telomerase-mediated. Therefore, a controlled and transient increase in telomerase expression and activity in the brain by AGS-499 may exert neuroprotective effects.
authors.affiliation: The Shraga Segal Department of Immunology and Microbiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Erez
authors.initials: E
authors.lastname: Eitan
authors.forename: Ailon
authors.initials: A
authors.lastname: Tichon
authors.forename: Aviv
authors.initials: A
authors.lastname: Gazit
authors.forename: Daniel
authors.initials: D
authors.lastname: Gitler
authors.forename: Shimon
authors.initials: S
authors.lastname: Slavin
authors.forename: Esther
authors.initials: E
authors.lastname: Priel
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use*; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014320:Triphenylmethyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C573922:AGS-499; D018696:Neuroprotective Agents; D010636:Phenols; D014320:Triphenylmethyl Compounds; D019098:Telomerase